Vofopitant hydrochloride, GR-205171A, GR-205171(free base), -Drug Synthesis Database

【结构式】

【药物名称】Vofopitant hydrochloride, GR-205171A, GR-205171(free base)

【化学名称】(2S,3S)-N-[2-Methoxy-5-[5-(trifluoromethyl)-1-tetrazolyl]benzyl]-N-(2-phenylpiperidin-3-yl)amine dihydrochloride

【CA登记号】168266-51-1, 168266-90-8 (free base)

【分子式】C₂₁H₂₅Cl₂F₃N₆O

【分子量】505.3742

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, Tachykinin NK1 Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

The acylation of 4-benzyloxyaniline (I) with trifluoroacetyl chloride and triethylamine in dichloromethane gives the corresponding amide (II), which is treated with resin-supported triphenylphosphine and CCl4 to yield the iminochloride (III). The cyclization of (III) with sodium azide in hot acetic acid affords the tetrazole (IV), which is debenzylated with H2 over Pd/C in ethanol/THF, giving the phenol (V). The reaction of (V) with hexamethylenetetramine (HMT) in hot trifluoroacetic acid yields the benzaldehyde (VI), which by methylation with methyl iodide/K2CO3 in acetone affords 2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]benzaldehyde (VII). Finally, this compound is reductocondensed with (2S,3S)-2-phenylpiperidin-3-amine (VIII) by means of sodium triacetoxyborohydride/acetic acid in dichloromethane. The chiral (2S,3S)-2-phenylpiperidin-3-amine (VIII) has been obtained as follows: The condensation of 2-chloro-3-nitropyridine (IX) with phenylboronic acid (X) by means of palladium tetrakis(triphenylphosphine) and Na2CO3 in dimethoxyethane gives 3-nitro-2-phenylpyridine (XI), which is hydrogenated with H2 over Pd/C in ethanol/HCl, yielding (?-cis-2-phenylpiperidin-3-amine (XII). Finally, this compound is submitted to optical resolution by means of di-p-toluoyl-L-tartaric acid in ethanol/water.

参考文献中间体

【1】 Congreve, M.; Chung, K.M.L.; Armour, D.R.; et al.; Tetrazole NK1 receptor antagonists: The identifica. Bioorg Med Chem Lett 1996, 6, 9, 1015.
【2】 Silvestre, J.S.; Castañer, J.; Sorbera, L.A.; GR-205171. Drugs Fut 1999, 24, 3, 254.
【3】 Armour, D.R.; Evans, B.; Giblin, G.M.P.; Hann, M.M.; Hubbard, T.; Lewell, X.; Middlemiss, D.; Naylor, A.; Pegg, N.A.; Vinader, M.V.; Watson, S.P. (Glaxo Wellcome plc); 3-(5-Tetrazolyl-benzyl)amino-piperidine derivs. an. EP 0720609; JP 1999106341; US 5703240; US 5843966; WO 9508549 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	22460	4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine		C₁₃H₁₃NO	详情	详情
(II)	22461	N-[4-(benzyloxy)phenyl]-2,2,2-trifluoroacetamide		C₁₅H₁₂F₃NO₂	详情	详情
(III)	22462	N-[4-(benzyloxy)phenyl]-2,2,2-trifluoroethanimidoyl chloride		C₁₅H₁₁ClF₃NO	详情	详情
(IV)	22463	1-[4-(benzyloxy)phenyl]-5-(trifluoromethyl)-1H-1,2,3,4-tetraazole; benzyl 4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenyl ether		C₁₅H₁₁F₃N₄O	详情	详情
(V)	22464	4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenol		C₈H₅F₃N₄O	详情	详情
(VI)	22465	2-hydroxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde		C₉H₅F₃N₄O₂	详情	详情
(VII)	22466	2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde		C₁₀H₇F₃N₄O₂	详情	详情
(VIII)	22467	(2S,3S)-2-phenylpiperidinylamine; (2S,3S)-2-phenyl-3-piperidinamine		C₁₁H₁₆N₂	详情	详情
(IX)	10321	2-Chloro-3-nitropyridine	5470-18-8	C₅H₃ClN₂O₂	详情	详情
(IX)	16593	Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide	98-80-6	C₆H₇BO₂	详情	详情
(XI)	22470	3-nitro-2-phenylpyridine		C₁₁H₈N₂O₂	详情	详情

合成路线2

The reduction of 2-iodo-4-nitroanisole (I) with Fe and HOAc/HCl in methanol gives 4-amino-2-iodoanisole (II), which is acylated with trifluoroacetic anhydride and triethylamine to give the corresponding amide (III). The reaction of (III) with PPh3 and CCl4 affords the iminochloride (IV), which is cyclized with sodium azide in acetic acid, giving 1-(3-iodo-4-methoxyphenyl)-5-(trifluoromethyl)tetrazole (V). The reaction of (V) with 13C- or 14C-labeled zinc cyanide and palladium tetrakis triphenylphosphine in DMF yields the labeled benzonitrile (VI), which is treated with Raney-Ni and NaH2PO2 in pyridine/HOAc/water to afford the benzaldehyde (VII). Finally, this compound is reductocondensed with 2(S)-phenylpiperidin-3(S)-amine (VIII) by means of NaH(OAc)3 in dichloromethane.

