VESTIPITANT (Phase II GSK)

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VESTIPITANT

(2S)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperazine-1-carboxamide

 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-l- carboxylic acid [l-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide 

2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant)

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vestipitant

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VESTIPITANT MESYLATE

CAS:  334476-64-1 of MESYLATE

• GW597588B
• UNII-OWR424W90Q

D06293, 334476-64-1

Journal of Thermal Analysis and Calorimetry, 2010 ,  vol. 102,   1  pg. 297 – 303

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INTRODUCTION

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Synthetic Process of Vestipitant

The following synthetic route was reported by Giuseppe Guercio et al from GlaxoSmithKline:

Org. Process Res. Dev., 2009, 13 (6), pp 1100–1110

The initial chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields and produced high levels of waste. Through a targeted process of research and development, application of novel techniques and extensive route scouting, a new synthetic route for GW597599 was developed. This paper reports the optimisation work of the third and last stage in the chemical synthesis of GW597599 and the development of a pilot-plant-suitable process for the manufacturing of optically pure arylpiperazine derivative 1. In particular, the process eliminated the use of triphosgene in the synthesis of an intermediate carbamoyl chloride, substantially enhancing safety, overall yield, and throughput.

¹H NMR (600 MHz, DMSO-d₆) δ 1.48 (d, J = 6.9 Hz, 3H); 2.31 (s, 3H); 2.39 (s, 3H); 2.74 (s, 3H); 2.95 (t, J = 12.2 Hz, 1H); 3.00−3.06 (m, 1H); 3.27 (dd, J = 12.5, 2.3 Hz, 1H); 3.28−3.35 (m, 1H); 3.38−3.43 (m, 1H); 3.47 (dt, J = 13.3, 3.1 Hz, 1H); 4.49 (dd, J = 11.8, 3.3 Hz, 1H); 5.35 (q, J = 6.5 Hz, 1H); 6.84 (td, J = 8.4, 2.6 Hz, 1H); 7.01 (dd, J = 10.2, 2.7 Hz, 1H); 7.29 (dd, J = 8.5, 6.0 Hz, 1H); 7.71 (bs, 2H); 8.02 (bs, 1H); 8.71 (bs, 1H); 9.02 (bs, 1H).

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SYNTHESIS

 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-l- carboxylic acid [l-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide

http://www.google.com/patents/WO2012175434A1

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SYNTHESIS

https://www.google.co.in/patents/WO2001025219A2

Example 36 2-(SM4-Fluoro-2-methyl-phenyl)-piperazine-1 -carboxylic acid M -(R)-

(3.5-bis-trifluoromethyl-phenyl)-ethvn-methyl-amide methansulphonate

To a suspension of intermediate 81 (4.9Kg) in AcOEt (137.2L), triethylamine (5.63L) was added. The mixture was cooled to 0°C then a solution of diterbuthyl dicarbonate (3.134Kg) in AcOEt (24.5L) was added in 35 min, maintaining the temperature between 0 and 5°C. The suspension was stirred at 0°C for 15 min, at 20/25°C for 1 hr, then washed with water (3 x 39.2L), concentrated to 24.5L and then added to a solution of triphosgene (1.97Kg) in AcOEt (24.5L) cooled to 0°C. Triethylamine (3.28L) was then added in 40 min, maintaining the temperature between 0 and 8°C. The suspension was stirred for 1 h and 45 min at 20/25°C and 30 min at 70Cand then the solution of intermediate 82 diluted with AcOEt (49L) and triethylamine (2.6L) was added in 30 min. The mixture was refluxed for 15 hrs.

