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【结 构 式】

【分子编号】17616

【品名】bromo(phenyl)magnesium; Phenyl Magnesium Bromide

【CA登记号】100-58-3

【 分 子 式 】C6H5BrMg

【 分 子 量 】181.3147

【元素组成】C 39.75% H 2.78% Br 44.07% Mg 13.4%
与该中间体有关的原料药合成路线共 21 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21

合成路线1

该中间体在本合成路线中的序号：(A)

The reaction of methyl N-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate (I) with phenylmagnesium bromide (A) gives methyl 1-methyl-4-phenylpiperidine-3-carboxylate (II), which is reduced with LiAlH4 yielding 1-methyl-3-hydroxymethyl-4-phenylpiperidine (III), which, in turn is resolved into its optical isomers. The alcohol (III) is esterified with methanesulfonyl chloride in pyridine affording 3-(methansulfonyloxymethyl)-1-methyl-4-phenylpiperidine (IV), which is finally condensed with p-methoxyphenol (B) by means of sodium methoxide in refluxing methanol.

参考文献 中间体
合成目标
【1】 Christensen, J.A.; Squires, R.F.; 4-Phenylpiperidine compounds. DE 2404113; FR 2215233; GB 1422263; JP 49101385; JP 58174363; US 3912743 .
【2】 Chatterjee, S.S.; Femoxetine. Drugs Fut 1977, 2, 5, 309.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(B) 32744 4-methoxyphenol 150-76-5 C7H8O2 详情 详情
(I) 38648 methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate C8H13NO2 详情 详情
(II) 40118 methyl (3R,4S)-1-methyl-4-phenyl-3-piperidinecarboxylate C14H19NO2 详情 详情
(III) 40119 [(3R,4S)-1-methyl-4-phenylpiperidinyl]methanol C13H19NO 详情 详情
(IV) 40120 (3R,4S)-1-methyl-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-4-phenylpiperidine C16H25NOS 详情 详情

合成路线2

该中间体在本合成路线中的序号：(E)

The starting benzophenone (I) can also be obtained in several different ways: a) By a Friedel-Crafts reaction of p-chloroaniline (X) and benzoyl chloride (D). b) By reaction of 5-chloroanthranilic acid (XI) with acetic anhydride to the bicyclic compound (XII), which is then submitted to a Grignard reaction with phenylmagnesium bromide (E). c) By oxidation of 2,3-diphenyl-5-chloroindole (XIII) with CrO3 to the N-benzoylbenzophenone (XIV), followed by debenzoylation with NaOH.

参考文献 中间体
合成目标
【1】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 .
【2】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(E) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(I) 10279 (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone 719-59-5 C13H10ClNO 详情 详情
(X) 12034 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline 106-47-8 C6H6ClN 详情 详情
(XI) 10285 2-Amino-5-chlorobenzoic acid 635-21-2 C7H6ClNO2 详情 详情
(XII) 33853 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one C9H6ClNO2 详情 详情
(XIII) 33854 5-chloro-2,3-diphenyl-1H-indole C20H14ClN 详情 详情
(XIV) 33855 N-(2-benzoyl-4-chlorophenyl)benzamide C20H14ClNO2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(I)

The Grignard reaction of phenylmagnesium bromide (I) with 11C labeled CO2 (II) in THF gives the radiolabeled benzoic acid (III), which is treated with phthaloyl dichloride (IV) in the same solvent to yield radiolabeled benzoyl chloride (V). Finally, this compound is treated with N-debenzoylated paclitaxel (VI) in acetonitrile to afford the target radiolabeled paclitaxel.

参考文献 中间体
合成目标
【1】 Ravert, H.T.; et al.; Radiosynthesis of [11C]paclitaxel. J Label Compd Radiopharm 2002, 45, 6, 471.
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) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(III) 10202 Benzoic acid 65-85-0 C7H6O2 详情 详情
(III) 55347 benzoic acid C7H6O2 详情 详情
(IV) 23811 phthaloyl dichloride;1,2-Benzenedicarbonyl dichloride;o-Phthaloyl chloride 88-95-9 C8H4Cl2O2 详情 详情
(V) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(V) 55348 benzoyl chloride C7H5ClO 详情 详情
(VI) 10729 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C40H47NO13 详情 详情

合成路线4

该中间体在本合成路线中的序号：(A)

Grignard addition of phenylmagnesium bromide to (+)-camphor (I) yielded the endo-alcohol (II), which was reacted with 1-dimethylamino-2-chloroethane (III) to give the base corresponding to EGYT-3886. EGYT-3886 is the 2-(E)-butenedioate salt (1:1).

