Telmapitant……Tachykinin NK1 Antagonists

Telmapitant

TELMAPITANT; Telmapitant (USAN); Telmapitant [USAN]; 552292-58-7; HJ5FE4153B; D10391

(5R,8S)-8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,3,9-triazaspiro[4.5]decane-2,4-dione

1,​3,​7-​Triazaspiro[4.5]​decane-​2,​4-​dione, 8-​[[(1R)​-​1-​[3,​5-​bis(trifluoromethyl)​phenyl]​ethoxy]​methyl]​-​8-​phenyl-​, (5R,​8S)​-

(5R,8S)-8-(((1R)-1-(3,5-Bis(Trifluoromethyl)phenyl)ethoxy)methyl)-8-phenyl-1,3,7- triazaspiro(4.5)decane-2,4-dione
1,3,7-Triazaspiro(4.5)decane-2,4-dione,

8-(((1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-8-phenyl-, (5R,8S)-

Molecular Formula: C₂₄H₂₃F₆N₃O₃

Molecular Weight: 515.448139

cas 552292-58-7

Merck & Co. (innovator)

Treatment of Nausea and Vomiting,

SYNTHESIS

……………………………………….

US7902366

http://www.google.com/patents/US7902366

Example 43a Example 43b

 

Step 1:

 

To a suspension of lactol Compound 3 (60 g, 93.0 mmol, 1 equiv.) and Wittig Reagent (93.5 g, 200.0 mmol, 2.15 equiv.) in toluene (800 ml) stirred at −78° C. under N₂, a solution of KHMDS (0.5M in toluene, 558 ml, 280.0 mmol, 3 equiv.) was added dropwise at −78° C. The cooling bath was removed and the yellow mixture was warmed to RT to form a red solution. The mixture was allowed to stir at 23° C. for further 1 h before being quenched with saturated NH₄Cl solution. EtOAc was added and layers were separated. The separated aqueous layer was extracted with EtOAc (2×500 ml). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [5% EtOAc-hexane to 10% EtOAc-hexane] gave alkene Compound 42 as white solid (40.5 g, 68%), Electrospray MS [M+1]⁺ 638.1. Continuous elution gave an impure cyclized product Compound 43.

Step 2:

 

A suspension of alkene Compound 42 (40.5 g, 64 mmol, 1 equiv.) and PtO₂ (1.44 g, 6.4 mmol, 0.1 equiv.) in EtOH (400 ml) were stirred under a H₂ balloon at 23° C. for 24 h. Another batch of PtO₂ (1.44 g, 6.4 mmol, 0.1 equiv) was added and the mixture was stirred for another 24 h at 23° C. The catalyst was filtered via a pad of Celite. This solution of alkane Compound 44 was used in the next step without further purification.

Step 3:

 

p-TsOH.H₂O (2.42 g, 13.0 mmol) was added to the ethanolic solution of alkane Compound 44 from above and the solution was heated to reflux for 4 h. The solution was cooled to RT and neutralized with Et₃N. Solvents were removed in vacuum and EtOAc was added. Saturated NaHCO₃ solution was added and layers were separated. The separated aqueous layer was extracted with EtOAc (300 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [10% ether-hexane] gave enamide Compound 45 (first batch) as yellow oil. Some intermediate and starting material were recovered as yellow oil by continuous elution with [50% EtOAc-hexane]. The yellow oil was dissolved in toluene and 10 mol % p-TsOH was added. The mixture was heated to reflux for 2 h and cooled to RT. Work up was as above and the combined enamide Compound 45 (25 g, 70%), Electrospray MS [M+1]⁺ 564.1, was obtained as yellow oil.

Step 4:

 

BH₃.Me₂S (13.6 ml, 133 mmo, 3.02 equiv) was added to a solution of enamide Compound 45 (25 g, 44.0 mmol,1 equiv.) in THF at 23° C. under N₂. The mixture was stirred at 23° C. for 18 h and then cooled over an ice-water bath. A solution of NaOH (500 ml, 2N) was added slowly followed by a solution of H₂0₂ (500 ml, 30% aqueous). The mixture was allowed to stir from 0° C. to 23° C. for 18 h. Layers were separated and the separated aqueous layer was extracted with Et₂O (500 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [hexane-EtOAc, 3:1 (v/v)] gave alcohol Compound 46 as colorless oil (19 g, 74%), Electrospray MS [M+1]⁺ 582.1.