The reaction mixture, cooled at 20/25°C was treated with aqueous solution of NaOH 10%v/v (36.75L). Organic phase was washed with HCI 4%v/v (46.55L) and NaCI 11 ,5%p/p (4 x 24.5L) then concentrated to 14.7L. and diluted with Ciclohexane (39.2L). The mixture was filtered through a silica pad (4.9Kg) that was washed twice with a mixture of CH/AcOEt 85/15 (2 x 49L). To the Eluted phases (14.7L) cooled at 20/25°C, methyl tertbutyl ether (49L) and methansulphonic acid (4.067L) were added. The mixture was washed with NaOH 10%v/v (31.85L) then with water (4 x 31.85L). Organic phase was concentrated to 9.8L, methyl tertbutyl ether (49L) was added and the solution filtered through a δmicron filter then concentrated to 9.8L. At 20/25°C MTBE (29.4L) and metansulphonic acid (1.098L) were added. The suspension was refluxed for 10 min, stirred at 20/25°C for 10hrs and 2 hrs at O°C.Then the precipitate was filtered, washed with methyl tertbutyl ether (4.9L) dried under vacuum at 20/25°C for 24 hrs to obtain the title compound (5.519Kg.) as white solid.

¹H-NMR (DMSO) δ (ppm) 8.99 (bm, 1 H); 8.66 (bm, 1 H); 8.00 (bs, 1 H) 7.69 (bs, 2H); 7.27 (dd, 1 H); 7.00 (dd, 1 H); 6.83 (m, 1 H); 5.32 (q, 1 H) 4.47 (dd, 1 H); 3.50-3.20 (m, 4H); 2.96 (m, 2H); 2.72 (s, 3H); 2.37 (s, 3H) 2.28 (s, 3H); 1.46 (d, 3H). ES⁺: m/z 492 [MH – CH₃SO₃H]⁺ ES^“: m/z 586 [M – H]^“; 95 [CH₃SO₃]^“

Example 37

2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1 -carboxylic acid Ii -(R)- (3.5-bis-trifluoromethyl-phenyl)-ethvn-methyl-amide

To a solution of intermediate 40a (15.6g) in anhydrous THF (94ml), at 0°C, under N₂, BH₃THF 1 M/THF (154ml) was added. The solution was heated at reflux for 3 hr. HCI 37% (54ml) was slowly added maintaining the reaction mixture in an ice-bath and the reaction mixture was stirred at rt for 1 hr. Water was then added (125 ml) and solid NaHCO₃ (62.4g) was added portionwise until a pH of 6.5.The aqueous phase was extracted with Et O (4×160 ml) and the combined organic extracts were dried over

Na₂SO , the solids were filtered and evaporated to leave a colourless oil which was purified by flash chromatography (silica gel, EtOAc/Methanol 7/3). The obtained product was suspended in Et₂O (220ml) and washed with NaHCO₃ sat. (2x36ml). The combined organic phases were dried (Na₂SO ) and evaporated to give the title compound as white foam (8.7g,). ¹H-NMR (CDCI₃) δ (ppm) 7.78 (s, 1 H); 7.60 (s, 2H); 7.28 (m, 1 H); 6.85 (dd, 1 H); 6.79 (td, 1 H); 5.53 (q, 1 H); 4.43 (dd, 1 H); 2.9-3.5 (m, 5H); 2.78 (m, 1 H), 2.71 (s, 3H); 2.43 (s, 3H); 1.47 (d, 3H).

Intermediate 40

2-(S)-(4-Fluoro-2-methyl-phenyl)-3-oxo-piperazine-1 -carboxylic acid ri-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethvn-methyl-amide ( 40a ) 2-(S)-(4-Fluoro-2-methyl-phenyl)-3-oxo-piperazine-1 -carboxylic acid ri-(S)-(3.5-bis-trifluoromethyl-phenyl)-ethvn-methyl-amide.(-40b) To a solution of intermediate 39 (12.1g) in anhydrous DCM (270 mL), TEA (16.4 mL) was added. The solution was cooled down to 0°C and a solution of triphosgene (7.3 g) in anh. DCM (60 mL) was added drop-wise over 40 min. The reaction mixture was stirred at 0°C for 4 hr and was brought back to r.t. DIPEA (20.2 mL) was then added, followed by a solution of [1-(3,5- bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (23.6 g) in acetonitrile (300 mL) and an additional amount of acetonitrile (300 mL). The reaction mixture was warmed up to 95°C (oil bath T°C) without a water condenser to evaporate the DCM. When the internal temperature had reached 70°C, the flask was equipped with a water condenser, and the reaction mixture was heated at 70°C for an additional 2 hr (4 hr total). It was then brought back to r.t. and the solvent was evaporated. The residue was partitioned between DCM / 2% HCI and the phases were separated. The aqueous layer was extracted with DCM (1x) and the combined organic extracts were dried. The solids were filtered and the solvent evaporated to give a crude mixture of title compounds which were purified by flash chromatography (AcOEt/CH 8:2) to obtain the title compounds 40a (8.8 g) and 40 b (9.0 g) as white foams.