参考文献 中间体
合成目标
【1】 Budai, Z.; Magdanyi, L.; Lay, A.; Mezei, T.; Grasser, K.; Petocz, L.; Kosoczky, I. (Egis Pharmaceuticals Ltd.); Basic ethers and pharmaceutical compsns. containing the same. US 4342762 .
【2】 Berényi, E.; Baskó, G.; Fekete, M.; Nógrádi, M.; EGYT-3886. Drugs Fut 1990, 15, 12, 1174.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(I) 28296 1-[4-(difluoromethoxy)phenyl]-2-phenyl-1-ethanone C15H12F2O2 详情 详情
(II) 31225 1,7,7-trimethyl-2-phenylbicyclo[2.2.1]heptan-2-ol C16H22O 详情 详情
(III) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情

合成路线5

该中间体在本合成路线中的序号：(XIII)

Synthesis of [14C]-labeled CI-980: The reaction of N-(ethoxycarbonyl)-L-alanine (VII) with N-methoxy-N-methylamine (VIII) by means of carbonyldiimidazole (CDI) in THF/dichloromethane gives the corresponding amide (IX), which is treated with phenylmagnesium bromide (1 mol) yielding the bromomagnesium salt (X). The bromination of [14C]-labeled benzene (XI) with Br2/HBr/H2O2 gives the labeled bromobenzene (XII), which is converted into the corresponding Grignard reagent (XIII) by reaction with Mg and dibromoethane in ether. The reaction of the previously obtained magnesium salt of alaninamide (X) with the labeled Grignard reagent (XIII) affords the labeled carbamate (XIV), which is reduced with NaBH4 in methanol and treated with KOH giving a mixture of the oxazolidinone (XV) and the aminoalcohol (XVI), separated by acidic extraction. The hydrolysis of the oxazolidinone (XV) with KOH yielded the desired aminoalcohol (XVI). The aminoalcohol (XVI) by means of triethylamine in refluxing ethanol gives (1S,2R)-N-[2-amino-4-(2-hydroxy-1-methyl-2-phenylethylamino)-3-nitropyridin-6-yl]carbamic acid ethyl ester (XVII), which is oxidized with CrO3-pyridine in dichloromethane yielding the corresponding ketone (XVIII). The reductocyclization of (XVIII) with H2 over RaNi in glacial acetic acid affords the free base of title compound (XIX), which is finally treated with 2-hydroxyethanesulfonic acid in methanol.

参考文献 中间体
合成目标
【1】 Graul, A.; Martell, A.M.; Castaner, J.; Mivobulin Isethionate. Drugs Fut 1997, 22, 9, 980.
【2】 Woo, P.W.K.; Lee, H.T.; Synthesis of [14C]CI-980, ethyl [5-amino-1,2-dihydro-2(S)-methyl-3-[14C]phenylpyrido[3,4-b]pyrazin-7 -yl]carbamate isethionate salt, a tubulin-binding, antimitotic, broad-spectrum antitumor agent. J Label Compd Radiopharm 1994, 34, 1, 1-10.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 13359 2-Hydroxy-1-ethanesulfonic acid 107-36-8 C2H6O4S 详情 详情
(VII) 13360 (2S)-2-[(Ethoxycarbonyl)amino]propionic acid C6H11NO4 详情 详情
(VIII) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(IX) 13358 ethyl (2S)-5-amino-2-methyl-3-phenyl-1,2-dihydropyrido[3,4-b]pyrazin-7-ylcarbamate C17H19N5O2 详情 详情
(IX) 13362 ethyl (1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethylcarbamate C8H16N2O4 详情 详情
(X) 13363 N-(Ethoxycarbonyl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)ethyl]amide anion C8H15N2O4 详情 详情
(XI) 13364 Benzene 71-43-2 C6H6 详情 详情
(XI) 44622 　 C6H6 详情 详情
(XII) 13365 Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene 108-86-1 C6H5Br 详情 详情
(XII) 45166 　 C6H5Br 详情 详情
(XIII) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(XIII) 45167 　 C6H5BrMg 详情 详情
(XIV) 13367 ethyl (1S)-1-methyl-2-oxo-2-phenylethylcarbamate C12H15NO3 详情 详情
(XIV) 45168 　 C12H15NO3 详情 详情
(XV) 13368 (4S)-4-Methyl-5-phenyl-1,3-oxazolidin-2-one; (4S,5R)-(-)-4-Methyl-5-phenyl-2-oxazolidinone 16251-45-9 C10H11NO2 详情 详情
(XV) 45169 　 C9H13NO 详情 详情
(XVI) 13355 2-Amino-1-phenyl-1-propanol; (1S,2R)-(+)-Norephedrine 37577-28-9 C9H13NO 详情 详情
(XVI) 45170 　 C10H11NO2 详情 详情
(XVII) 13356 ethyl 6-amino-4-[[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]amino]-5-nitro-2-pyridinylcarbamate C17H21N5O5 详情 详情
(XVII) 63746 　 C17H21N5O5 详情 详情
(XVIII) 13357 ethyl 6-amino-4-[[(1S)-1-methyl-2-oxo-2-phenylethyl]amino]-5-nitro-2-pyridinylcarbamate C17H19N5O5 详情 详情
(XVIII) 63747 　 C17H19N5O5 详情 详情
(XIX) 63748 　 C17H19N5O2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

Treatment of anhydroecgonine methyl ester (I) with phenylmagnesium bromide (II) in Et2O affords a mixture of isomers from which phenyltropane derivative (III) is chromatographically separated. Nitration of (III) using nitronium tetrafluoroborate (NO2BF4) in acetonitrile provides derivative (IV), whose nitro group is then reduced by hydrogenation over Raney-Ni in MeOH to yield the p-amino derivative (V). Finally, the desired product is obtained by treatment of (V) with diiodomethane and isoamyl nitrite (VI).

