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【结 构 式】

【分子编号】27677

【品名】1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene

【CA登记号】32247-96-4

【 分 子 式 】C9H5BrF6

【 分 子 量 】307.0331192

【元素组成】C 35.21% H 1.64% Br 26.02% F 37.13%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(X)

The cyclization of benzaldehyde (I) with methyl 4-nitrobutyrate (II) and ammonium acetate in refluxing acetic acid gives 5-nitro-6-phenylpiperidone (III), which is treated with ozone and t-BuOK in dichloromethane/methanol to yield 2-phenylpiperidine-3,6-dione (IV). The reduction of (IV) by means of LiAlH4 in THF affords 2-phenylpiperidin-3-ol (V) as a mixture of cis- and trans-isomers. The reaction of (V) with TsOH, followed by crystallization in methanol/ethyl acetate provides the corresponding tosylate (VI) as the (rac)(cis)-isomer. The neutralization of the tosylate (VI) with Na2CO3 in ethyl acetate/water gives 2-phenylpiperidin-3-ol (VII) as a racemic cis mixture, which is submitted to optical resolution with (+)-dibenzoyltartaric acid to yield (+)(cis)-(VIII). The reaction of (VIII) with Boc2O affords the N-protected compound (IX), which is alkylated with 3,5-bis(trifluoromethyl)benzyl bromide (X) and NaH to provide the benzyl ether (XI). Finally, this compound is N-deprotected by means of TFA to obtain the target piperidine.

1 Baker, R.; Harrison, T.; Swain, C.J.; Williams, B.J. (Merck Sharp & Dohme Ltd.); Azacyclic cpds., processes for their preparation and pharmaceutical compsns. containing them. EP 0528495; EP 0600952; JP 1994510034; WO 9304040 .
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 64492 methyl 4-nitrobutanoate C5H9NO4 详情 详情
(III) 64493 5-nitro-6-phenyl-2-piperidinone C11H12N2O3 详情 详情
(IV) 64494 6-phenyl-2,5-piperidinedione C11H11NO2 详情 详情
(V) 64495 (cis),(trans)2-phenyl-3-piperidinol C11H15NO 详情 详情
(VI) 64496 (rac)(cis)3-hydroxy-2-phenylpiperidinium 4-methylbenzenesulfonate C18H23NO4S 详情 详情
(VII) 64497 (rac)(cis)[(2S,3S)-2-phenyl-3-piperidinol] C11H15NO 详情 详情
(VIII) 64498 (2S,3S)-2-phenyl-3-piperidinol C11H15NO 详情 详情
(IX) 64499 tert-butyl (2S,3S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate C16H23NO3 详情 详情
(X) 27677 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene 32247-96-4 C9H5BrF6 详情 详情
(XI) 64500 tert-butyl (2S,3S)-3-{[3,5-bis(trifluoromethyl)benzyl]oxy}-2-phenyl-1-piperidinecarboxylate C25H27F6NO3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XIV)

The esterification of L-phenylglycine (I) with AcCl and methanol gives the methyl ester (II), which is N-protected by means of Boc2O and TEA to yield the N-Boc derivative (III). The reduction of (III) with NaBH4 in ethanol/THF affords the alcohol (IV), which is oxidized by means of (COCl)2 and DMSO to provide the carbaldehyde (V). The reaction of (V) with vinylmagnesium bromide (VI) in THF gives the allyl alcohol (VII), which is protected with Tbdms-Cl and imidazole to yield the silyl ether (VIII). The alkylation of (VIII) with allyl bromide (IX) and NaH in DMF affords the N-allyl derivative (X), which is desilylated by means of TBAF and AcOH in THF to provide the allyl alcohol (XI). The ring closing metathesis reaction of (XI) with a Grubbs' catalyst in dichloromethane gives the tetrahydropyridine (XII), which is treated with H2 over Pd/C in ethanol to yield the chiral protected piperidine (XIII). The condensation of (XIII) with 3,5-bis(trifluoromethyl)benzyl bromide (XIV) by means of NaH in DMF affords the benzyl ether (XV), which is finally deprotected with TFA to provide the target piperidine.