NMR (¹H, DMSO-de): δ 8.16 (s, 1 H), 7.98 (s, 2H), 7.19 (dd, 1 H), 6.97 (dd, 1 H), 6.87 (td, 1 H), 5.34 (s, 1 H), 5.14 (q, 1 H), 3.45-3.2 (m, 4H), 2.53 (s, 3H), 2.27 (s, 3H), 1.56 (d, 3H).

Intermediate 40b: NMR (¹H, DMSO-d₆): δ 8.16 (s, 1 H), 7.95 (s, 2H), 7.19 (dd, 1 H), 6.98 (dd, 1 H), 6.90 (td, 1 H), 5.29 (q, 1 H), 5.28 (s, 1 H), 3.45-3.15 (m, 4H), 2.66 (s, 3H), 2.27 (s, 3H), 1.52 (d, 3H).

Intermediate 81 (S)-3-(4-Fluoro-2-methyl-phenyl)-piperazine dihydrochloride

To a solution of intermediate 39 (60.35g) in dry THF (180ml), at 0-3°C, under N₂, BH₃ THF 1 M/THF (1220mL) was added dropwise. The solution was refluxed for 4 hours then cooled to 0-3°C and methanol (240mL) was added. The reaction mixture was heated to room temperature then it was concentrated to dryness. The residue was redissolved in methanol (603.5mL), excess HCI 1 N in Et₂O (1207mL) was added and the mixture was refluxed for 2 hours then cooled at 3°C for 4 hours. The suspension was filtered to obtain a white solid that was washed with Et₂O (60.35mL) and dried to yield the title compound (72.02q)

¹H-NMR (DMSO) δ (ppm) 11.0-9.5 (b, 4H); 7.99-7.19 (dd-m, 3H); 4.96 (dd, 1 H); 3.65-3.15 (m, 6H); 2.42 (s, 3H).

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HYDROCHLORIDE SALT

WO2001025219A2

Example 38

2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1 -carboxylic acid |i -(R)-

(3,5-bis-trifluoromethyl-phenyl)-ethvπ-methyl-amide hydrochloride Example 37 (0.1 g) was dissolved in Ethyl Ether (0.8ml) at room temperature, then 1 M HCI solution in Ethyl Ether (0.6ml) was added. The suspension was stirred at 3°C for 3 hour, then filtered and washed with Ethyl Ether (1 ml) to afford the title compound ( 0.015g ) as a white solid. ¹H-NMR (DMSO) δ (ppm) 9.31 (bm, 1 H); 9.11 (bm, 1 H); 8.02 (bs, 1 H); 7.72 (bs, 2H); 7.28 (dd, 1 H); 7.00 (dd, 1 H); 6.84 (m, 1 H); 5.34 (q, 1 H); 4.54 (dd, 1 H); 3.50-3.20 (m, 4H); 3.08 (m, 1 H); 2.93 (m, 1 H); 2.73 (s, 3H); 2.38 (s, 3H); 1.48 (d, 3H).

ACETATE SALT

Example 18

2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1 -carboxylic acid M -(R)-

(3.5-bis-trifluoromethyl-phenyl)-ethvn-methyl-amide acetate salt

To a solution of intermediate 40a (8.8 g) in dry THF (33 mL) under N2 BH3.THF (1 M solution in THF – 87 mL) was added and the reaction mixture was stirred at reflux for 3 hr, then cooled to r.t. and HCI (37%, 30 mL) was added drop-wise maintaining the reaction mixture in an ice-bath. The reaction mixture was stirred at r.t. for 1 hr. Water was then added (70 mL) and solid NaHCO3 (35.2 g) was added portion-wise until a pH of 6.5. The THF was evaporated and the aqueous phase was extracted with Et2θ (3 x 88 mL). The combined organic phases were dried, and evaporated to leave a colourless oil (7.37 g).