Step 5:

 

Oxalyl chloride (5.7 ml, 65.3 mmol, 2 equiv.) was added to a solution of DMSO (9.3 ml, 131.0 mmol, 4 equiv.) in CH₂Cl₂ (300 ml) at −78° C. under N₂. The mixture was stirred at −78° C. for 15 min before a solution of alcohol Compound 46 (19 g, 32.7 mmol. 1 equiv.) in CH₂Cl₂ (50 ml) was added. The mixture was stirred at −78° C. for a further 1 h and Et₃N (32 ml, 228.9 mmol, 7 equiv.) was added. The cooling bath was removed and the mixture was warmed to RT before it was quenched with saturated NaHCO₃ solution. Layers were separated and the aqueous was extracted with CH₂Cl₂ (300 ml×2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [hexane-ether, 4:1 (v/v)] gave ketone Compound 47 as colorless oil (15 g, 80%), Electrospray MS [M+1]⁺ 580.1.

Step 6:

 

EtOH (150 ml) was added to Cbz-ketone Compound 47 (15 g, 25.88 mmol, 1 equiv.), followed by NH₄(CO₃)₂ (9.95 g, 103.5 mmol, 4 equiv.) and a solution of KCN (3.4 g, 51.77 mmol, 2 equiv.). The resulting mixture was heated at 58° C. under N₂ for 72 h. TLC (1:1 EtOAc:hexane) revealed complete consumption of the starting material. The reaction mixture was cooled to RT and poured into sat. aq. NaHCO₃ (200 ml) and extracted with EtOAc (3×200 ml). The combined organic layers were dried over MgSO₄ and concentrated in vacuo to afford crude Cbz-hydantoin Compound 48 (16.5 g, 98%), Electrospray MS [M+1]⁺650.1. The crude material was used in the next reaction without further purification.

Step 7:

The crude Cbz-hydantoin Compound 48 (16.5 g, 25.4 mmol, 1 equiv.) was dissolved in MeOH (220 ml) and 20% Pd(OH)₂—C (3.6 g) was added. The reaction mixture was shaken in a parr shaker under H₂ atmosphere at 40 psi for 18 h. TLC (1:1 EtOAc:hexane) revealed complete consumption of the starting material. The reaction mixture was filtered through a pad of celite and the celite was washed with MeOH. The resulting solution was concentrated in vacuo. The crude product was purified by column chromatography on a Biotage (3:2, EtOAc:hex). Two major spots were collected. The less-polar spot corresponds to the isomer Example 43a (3 g, overall 20% over two steps), Electrospray MS [M+1]⁺ 516.1. The more polar spot corresponds to the isomer Example 43b (4.5 g, overall 30% over two steps), Electrospray MS [M+1]⁺ 516.1.

………………………………..

WO 2003051840

http://www.google.com/patents/WO2003051840A1?cl=en

Example 43a Example 43b

 

Step 1 :

Compound 3

 

To a suspension of lactol Compound 3 (60g, 93.0mmol, lequiv.) and Wittig Reagent (93. δg, 200.0mmol, 2.1 δequiv.) in toluene (800ml) stirred at -78°C under δ N₂, a solution of KHMDS (O.δM in toluene, δδδml, 280.0mmol, 3equiv.) was added dropwise at -78°C. The cooling bath was removed and the yellow mixture was warmed to RT to form a red solution. The mixture was allowed to stir at 23°C for further 1 h before being quenched with saturated NH CI solution. EtOAc was added and layers were separated. The separated aqueous layer was extracted with EtOAc 0 (2 x δOOml). The combined organic layers were dried (MgSO ) and filtered.