参考文献 中间体
合成目标
【1】 Carroll, F.I.; et al.; Synthesis, ligand binding, QSAR, and CoMFA study of 3beta-(p-substituted phenyl)tropane-2beta-carboxylic acid methyl esters. J Med Chem 1991, 34, 9, 2719.
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) 21118 methyl (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate C10H15NO2 详情 详情
(II) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(III) 49502 methyl (1R,2S,3S,5S)-8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate C16H21NO2 详情 详情
(IV) 49503 methyl (1R,2S,3S,5S)-8-methyl-3-(4-nitrophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate C16H20N2O4 详情 详情
(V) 49504 methyl (1R,2S,3S,5S)-3-(4-aminophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate C16H22N2O2 详情 详情
(VI) 49505 Isoamyl nitrite; iso-Amyl Nitrite; 3-Methylbutyl Nitrite; iso-Pentyl Nitrite; Isopentyl nitrite; Amyl Nitrite 110-46-3 C5H11NO2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VI)

In an alternative procedure, the reductive alkylation of 3-amino-2-chloropyridine (IV) with 2-methoxy-5-trifluoromethoxybenzaldehyde (III) in the presence of NaBH(OAc)3 produced the 3-(benzylamino)pyridine (V). The 2-phenyl pyridine derivative (VII) was then prepared by chloride displacement with phenylmagnesium bromide (VI) in the presence of bis(triphenylphosphino)nickel(II) chloride. Catalytic hydrogenation of pyridine (VII) produced the racemic cis-piperidine, which was finally resolved into the enantiomers by using (S)-mandelic acid.

参考文献 中间体
合成目标
【1】 Rosen, T.J.; Godek, D.M.; Ruggeri, S.G.; Wint, L.T. (Pfizer Inc.); Preparation of substd. piperidines. WO 9311110 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 59236 2-methoxy-5-(trifluoromethoxy)benzaldehyde C9H7F3O3 详情 详情
(IV) 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
(V) 59237 N-(2-chloro-3-pyridinyl)-N-[2-methoxy-5-(trifluoromethoxy)benzyl]amine; 2-chloro-N-[2-methoxy-5-(trifluoromethoxy)benzyl]-3-pyridinamine C14H12ClF3N2O2 详情 详情
(VI) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(VII) 59238 N-[2-methoxy-5-(trifluoromethoxy)benzyl]-2-phenyl-3-pyridinamine; N-[2-methoxy-5-(trifluoromethoxy)benzyl]-N-(2-phenyl-3-pyridinyl)amine C20H17F3N2O2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(III)

Swern oxidation of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (I) with oxalyl chloride in DMSO/dichloromethane gives the corresponding piperidone (II), which is submitted to a Grignard reaction with [U-14C]phenylmagnesium bromide (III) in THF to yield 4-hydroxy-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (IV). The reaction of (IV) with BF3/Et2O in dichloromethane affords labeled 4-phenyl-1,2,3,6-tetrahydropyridine (V), which is condensed with 3-phenyl-3-cyclohexene-1(R)-carboxylic acid (VI) by means of HOBT, DCC and TEA in ethyl acetate to provide the labeled 1-(3-phenyl-3-cyclohexen-1(R)-yl)-1-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methanone (VII). Finally, this compound is reduced with LiAlH4 and AlCl3 in THF to obtain the target tetrahydropyridine derivative.

参考文献 中间体
合成目标
【1】 Ekhato, I.V.; Huang, C.C.; Synthesis of (R)-(+)-1,2,3,6-tetrahydro-4-[U-14C]phenyl-1[(3-phenyl-3-cyclohexenyl-1-yl)methyl]pyridine, a potential antipsychotic agent. J Label Compd Radiopharm 1995, 36, 1, 57.
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) 18625 tert-butyl 4-hydroxy-1-piperidinecarboxylate C10H19NO3 详情 详情
(II) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 45167 　 C6H5BrMg 详情 详情
(III) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(IV) 57878 tert-butyl 4-hydroxy-4-phenyl-1-piperidinecarboxylate C16H23NO3 详情 详情
(IV) 64702 tert-butyl 4-hydroxy-4-phenyl-1-piperidinecarboxylate C16H23NO3 详情 详情
(V) 13002 4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine 10338-69-9 C11H13N 详情 详情
(V) 64703 4-Phenyl-1,2,3,6-tetrahydro-pyridine 10338-69-9 C11H13N 详情 详情
(VI) 57879 (1R)-3-phenyl-3-cyclohexene-1-carboxylic acid C13H14O2 详情 详情
(VII) 54955 [(1R)-3-phenyl-3-cyclohexen-1-yl][4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone C24H25NO 详情 详情
(VII) 64704 [(1R)-3-phenyl-3-cyclohexen-1-yl][4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone C24H25NO 详情 详情

合成路线9

该中间体在本合成路线中的序号：(VI)

The reaction of 7-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-one (I) with NaNO2 and BF4H in water gives the corresponding diazo compound (II), which is treated with H2SO4 in refluxing water yielding 7-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-one (III). The reaction of (III) with trifluoromethanesulfonic anhydride in pyridine affords the expected sulfonate (IV), which is carboxylated with CO, PdAc2 and 1,3-bis(diphenylphosphino)propane in methanol/DMSO yielding 5,5-dimethyl-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (V). The Grignard condensation of (V) with phenylmagnesium bromide (VI) in THF affords the corresponding addition product (VII), which is dehydrated with p-toluenesulfonic acid in hot toluene affording the dihydronaphtoic ester (VIII). The hydrolysis of (VIII) with NaOH in ethanol gives the corresponding free acid (IX), which is treated with SOCl2 and DMF yielding the expected acyl chloride (X). The condensation of (X) with methyl 4-aminobenzoate (XI) in pyridine affords the expected amide (XII), which is finally hydrolyzed to the target compound with NaOH in ethanol/water.