This crude oil was purified by flash chromatography (AcOEt/MeOH 7:3). The product obtained was suspended in Et2θ (125 mL) and washed with NaHCO3 sat. (2 x 20 mL). The clear combined organic phases were dried and evaporated to obtain the 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine- 1 -carboxylic acid [1 -(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl- amide as white foam (5.27 g). This material (5.27 g) was dissolved in Et2θ (79 mL) and acetic acid (613 μL) was added drop-wise. The mixture was stirred at r.t. for 1 h and then at 0°C for 1h. The suspension was filtered to give the title compound (4.366 g) as a white solid. NMR (¹H, DMSO-de): δ (ppm) 7.98 (s, 1 H), 7.70 (s, 2H), 7.87 (m, 1 H), 6.91 (m, 1 H), 6.77 (m, 1 H), 5.29 (q, 1 H), 4.23 (dd, 1 H), 3.2-2.6 (m, 6H), 2.68 (s, 3H), 2.3 (s, 3H), 1.89 (s, 3H), 1.48 (d, 3H). MS (m/z): 492 [M-CH₃COO]⁺.

[ ]^D = – 120.4°C Solvent (CHCI3); Source: Na; Cell volume [mL]: 1 ; Cell pathlength [dm]: 1 ; Cell temperature [°C]: 20; Wavelength [nm]: 589

””””””””””””””””””””””””””””””””””’

http://www.google.com/patents/US8188290

EXAMPLE 1 N-[1-(R) 3,5-bis-trifluoromethyl phenyl)-ethyl]-N-methyl carbamoyl chloride

[1-(R) 3,5-bis-trifluoromethyl phenyl)-ethyl]methyl amine L(−)maleate (13.5 g; 33.33 mmol) was suspended in ethyl acetate (39.9 ml) and ethanol (0.1 ml); aqueous sodium carbonate 13% (40 ml) was added and the mixture was stirred at a temperature 20-25° C. until a clear solution was formed. The water phase was discarded and the organic phase was washed with water (40 ml). Fresh ethyl acetate (49.87 ml) and ethanol (0.13 ml) were added, the solution was concentrated to 40 ml, a second amount of fresh ethyl acetate (49.87 ml) and ethanol (0.13 ml) was added and the solution was concentrated to 40 ml. Fresh ethyl acetate (109.7 ml) and ethanol (0.3 ml) were added under CO₂ flow. A cycle of vacuum and CO₂ in the vessel was applied, then CO₂ was maintained for 10 minutes. Then, a neat Et₃N (6.1 ml; 46.34 mmol) was added and the reaction mixture was stirred at a temperature 20-25° c. for 30 minutes. Trimethylmethylsilylchloride (6.4 ml; 40.42 mmol) was added in 30 minutes (exothermic step) and the reaction mixture was stirred for further 30 minutes at room temperature. Pyridine (5.4 ml; 66.66 mmol) was added, then SOCl₂ (3.6 ml; 40.42 mmol) was added in 10 minutes. The reaction mixture was stirred at room temperature for 10 hours under CO₂ atmosphere. 13% w/w aqueous racemic malic acid (60 ml) was added and the mixture was stirred for 15 minutes; the water phase was discarded then the organic phase was washed with water (60 ml); the water phase was discarded then the organic phase was washed with sodium carbonate 13% w/w (60 ml). Finally, the water phase was discarded and ethyl acetate (49.87 ml) and ethanol (0.13 ml) were added and the solution was concentrated to 50 ml; further ethyl acetate (49.87 ml) and ethanol (0.13 ml) were added and the solution was concentrated to dryness to give the title compound as a pale yellow (10.41 gr; 31.33 mmol 94% yield)

NMR-(d₆-DMSO) δ (ppm)

8.04 δ (br s, 1H), 7.97 δ (br s, 2H), 5.52 δ (q, 1H), 2.97 δ (s, 3H), 1.66 δ (d, 3H)

EXAMPLE 2 (2R)-2-(4-fluoro-2-methylphenyl)-4-oxo-1-piperidinyl carbonyl; chloride

(2R)-2-(4-fluoro-2-methylphenyl)-4-oxo-1-piperidine L(−) mandelate (2 g; 5.57 mmol) was suspended in ethyl acetate (8 ml); aqueous sodium carbonate 13% w/w (10 ml) was added and the mixture was stirred at a temperature 20-25° C. until a clear solution was formed.