参考文献中间体

【1】 Sutherland, D.R.; Cable, K.M.; Wells, G.N.; Synthesis of carbon-14 labelled NK-1 receptor antagonists GR203040 and GR205171. J Label Compd Radiopharm 2000, 43, 1, 29.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIIc)	22466	2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde	C₁₀H₇F₃N₄O₂	详情	详情
(VIa)	44429	2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzonitrile	C₁₀H₆F₃N₅O	详情	详情
(VIb)	44430	2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzonitrile	C₁₀H₆F₃N₅O	详情	详情
(VIIa)	44431	2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde	C₁₀H₇F₃N₄O₂	详情	详情
(VIIb)	44432	2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde	C₁₀H₇F₃N₄O₂	详情	详情
(VIc)	44433	2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzonitrile	C₁₀H₆F₃N₅O	详情	详情
(I)	44424	2-iodo-1-methoxy-4-nitrobenzene; 2-iodo-4-nitrophenyl methyl ether	C₇H₆INO₃	详情	详情
(II)	44425	3-iodo-4-methoxyaniline; 3-iodo-4-methoxyphenylamine	C₇H₈INO	详情	详情
(III)	44426	2,2,2-trifluoro-N-(3-iodo-4-methoxyphenyl)acetamide	C₉H₇F₃INO₂	详情	详情
(IV)	44427	2,2,2-trifluoro-N-(3-iodo-4-methoxyphenyl)ethanimidoyl chloride	C₉H₆ClF₃INO	详情	详情
(V)	44428	1-(3-iodo-4-methoxyphenyl)-5-(trifluoromethyl)-1H-1,2,3,4-tetraazole; 2-iodo-4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenyl methyl ether	C₉H₆F₃IN₄O	详情	详情
(VIII)	22467	(2S,3S)-2-phenylpiperidinylamine; (2S,3S)-2-phenyl-3-piperidinamine	C₁₁H₁₆N₂	详情	详情

合成路线3

The 2-phenylpyridine-3-amine (V), an intermediate in the synthesis of 235944, has been obtained with better yields by three related ways: 1. The acylation of 2-chloropyridine-3-amine (I) with Ac2O and TEA in dichloromethane gives the corresponding acetamide (II), which is condensed with phenylboronic acid (III) by means of Pd(PPh3)4 and Na2CO3 in ethanol/toluene, yielding N-(2-phenylpyridin-3-yl)acetamide (IV). Finally, this compound is hydrolyzed with HCl in methanol to afford the target 2-phenylpyridine-3-amine (V) intermediate. 2. The condensation of 2-chloropyridine-3-amine (I) with benzaldehyde (VI) in refluxing toluene gives the corresponding imine (VII), which is condensed with phenylboronic acid (III) as before to yield the 2-phenylpyridine derivative (VIII). Finally, the imino group of (VIII) is hydrolyzed with aqueous HCl to afford the target intermediate (V). 3. The one-pot condensation of 2-chloropyridine-3-amine (I), boronic acid (III) and benzaldehyde (VI) by means of Pd(PPh3)2Cl2 and Na2CO3 in hot toluene gives the already reported 2-phenylpyridine derivative (VIII), which is hydrolyzed as before to afford the target intermediate (V).

参考文献中间体

【1】 Caron, S.; et al.; An efficient and cost-effective synthesis of 2-phenyl-3-aminopyridine. Org Process Res Dev 2001, 5, 3, 254.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	11160	2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine	6298-19-7	C₅H₅ClN₂	详情	详情
(II)	51952	N-(2-Chloropyridin-3-yl)acetamide		C₇H₇ClN₂O	详情	详情
(III)	16593	Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide	98-80-6	C₆H₇BO₂	详情	详情
(IV)	51953	N-(2-phenyl-3-pyridinyl)acetamide		C₁₃H₁₂N₂O	详情	详情
(V)	51954	2-phenyl-3-pyridinylamine; 2-phenyl-3-pyridinamine		C₁₁H₁₀N₂	详情	详情
(VI)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(VII)	51955	N-(2-chloro-3-pyridinyl)-N-[(E)-benzylidene]amine; 2-chloro-N-[(E)-benzylidene]-3-pyridinamine		C₁₂H₉ClN₂	详情	详情
(VIII)	51956	2-phenyl-N-[(E)-benzylidene]-3-pyridinamine; N-[(E)-benzylidene]-N-(2-phenyl-3-pyridinyl)amine		C₁₈H₁₄N₂	详情	详情

Extended Information