参考文献 中间体
合成目标
【1】 Starrett, J.E. Jr.; Yu, K.-L.; Mansuri, M.M.; Tortolani, D.R. (Bristol-Myers Squibb Co.); Substd. (5,6)-dihydronaphthalenyl cpds. having retinoid-like activity. CA 2138000; EP 0661259; JP 1995242591; US 5648385 .
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) 27269 7-amino-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone C12H15NO 详情 详情
(II) 27793 5,5-Dimethyl-8-oxo-5,6,7,8-tetrahydronaphthalen-2-yldiazonium tetrafluoroborate C12H13BF4N2O 详情 详情
(III) 27794 7-hydroxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone C12H14O2 详情 详情
(IV) 27795 5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthalenyl trifluoromethanesulfonate C13H13F3O4S 详情 详情
(V) 27796 methyl 5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylate C14H16O3 详情 详情
(VI) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(VII) 27797 methyl 8-hydroxy-5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylate C20H22O3 详情 详情
(VIII) 27798 methyl 5,5-dimethyl-8-phenyl-5,6-dihydro-2-naphthalenecarboxylate C20H20O2 详情 详情
(IX) 27799 5,5-dimethyl-8-phenyl-5,6-dihydro-2-naphthalenecarboxylic acid C19H18O2 详情 详情
(X) 27800 5,5-dimethyl-8-phenyl-5,6-dihydro-2-naphthalenecarbonyl chloride C19H17ClO 详情 详情
(XI) 20537 methyl 4-aminobenzoate 619-45-4 C8H9NO2 详情 详情
(XII) 27801 methyl 4-[[(5,5-dimethyl-8-phenyl-5,6-dihydro-2-naphthalenyl)carbonyl]amino]benzoate C27H25NO3 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IV)

Reductive condensation of 3-amino-2-chloropyridine (I) with 5-isopropylbenzofuran-7-carbaldehyde (II) in the presence of sodium triacetoxyborohydride provided secondary amine (III). Displacement of the chlorine atom of (III) with phenylmagnesium bromide (IV) using NiCl2 produced phenylpyridine (V), which was hydrogenated with hydrogen over PtO2 in acetic acid to give racemic piperidine (VI). Resolution of (VI) with (R)-(-)-mandelic acid yielded the (2S,3S)-isomer, which was finally isolated as the dihydrochloride salt.

参考文献 中间体
合成目标
【1】 Tanaoue, Y.; Beppu, K.; Okayama, A.; Sakamoto, O. (Hisamitsu Pharmaceutical Co., Ltd.); Piperidine derivs.. EP 0826684; US 5886011; WO 9630367 .
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) 26501 5-isopropyl-2,3-dihydro-1-benzofuran-7-carbaldehyde C12H14O2 详情 详情
(III) 26502 2-chloro-N-[(5-isopropyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-3-pyridinamine C17H19ClN2O 详情 详情
(IV) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(V) 26503 N-[(5-isopropyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-2-phenyl-3-pyridinamine C23H24N2O 详情 详情
(VI) 26504 N-[(5-isopropyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-2-phenyl-3-piperidinamine C23H30N2O 详情 详情

合成路线11

该中间体在本合成路线中的序号：(A)

The esterification of 4,4-bis(4-hydroxyphenyl)pentanoic acid (I) with diazomethane in ethyl ether/methanol gives the methyl ester (II), which is treated with phenylmagnesium bromide in THF to yield 4,4-bis(4-hydroxyphenyl)-1,1-diphenyl-1-pentanol (III). The reduction of (III) with H2 over Pd/C in methanol affords 4,4-bis(4-hydroxyphenyl)-1,1-diphenylpentane (IV), which is finally condensed with azepane (V) and formaldehyde in hot ethanol/water.

参考文献 中间体
合成目标
【1】 Yuen, P.-w.; Malone, T.C.; Tarczy-Hornoch, K.; Rock, D.M.; Szoke, B.; Stoehr, S.; Schelkun, R.M.; Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N-type calcium channel blockers. Bioorg Med Chem Lett 1999, 9, 16, 2447.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(I) 22391 4,4-bis(4-hydroxyphenyl)pentanoic acid 126-00-1 C17H18O4 详情 详情
(II) 22392 methyl 4,4-bis(4-hydroxyphenyl)pentanoate C18H20O4 详情 详情
(III) 31669 4-[4-hydroxy-1-(4-hydroxyphenyl)-1-methyl-4,4-diphenylbutyl]phenol C29H28O3 详情 详情
(IV) 31670 4-[1-(4-hydroxyphenyl)-1-methyl-4,4-diphenylbutyl]phenol C29H28O2 详情 详情
(V) 18672 azepane 111-49-9 C6H13N 详情 详情

合成路线12

该中间体在本合成路线中的序号：

Ethyl levulinate (I) was reacted with one equivalent of methylmagnesium bromide to produce 5,5-dimethyldihydrofuran-2-one (II). Friedel-Crafts condensation of (III) with benzene in the presence of AlCl3 afforded 4,4-dimethyl-1-tetralone (III) which, after nitration and reduction furnished the aminotetralone (V). This was converted to iodide (VI) upon diazotization, followed by treatment with KI. Methyl 4-vinylbenzoate (VIII) was obtained by alkylation of the corresponding carboxylic acid (VII) with MeI in the presence of DBU. Coupling of this olefin (VIII) with iodide (VI) was carried out using palladium diacetate and tetrabutylammonium chloride at 70 C to yield the diaryl ethylene derivative (IX). Subsequent addition of phenylmagnesium bromide to (IX) produced the tertiary alcohol (X). Finally, dehydration of (X) using p-toluenesulfonic acid, followed by basic hydrolysis, provided the title compound.

