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【结 构 式】 
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【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% |
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 |