Removal of solvents in vacuum followed by Biotage column chromatography [δ% EtOAc-hexane to 10% EtOAc-hexane] gave alkene Compound 42 as white solid (40. δg, 68%), Electrospray MS [M+1]⁺ 638.1. Continuous elution gave an impure cyclized product Compound 43. δ Step 2:

Compound 42

 

A suspension of alkene Compound 42 (40. δg, 64mmol, lequiv.) and PtO₂ (1.44g, 6.4mmol, 0.1 equiv.) in EtOH (400ml) were stirred under a H₂ balloon at 23°C for 24 h. Another batch of PtO₂ (1.44g, 6.4mmol, 0.1 equiv) was added and the 0 mixture was stirred for another 24 h at 23°C. The catalyst was filtered via a pad of Celite. This solution of alkane Compound 44 was used in the next step without further purification. Step 3:

Compound 44

 

p-TsOH.H₂O (2.42g, 13.0mmol) was added to the ethanolic solution of alkane

Compound 44 from above and the solution was heated to reflux for 4 h. The solution was cooled to RT and neutralized with Et₃N. Solvents were removed in vacuum and EtOAc was added. Saturated NaHCO₃ solution was added and layers

5 were separated. The separated aqueous layer was extracted with EtOAc (300ml x

2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [10% ether- hexane] gave enamide Compound 45 (first batch) as yellow oil. Some intermediate and starting material were recovered as yellow oil by continuous elution with 0 [50%EtOAc-hexane]. The yellow oil was dissolved in toluene and 10mol% p-TsOH was added. The mixture was heated to reflux for 2 h and cooled to RT. Work up was as above and the combined enamide Compound 45 (2δg, 70%), Electrospray

MS [M+1]⁺ 664.1 , was obtained as yellow oil.

Step 4:

 

BH₃.Me₂S (13.6ml, 133mmo, 3.02 equiv) was added to a solution of enamide Compound 45T25g, 44.0mmol, lequiv.) in THF at 23°C under N₂. The mixture was stirred at 23°C for 18 h and then cooled over an ice-water bath. A solution of NaOH (600ml, 2N) was added slowly followed by a solution of H O₂ (600ml, 30% 0 aqueous). The mixture was allowed to stir from 0°C to 23°C for 18 h. Layers were separated and the separated aqueous layer was extracted with Et.₂0 (600ml x 2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [hexane-EtOAc, 3:1 (v/v)] gave alcohol Compound 46 as colorless oil (19g, 74%), Electrospray MS [M+1]⁺ δ 582.1. Step 5:

Compound 46

 

Oxalyl chloride (δ.7ml, 6δ.3mmol, 2equiv.) was added to a solution of DMSO (9.3ml, 131.0mmol, 4equiv.) in CH₂CI₂ (300ml) at -78°C under N₂. The mixture was 0 stirred at -78°C for 1 δ min before a solution of alcohol Compound 46 (19g, 32.7mmol. lequiv.) in CH₂CI₂ (50ml) was added. The mixture was stirred at -78°C for a further 1 h and Et₃N (32ml, 228.9mmol, 7equiv.) was added. The cooling bath was removed and the mixture was warmed to RT before it was quenched with saturated NaHCO₃ solution. Layers were separated and the aqueous was extracted with CH₂CI₂ (300ml x 2). The combined organic layers were dried (MgSO₄) and filtered. Removal of solvents in vacuum followed by Biotage column chromatography [hexane-ether, 4:1 (v/v)] gave ketone Compound 47 as colorless oil (1δg, 80%), Electrospray MS [M+1]⁺ 680.1.

 

EtOH (150ml) was added to Cbz-ketone Compound 47 (15g, 2δ.88mmol, lequiv.), followed by NH (CO )₂ (9.9δg, 103.5mmol, 4equiv.) and a solution of KCN (3.4g, 61.77mmoI, 2equiv.). The resulting mixture was heated at 68°C under N2 for 72 h. TLC (1 :1 EtOAc:hexane) revealed complete consumption of the starting

1δ material. The reaction mixture was cooled to RT and poured into sat. aq. NaHCO₃ (200 ml) and extracted with EtOAc (3 x 200ml). The combined organic layers were dried over MgSO₄ and concentrated in vacuo to afford crude Cbz-hydantoin Compound 48 (16.δg, 98%), Electrospray MS [M+1]⁺ 650.1. The crude material was used in the next reaction without further purification.