参考文献 中间体
合成目标
【1】 Starrett, J.E. Jr.; Yu, K.-L.; Mansuri, M.M.; Tortolani, D.R. (Bristol-Myers Squibb Co.); Substd. (5,6)-dihydronaphthalenyl cpds. having retinoid-like activity. CA 2138000; EP 0661259; JP 1995242591; US 5648385 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(I) 27267 ethyl 4-oxopentanoate 539-88-8 C7H12O3 详情 详情
(II) 23768 5,5-dimethyldihydro-2(3H)-furanone C6H10O2 详情 详情
(III) 23791 4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone 2979-69-3 C12H14O 详情 详情
(IV) 27268 4,4-dimethyl-7-nitro-3,4-dihydro-1(2H)-naphthalenone C12H13NO3 详情 详情
(V) 27269 7-amino-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone C12H15NO 详情 详情
(VI) 27270 7-iodo-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone C12H13IO 详情 详情
(VII) 27271 4-vinylbenzoic acid 1075-49-6 C9H8O2 详情 详情
(VIII) 27272 methyl 4-vinylbenzoate C10H10O2 详情 详情
(IX) 27273 methyl 4-[(E)-2-(5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl]benzoate C22H22O3 详情 详情
(X) 27274 methyl 4-[(E)-2-(8-hydroxy-5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl]benzoate C28H28O3 详情 详情

合成路线13

该中间体在本合成路线中的序号：

Dipolar cycloaddition of hydroxypyridinium betaine (I) with R-(+)-p-tolyl vinyl sulfoxide (II) furnished the chiral tropenone (III). Subsequent copper-catalyzed conjugate addition of phenyl-magnesium bromide on the beta-face of (III) provided the trans diaryltropanone (IV). Then, ketone reduction of (IV) with LiAlH4 gave alcohol (V), which was condensed with phenyl thionochloroformate (VI) to afford thiocarbonate (VII). This was reduced with tributyltin hydride and azobis(isobutyronitrile) to produce tropane (VIII). The sulfoxide group of (VIII) was further reduced to sulfide (IX) with PCl3 in DMF. Finally, Raney Nickel-promoted desulfurization in boiling EtOH yielded the title compound.

参考文献 中间体
合成目标
【1】 Kozikowski, A.P.; Araldi, G.L.; Prakash, K.R.; Zhang, M.; Johnson, K.M.; Synthesis and biological properties of new 2beta-alkyl- and 2beta-aryl-3-(substituted phenyl)tropane derivatives: Stereochemical effect of C-3 on affinity and selectivity for neuronal dopamine and serotonin transporters. J Med Chem 1998, 41, 25, 4973.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(I) 25800 1-methyl-4-(4-methylphenyl)-3-pyridiniumolate C13H13NO 详情 详情
(II) 25801 (4-methylphenyl)(oxo)vinyl-lambda(4)-sulfane; 4-methylphenyl vinyl sulfoxide C9H10OS 详情 详情
(III) 25802 (1S,5S,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-8-azabicyclo[3.2.1]oct-3-en-2-one C22H23NO2S 详情 详情
(IV) 25803 (1S,3R,4R,5S,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-4-phenyl-8-azabicyclo[3.2.1]octan-2-one C28H29NO2S 详情 详情
(V) 25804 (1S,3R,4R,5S,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-4-phenyl-8-azabicyclo[3.2.1]octan-2-ol C28H31NO2S 详情 详情
(VI) 25805 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate 1005-56-7 C7H5ClOS 详情 详情
(VII) 25806 O-[(1S,3R,4R,5S,6R)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-4-phenyl-8-azabicyclo[3.2.1]oct-2-yl] O-phenyl carbonothioate C35H35NO3S2 详情 详情
(VIII) 25807 (1R,3R,4R,5S,6R)-8-methyl-3-(4-methylphenyl)-4-phenyl-8-azabicyclo[3.2.1]oct-6-yl 4-methylphenyl sulfoxide; (1S,2R,3R,5R,7R)-8-methyl-3-(4-methylphenyl)-7-[(4-methylphenyl)sulfinyl]-2-phenyl-8-azabicyclo[3.2.1]octane C28H31NOS 详情 详情
(IX) 25808 (1R,3R,4R,5S,6R)-8-methyl-3-(4-methylphenyl)-4-phenyl-8-azabicyclo[3.2.1]oct-6-yl 4-methylphenyl sulfide; (1S,2R,3R,5R,7R)-8-methyl-3-(4-methylphenyl)-7-[(4-methylphenyl)sulfanyl]-2-phenyl-8-azabicyclo[3.2.1]octane C28H31NS 详情 详情