1 Bhaskar, G.; Rao, B.V.; Stereoselective synthesis of L-733,060. Tetrahedron Lett 2003, 44, 5, 915.
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) 10716 (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine 2935-35-5 C8H9NO2 详情 详情
(II) 10717 methyl (2S)-2-amino-2-phenylethanoate C9H11NO2 详情 详情
(III) 12485 methyl (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoate C14H19NO4 详情 详情
(IV) 59225 (R)-N-(tert-Butoxycarbonyl)-phenylglycinol; N-t-BOC-D-phenylglycinol 102089-74-7 C13H19NO3 详情 详情
(V) 45428 tert-butyl (1S)-2-oxo-1-phenylethylcarbamate C13H17NO3 详情 详情
(VI) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(VII) 64501 tert-butyl (1S,2S)-2-hydroxy-1-phenyl-3-butenylcarbamate C15H21NO3 详情 详情
(VIII) 64502 tert-butyl (1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-3-butenylcarbamate C21H35NO3Si 详情 详情
(IX) 11463 3-Bromo-1-propene; 3-Bromopropene;allyl bromide 106-95-6 C3H5Br 详情 详情
(X) 64503 tert-butyl allyl((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-3-butenyl)carbamate C24H39NO3Si 详情 详情
(XI) 64504 tert-butyl allyl[(1S,2S)-2-hydroxy-1-phenyl-3-butenyl]carbamate C18H25NO3 详情 详情
(XII) 64505 tert-butyl (2S,3S)-3-hydroxy-2-phenyl-3,6-dihydro-1(2H)-pyridinecarboxylate C16H21NO3 详情 详情
(XIII) 64499 tert-butyl (2S,3S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate C16H23NO3 详情 详情
(XIV) 27677 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene 32247-96-4 C9H5BrF6 详情 详情
(XV) 64500 tert-butyl (2S,3S)-3-{[3,5-bis(trifluoromethyl)benzyl]oxy}-2-phenyl-1-piperidinecarboxylate C25H27F6NO3 详情 详情

合成路线3

该中间体在本合成路线中的序号:(IV)

This compound can be obtained by two related ways: 1.- The reduction of 4-phenylpiperidine-4-carboxylic acid (I) with LiAlH4 in THF gives the corresponding methanol derivative (II), which is treated with tert-butoxycarbonyl anhydride in THF to yield the N-protected piperidine (III). The acylation of (III) with 3,5-bis(trifluoromethyl)benzyl bromide (IV) by means of NaH in DMF affords the corresponding ether (V), which is deprotected with HCl in ethyl ether to afford the free piperidine (VI) (1,2). Finally, (VI) is reductocondensed with 2-methylthiazole-5-carbaldehyde (VII) by means of sodium cyanoborohydride in methanol/acetic acid. 2.- The piperidine derivative (VI) can also be condensed with 5-(bromomethyl)-2-methylthiazole (VIII) by means of K2CO3 in DMF.

1 Stevenson, G.I.; Huscroft, I.; Macleod, A.M.; Swain, C.J.; Cascieri, M.A.; Chicchi, G.G.; Graham, M.I.; Harrison, T.; Kelleher, F.J.; Kurtz, M.; Ladduwahetty, T.; Merchant, K.J.; Metzger, J.M.; MacIntyre, D.E.; Sadowski, S.; Sohal, B.; Owens, A.P.; 4,4-Disubstituted piperidine high-affinity NK1 antagonists: Structure-activity relationships and in vivo activity. J Med Chem 1998, 41, 23, 4623.
2 Harrison, T.; Mcleod, A.M.; Stevenson, G.I.; Williams, B.J. (Merck Sharp & Dohme Ltd.); 4-Arylmethyloxymethyl piperidines as tachykinin antagonists. EP 0666856; JP 1996502510; US 5620989; WO 9410165 .
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) 25447 4-phenyl-4-piperidinecarboxylic acid 3627-45-0 C12H15NO2 详情 详情
(II) 27675 (4-phenyl-4-piperidinyl)methanol C12H17NO 详情 详情
(III) 27676 tert-butyl 4-(hydroxymethyl)-4-phenyl-1-piperidinecarboxylate C17H25NO3 详情 详情
(IV) 27677 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene 32247-96-4 C9H5BrF6 详情 详情
(V) 27678 tert-butyl 4-([[3,5-bis(trifluoromethyl)benzyl]oxy]methyl)-4-phenyl-1-piperidinecarboxylate C26H29F6NO3 详情 详情
(VI) 27679 3,5-bis(trifluoromethyl)benzyl (4-phenyl-4-piperidinyl)methyl ether C21H21F6NO 详情 详情
(VII) 27680 2-methyl-1,3-thiazole-5-carbaldehyde C5H5NOS 详情 详情
(VIII) 27681 5-(bromomethyl)-2-methyl-1,3-thiazole C5H6BrNS 详情 详情