20 Step 7:

The crude Cbz-hydantoin Compound 48 (16.5g, 2δ.4mmol, lequiv.) was dissolved in MeOH (220ml) and 20% Pd(OH)₂-C (3.6g) was added. The reaction mixture was shaken in a parr shaker under H₂ atmosphere at 40 psi for 18 h. TLC (1 :1 EtOAc:hexane) revealed complete consumption of the starting material. The

26 reaction mixture was filtered through a pad of celite and the celite was washed with MeOH. The resulting solution was concentrated in vacuo. The crude product was purified by column chromatography on a Biotage (3:2, EtOAc:hex). Two major spots were collected. The less-polar spot corresponds to the isomer Example 43a (3 g, overall 20% over two steps), Electrospray MS [M+1]⁺ 616.1. The more polar spot

30 corresponds to the isomer Example 43b (4.6 g, overall 30% over two steps), Electrospray MS [M+1]⁺ 616.1.

 

 

US2011098468	4-29-2011	NK1 ANTAGONISTS
US7902366	3-9-2011	NK1 antagonists

 

English translation of Knabe, J., et al., “Racemates and Enantiomers of . . . ,” Pharmazie 52(12):912-919 (1997).
2		English translation of Schult, Karl E., et al., “Hydantoin-Derivate as Potential . . . ,” Eur. J. Med. Chem.-Chimica Therapeutics 13(1):25-31 (1978).
3		English translation of Schult, Karl E., et al., “Hydantoin-Derivate as Potential . . . ,” Eur. J. Med. Chem.—Chimica Therapeutics 13(1):25-31 (1978).
4		Knabe, J., et al., “Racemates and Enantiomers of Basic Substituted 5-Phenylhydantoins . . . ,” Pharmazie 52(12): 912-919 (1997).
5		Oh, Chang-Hyun et al., “Synthesis of New Hydantoin-3-Acetic Acid Derivatives . . . ,” Bull. Korean Chem. Soc. 9(4):231-235 (1988).
6		Shulte, Karl E., et al., “Hydantoin-Derivate als . . . ,” Eur. J. Med. Chem.-Chimica Therapeutica 13(1):25-31 (1978).
7		Shulte, Karl E., et al., “Hydantoin-Derivate als . . . ,” Eur. J. Med. Chem.—Chimica Therapeutica 13(1):25-31 (1978).
8		Wu, X. et al., “Generation of Cyclopenta [c] piperidines and Pyrrolo [3,4-c]piperidines- . . . ,” Tetrahedron 56(34): 6279-6290 (2000).
9	*	Xiujuan Wu et al 2000. , Stereoselective transformation of 2H-1,4-Oxazin-2-ones into 2,(2),5,5-tri- and tetrasubstituted Analogues. . .

 

US6436928 *	Dec 14, 2000	Aug 20, 2002	Schering Corporation	Selective neurokinin antagonists
US6635639 *	Feb 13, 2002	Oct 21, 2003	Nps Allelix Corp.	Use of N-alkylamino-heterocylic compounds for the treatment of migraine
US7041682 *	Jul 2, 2003	May 9, 2006	Schering Corporation	Antiemetics, antidepressants, anxiolytic agents, antitussive agents
US7122677 *	Nov 12, 2002	Oct 17, 2006	Scherig Corporation	NK1 antagonists
US20060094720 *	Dec 15, 2005	May 4, 2006	Neng-Yang Shih	NK1 antagonists
US20060223804 *	Jun 30, 2005	Oct 5, 2006	Schering Corporation	NK1 antagonists
EP0790248A1	Jan 20, 1997	Aug 20, 1997	Pfizer Limited	3-Aza-piperidone- (tetrahydropyrimidin-2-one) and 3-oxa-piperidone (1,3 oxazin-2-one) derivatives, their preparation and their use as tachykinin/neurokinin antagonists

key

Telmapitant, Merck, Tachykinin NK1 Antagonists