合成路线14

该中间体在本合成路线中的序号：

Addition of phenylmagnesium bromide to 6-methoxy-1-indanone (I) gave carbinol (II), which was dehydrated to phenylindene (III) upon treatment with p-toluenesulfonic acid in refluxing toluene. Oxidative cleavage of (III) with Jones reagent in the presence of OsO4 provided 2-benzoyl-4-methoxyphenylacetic acid (IV), which was further reduced to the 2-benzyl analogue (V) by hydrogenation over Pd/C. After conversion of (V) to the corresponding acid chloride (VI) using oxalyl chloride and a trace of DMF, Friedel-Crafts cyclization with AlCl3 furnished the dibenzocycloheptenone (VII). Addition of the lithium enolate of ethyl acetate to the carbonyl group of (VII) in the presence of tetramethylethylenediamine at -78 C generated the hydroxyester (VIII). Then, hydrogenolysis of the benzylic alcohol of (VIII) in the presence of Pd/C gave (IX). Subsequent cleavage of the methyl ether of (IX) by means of ethane thiol and AlCl3 provided the corresponding racemic phenol. Isolation of the required (S)-enantiomer (X) was carried out by chiral HPLC.

参考文献 中间体
合成目标
【1】 Drake, F.H. (SmithKline Beecham plc); Method for stimulating bone formation. EP 0946180; WO 9815278 .
【2】 Miller, W.H.; Samanen, J.M.; Heerding, D.; Bondinell, W.E. (SmithKline Beecham Corp.); Vitronectin receptor antagonists. EP 1025090; WO 9915508 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17491 ethyl acetate 141-78-6 C4H8O2 详情 详情
17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(I) 34514 6-methoxy-1-indanone 13623-25-1 C10H10O2 详情 详情
(II) 34515 6-methoxy-1-phenyl-1-indanol C16H16O2 详情 详情
(III) 34516 5-methoxy-3-phenyl-1H-indene; methyl 3-phenyl-1H-inden-5-yl ether C16H14O 详情 详情
(IV) 34517 2-(2-benzoyl-4-methoxyphenyl)acetic acid C16H14O4 详情 详情
(V) 34518 2-(2-benzyl-4-methoxyphenyl)acetic acid C16H16O3 详情 详情
(VI) 34519 2-(2-benzyl-4-methoxyphenyl)acetyl chloride C16H15ClO2 详情 详情
(VII) 34520 3-methoxy-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one C16H14O2 详情 详情
(VIII) 34521 ethyl 2-(10-hydroxy-3-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)acetate C20H22O4 详情 详情
(IX) 34522 ethyl 2-(3-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)acetate C20H22O3 详情 详情
(X) 34523 ethyl 2-[(10S)-3-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]acetate C19H20O3 详情 详情

合成路线15

该中间体在本合成路线中的序号：

The Grignard reaction of vinyloxirane (I) with phenylmagnesium bromide and CuCN in THF gives 4-phenyl-2-buten-1-ol (II), which is submitted to a Sharpless epoxidation with t-BuOOH and Ti(Oi-Pr)4 in dichloromethane in the presence of (-)-diethyl tartrate [(-)-DET] yielding the chiral epoxide (III). The reaction of (III) with Ti(Oi-Pr)2(N3)2 in refluxing benzene affords the 3(S)-azido-4-phenylbutane-1,2(S)-diol (IV), which is epoxidized with 2-acetoxy-2-methylpropionyl chloride (A) and NaOMe in THF to give the chiral azidoepoxide (V). The reaction of (V) with isobutylamine (VI) in hot isopropanol yields the secondary amine (VII), which is condensed with 4-methoxyphenylsulfonyl chloride (VIII) in pyridine affording the sulfonamide (IX). The reduction of the azido group of (IX) with H2 over Pd/C in methanol provides (X) with a primary amino group that is finally condensed with the succinimidinyl carbonate (XI) by means of triethylamine in acetonitrile.

参考文献 中间体
合成目标
【1】 Ghosh, A.K.; Kincaid, J.F.; Cho, W.; Walters, D.E.; Krishnan, K.; Hussain, K.A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.; Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 6, 687.
【2】 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 .
【3】 Ghosh, A.K.; et al.; Potent HIV protease inhibitors: The development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands. J Med Chem 1993, 36, 16, 2300.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(A) 32808 2-chloro-1,1-dimethyl-2-oxoethyl acetate 40635-66-3 C6H9ClO3 详情 详情
(I) 32805 2-vinyloxirane 930-22-3 C4H6O 详情 详情
(II) 32806 (E)-4-phenyl-2-buten-1-ol C10H12O 详情 详情
(III) 32807 [(2R,3S)-3-benzyloxiranyl]methanol 116949-62-3 C10H12O2 详情 详情
(IV) 14544 (2S,3S)-3-azido-4-phenyl-1,2-butanediol C10H13N3O2 详情 详情
(V) 14547 (1S)-1-[(2S)oxiranyl]-2-phenylethyl azide; (2S)-2-[(1S)-1-azido-2-phenylethyl]oxirane C10H11N3O 详情 详情
(VI) 13306 2-Methyl-1-propanamine; Isobutylamine 78-81-9 C4H11N 详情 详情
(VII) 32809 (2R,3S)-3-azido-1-(isobutylamino)-4-phenyl-2-butanol C14H22N4O 详情 详情
(VIII) 15719 4-methoxybenzenesulfonyl chloride 98-68-0 C7H7ClO3S 详情 详情
(IX) 32810 N-[(2R,3S)-3-azido-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide C21H28N4O4S 详情 详情
(X) 32811 N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide C21H30N2O4S 详情 详情
(XI) 32812 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione C11H13NO7 详情 详情