The water phase was discarded and the organic phase was washed with aqueous sodium chloride 10% w/w (4 ml). Fresh ethyl acetate (8 ml) were added, the solution was concentrated to 6 ml, a second amount of fresh ethyl acetate (8 ml) was added and the solution was concentrated to 6 ml.

Fresh ethyl acetate (2 ml) and neat Et₃N (1.94 ml; 13.92 mmol) were added under CO₂ flow at 0° C. The mixture was stirred for 10 minutes, then Trimethylmethylsilylchloride (1.42 ml; 11.14 mmol) was added in 5 minutes (exothermic step) and the reaction mixture was stirred for further 30 minutes at 0° C. Pyridine (0.58 ml; 7.24 mmol) was added, then SOCl₂ (0.53 ml; 7.24 mmol) was added in 5 minutes. The reaction mixture was stirred at 0° C. for 1 h, then at a temperature 20-25° C. for 5 hours under CO₂ atmosphere. Water (20 ml) was added was added; the water phase was discarded then the organic phase was washed with sodium carbonate 13% w/w (20 ml); the water phase was discarded then the organic phase was dried on sodium sulphate. The organic phase was filtered and concentrated to dryness to give the title compound as a pale yellow (1.5 gr; 5.57 mmol 100% yield)

HPLC Rt: 2.33 min; MS: [H+] 270

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J. Med. Chem., 2009, 52 (10), pp 3238–3247

^a(a) (i) Mg, I₂, THF, T = 70 °C, 2 h; (ii) LiBr, Cu₂Br₂, THF, room temp 1 h; (iii) CH₃OCOCOCl, room temp, 2 h; (b) ethylenediamine, toluene, reflux, 6 h; (c) H₂ (1 atm), 10% Pd/C, MeOH, 16 h; (d) (i) S-(+)-mandelic acid orR-(−)-mandelic acid, AcOEt, T = 3−5 °C, 2 h; (ii) filtration of the salt, then crystallization in AcOEt; (iii) 0.73 M NaOH; (e) (i) triphosgene, Et₃N, CH₂Cl₂, T = 0 °C, 4 h; (ii) 1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-N-methylamine, N(i-Pr)₂Et, CH₃CN, T = 70 °C, 2 h; (f) (i) 1 M BH₃·THF, THF, reflux, 3 h; (ii) Et₂O, AcOH.

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patents

WO 2012175434

WO 2008046882

WO 2004091624

WO 2004067093

WO 2001025219…

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1. Organic Process Research and Development, 2009 ,  vol. 13,   6  pg. 1100 – 1110

2. Magnetic Resonance in Chemistry, 2010 ,  vol. 48,   7  pg. 523 – 530

3. Org. Process Res. Dev., 2009, 13 (3), pp 489–493.

4. Synthesis of the NK1 receptor antagonist GW597599. Part 1: Development of a scalable route to a key chirally pure arylpiperazine
Org Process Res Dev 2008, 12(6): 1188………….

5.Journal of Thermal Analysis and Calorimetry, 2010 ,  vol. 102,   1  pg. 297 – 303

10.Discovery process and pharmacological characterization of 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) as a potent, selective, and orally active NK1 receptor antagonist.

Di Fabio R, Griffante C, Alvaro G, Pentassuglia G, Pizzi DA, Donati D, Rossi T, Guercio G, Mattioli M, Cimarosti Z, Marchioro C, Provera S, Zonzini L, Montanari D, Melotto S, Gerrard PA, Trist DG, Ratti E, Corsi M.

J Med Chem. 2009 May 28;52(10):3238-47. doi: 10.1021/jm900023b.

 

 

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