合成路线4

该中间体在本合成路线中的序号:(VI)

Conjugate addition of the lithium enolate of ethyl 1,3-dithiolane-2-carboxylate (II) to methyl 3,4-dichlorocinnamate (I) afforded the diester adduct (III). Reduction of (III) with LiAlH4 gave diol (IV), which was selectively monosilylated with tert-butyldimethylsilyl chloride, yielding (V). Condensation of the potassium alkoxide of (V) with 3,5-bis(trifluoromethyl)benzyl bromide (VI) provided ether (VII). After desilylation of (VII) with HF in acetonitrile to alcohol (VIII), the hydrolysis of its thioketal function with mercuric perchlorate and CaCO3 furnished ketone (IX). Treatment of (IX) with methoxyamine gave rise to a mixture of (E)- and (Z)-oximes from which the desired (Z)-isomer (X) was isolated by flash chromatography. Swern oxidation of the alcohol functionality of (X) produced the corresponding aldehyde, which was reductively condensed with piperidinyl pyrrolidone (XI) in the presence of NaBH3CN to afford the title compound.

1 Anthes, J.C.; Lee, J.F.; Piwinski, J.J.; Shih, N.-Y.; Ting, P.C.; Synthesis of substituted 4(Z)-(methoxyimino)penthyl-1-piperidines as dual NK1/NK2 inhibitors. Bioorg Med Chem Lett 2001, 11, 4, 491.
2 Shankar, B.B. (Schering Corp.); Substd. oximes, hydrazones and olefins useful as neurokinin antagonists. EP 0823896; EP 0937064; JP 1998506923; JP 2000504341; US 5688960; US 5696267; WO 9634857; WO 9818785 .
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) 49151 methyl (E)-3-(3,4-dichlorophenyl)-2-propenoate C10H8Cl2O2 详情 详情
(II) 49152 2-Carboethoxy-1,3-dithiolane; Ethyl glyoxylate ethylene thioacetal; 1,3-Dithiolane-2-carboxylic acid ethyl ester; 2-Ethoxycarbonyl-1,3-dithiolane; Glyoxylic acid ethyl ester ethylene mercaptal; Ethyl 1,3-dithiolane-2-carboxylate 20461-99-8 C6H10O2S2 详情 详情
(III) 49153 ethyl 2-[1-(3,4-dichlorophenyl)-3-methoxy-3-oxopropyl]-1,3-dithiolane-2-carboxylate C16H18Cl2O4S2 详情 详情
(IV) 49154 3-(3,4-dichlorophenyl)-3-[2-(hydroxymethyl)-1,3-dithiolan-2-yl]-1-propanol C13H16Cl2O2S2 详情 详情
(V) 49155 [2-[3-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl]methanol C19H30Cl2O2S2Si 详情 详情
(VI) 27677 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene 32247-96-4 C9H5BrF6 详情 详情
(VII) 49156 3,5-bis(trifluoromethyl)benzyl [2-[3-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl]methyl ether; [3-[2-([[3,5-bis(trifluoromethyl)benzyl]oxy]methyl)-1,3-dithiolan-2-yl]-3-(3,4-dichlorophenyl)propoxy](tert-butyl)dimethylsilane C28H34Cl2F6O2S2Si 详情 详情
(VIII) 49157 3-[2-([[3,5-bis(trifluoromethyl)benzyl]oxy]methyl)-1,3-dithiolan-2-yl]-3-(3,4-dichlorophenyl)-1-propanol C22H20Cl2F6O2S2 详情 详情
(IX) 49158 1-[[3,5-bis(trifluoromethyl)benzyl]oxy]-3-(3,4-dichlorophenyl)-5-hydroxy-2-pentanone C20H16Cl2F6O3 详情 详情
(X) 49159 1-[[3,5-bis(trifluoromethyl)benzyl]oxy]-3-(3,4-dichlorophenyl)-5-hydroxy-2-pentanone O-methyloxime C21H19Cl2F6NO3 详情 详情
(XI) 49160 1-(4-piperidinyl)-2-pyrrolidinone C9H16N2O 详情 详情
Extended Information