合成路线16

该中间体在本合成路线中的序号：(XXIII)

Condensation of desoxybenzoin (I) with 2-(tetra-hydropyranyloxy)ethyl bromide (XIV) by means of aqueous NaOH and TEBAC as before gives 1,2-diphenyl-4-(tetrahydropyranyloxy)-1-butanone (XV), which by a Grignard condensation with 4-methoxyphenylmagnesium bromide (XVI) -prepared from 4-bromoanisole (XVII) and Mg in THF- provides the triphenylbutanol derivative (XVIII). Cleavage of the THP-protecting group of compound (XVIII) with H2SO4 in ethanol/water at room temperature affords the butane-1,4-diol derivative (XIX), which is cyclized by means of H2SO4 in hot ethanol/ water to yield 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran (XX). Finally, this compound is treated with 48% HBr in refluxing AcOH to give 4-(4-hydroxyphenyl)-3,4-diphenyl-3-buten-1-ol (X) as a (Z):(E)-isomeric mixture, from which the desired (Z)-isomer is separated by chemical work up.

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castaner, J.; Bayes, M.; Ospemifene. Drugs Fut 2004, 29, 1, 38.
【2】 Toivola, R.J.; Karjalainen, A.J.; Kurkela, K.O.A.; Soderwall, M.-L.; Kangas, L.V.M.; Blanco, G.L.; Sundquist, H.K. (Orion Corporation); Tri-phenyl alkene derivs. and their oestrogenic, anti-oestrogenic and progestanic uses. US 4996225; US 5491173 .
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) 41003 1,2-diphenyl-1-ethanone; Deoxybenzoin-2-phenylacetophenone; Dexybenzoin 451-40-1 C14H12O 详情 详情
(X) 52025 4-[(Z)-4-hydroxy-1,2-diphenyl-1-butenyl]phenol C22H20O2 详情 详情
(XIV) 26934 2-bromoethyl tetrahydro-2H-pyran-2-yl ether C7H13BrO2 详情 详情
(XV) 52021 1,2-diphenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanone C21H24O3 详情 详情
(XVI) 37674 Bromo(4-methoxyphenyl)magnesium; 4-Methoxyphenylmagnesium bromide 352-13-6 C7H7BrMgO 详情 详情
(XVII) 63436 1-bromo-4-methoxybenzene; 4-bromophenyl methyl ether C7H7BrO 详情 详情
(XVIII) 52022 1-(4-methoxyphenyl)-1,2-diphenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanol C28H32O4 详情 详情
(XIX) 52023 1-(4-methoxyphenyl)-1,2-diphenyl-1,4-butanediol C23H24O3 详情 详情
(XX) 52024 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran; 4-(2,3-diphenyltetrahydro-2-furanyl)phenyl methyl ether C23H22O2 详情 详情
(XXI) 30343 1-(4-methoxyphenyl)-2-phenyl-1-ethanone C15H14O2 详情 详情
(XXII) 63437 1-(4-methoxyphenyl)-2-phenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanone C22H26O4 详情 详情
(XXIII) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

The Grignard condensation of 4,4'-difluorobenzophenone (I) with phenylmagnesium bromide (II) in refluxing tert-butyl methyl ether gives the corresponding carbinol (III), which is treated with acetyl chloride in dichloromethane to yield the methyl chloride (IV). Condensation of compound (IV) with copper cyanide by heating at 140 °C, followed by treatment with hot toluene affords 2,2-bis(4-fluorophenyl)-2-phenylacetonitrile (V), which is finally partially hydrolyzed with H2SO4 in refluxing glacial acetic acid.

参考文献 中间体
合成目标
【1】 Chilman-Blair, K.; Castaner, J.; Leeson, P.A.; ICA-17043. Drugs Fut 2003, 28, 9, 854.
【2】 Rigdon, G.C.; McNaughton-Smith, G.A.; Stocker, J.W. (ICAgen, Inc.); Gardos channel antagonists. EP 1158971; US 6288122; WO 0050026 .
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) 45633 bis(4-fluorophenyl)methanone; 4,4'-Difluorobenzophenone 345-92-6 C13H8F2O 详情 详情
(II) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(III) 62899 bis(4-fluorophenyl)(phenyl)methanol C19H14F2O 详情 详情
(IV) 62900 1-[chloro(4-fluorophenyl)phenylmethyl]-4-fluorobenzene C19H13ClF2 详情 详情
(V) 62901 2,2-bis(4-fluorophenyl)-2-phenylacetonitrile C20H13F2N 详情 详情

合成路线18

该中间体在本合成路线中的序号：(VII)

Conjugate addition of methyl acrylate (II) to 3-methoxybenzaldehyde (I) under reversion of reactivity conditions in the presence of KCN produced the keto ester (III). The Wolff-Kishner reduction of the keto group caused simultaneous ester hydrolysis, yielding acid (IV), which was further cyclized to the tetralone (V) employing hot polyphosphoric acid. Mannich reaction of ketone (V) with N-benzyl methylamine and paraformaldehyde furnished amino ketone (VI). To this was added phenylmagnesium bromide (VII), yielding amino alcohol (VIII), which was subsequently dehydrated to (IX) by means of trifluoroacetic acid. Catalytic hydrogenation of the olefin double bond of (IX) with simultaneous N-benzyl group hydrogenolysis gave the secondary amine (X). This was then alkylated with ethyl bromoacetate, producing the substituted glycine ester (XI), which was finally hydrolyzed by means of LiOH.

参考文献 中间体
合成目标
【1】 Jaap, D.R.; Gilfillan, R.; Gibson, S.G.; Thorn, S.N. (Akzo Nobel N.V.); Aminomethylcarboxylic acid derivs.. EP 1100769; WO 0007978 .
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) 20589 3-methoxybenzaldehyde; m-Anisaldehyde 591-31-1 C8H8O2 详情 详情
(II) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(III) 51352 methyl 4-(3-methoxyphenyl)-4-oxobutanoate C12H14O4 详情 详情
(IV) 51353 4-(3-methoxyphenyl)butyric acid C11H14O3 详情 详情
(V) 17594 6-methoxy-3,4-dihydro-1(2H)-naphthalenone; 6-Methoxytetralone; 6-Methoxy-1-tetralone; 3,4-dihydro-6-methoxy-1(2H)-naphthalenone 1078-19-9 C11H12O2 详情 详情
(VI) 51354 2-[[benzyl(methyl)amino]methyl]-6-methoxy-3,4-dihydro-1(2H)-naphthalenone C20H23NO2 详情 详情
(VII) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(VIII) 51355 2-[[benzyl(methyl)amino]methyl]-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-1-naphthalenol C26H29NO2 详情 详情
(IX) 51356 N-benzyl(6-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)-N-methylmethanamine; N-benzyl-N-[(6-methoxy-1-phenyl-3,4-dihydro-2-naphthalenyl)methyl]-N-methylamine C26H27NO 详情 详情
(X) 51357 [(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]-N-methylmethanamine; N-[[(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]-N-methylamine C19H23NO 详情 详情
(XI) 51358 ethyl 2-[[[(1S,2R)-6-methoxy-1-phenyl-1,2,3,4-tetrahydro-2-naphthalenyl]methyl](methyl)amino]acetate C23H29NO3 详情 详情

合成路线19

该中间体在本合成路线中的序号：(XII)

The reaction of butadiene monooxide (XI) with phenylmagnesium bromide (XII) and CuCN in THF gives trans-4-phenyl-2-buten-1-ol (XIII), which is enantioselectively epoxidated with Ti(O-iPr)4, diethyl D-tartrate and tBu-OOH to yield the (2R,3R)-epoxide (XIV). The reaction of (XIV) with Ti(O-iPr)4 and N3-SiMe3 in refluxing benzene affords the chiral azidodiol (XV), which is epoxidated by means of 2-acetoxyisobutyryl chloride (AcBCl) and NaOMe in THF to provide the chiral azidoepoxide (XVI) (1). Opening of the epoxide ring of (XVI) with isobutylamine (XVII) in hot isopropanol gives the secondary amine (XVIII), which is acylated with 4-aminophenylsulfonyl chloride (XIX) and pyridine in dichloromethane to yield the corresponding sulfonamide (XX). The reduction of the azido group of (XX) with H2 over Pd/C in THF/methanol/HOAc affords the expected primary amine (XXI), which is finally condensed with the already reported intermediate (X) in dichloromethane to provide the target carbamate.

参考文献 中间体
合成目标
【1】 Ghosh, A.K.; Kincaid, J.F.; Cho, W.; Walters, D.E.; Krishnan, K.; Hussain, K.A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.; Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 6, 687.
【2】 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 32812 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione C11H13NO7 详情 详情
(XI) 32805 2-vinyloxirane 930-22-3 C4H6O 详情 详情
(XII) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(XIII) 32806 (E)-4-phenyl-2-buten-1-ol C10H12O 详情 详情
(XIV) 53549 [(2R,3R)-3-benzyloxiranyl]methanol n/a C10H12O2 详情 详情
(XV) 14544 (2S,3S)-3-azido-4-phenyl-1,2-butanediol C10H13N3O2 详情 详情
(XVI) 14547 (1S)-1-[(2S)oxiranyl]-2-phenylethyl azide; (2S)-2-[(1S)-1-azido-2-phenylethyl]oxirane C10H11N3O 详情 详情
(XVII) 13306 2-Methyl-1-propanamine; Isobutylamine 78-81-9 C4H11N 详情 详情
(XVIII) 32809 (2R,3S)-3-azido-1-(isobutylamino)-4-phenyl-2-butanol C14H22N4O 详情 详情
(XIX) 53550 4-aminobenzenesulfonyl chloride 98-62-4 C6H6ClNO2S 详情 详情
(XX) 53551 4-amino-N-[(2R,3S)-3-azido-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide n/a C20H27N5O3S 详情 详情
(XXI) 45533 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide C20H29N3O3S 详情 详情

合成路线20

该中间体在本合成路线中的序号：(VII)

Addition of phenylmagnesium bromide (VII) to cyanuric chloride (VI) provided 2,4-dichloro-6-phenyltriazine (VIII). This was subsequently condensed with aniline (V) to afford the aminotriazine (IX). Finally, displacement of the remaining chlorine of (IX) with 2-(3-pyridyl)ethylamine (X) furnished the target diaminotriazine derivative.

参考文献 中间体
合成目标
【1】 Murali Dhar, T.G.; Pitts, W.J.; Guo, J.; et al.; Rapid synthesis of novel inosine monophosphate dehydrogenase (IMPDH) inhibitors. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 214.
【2】 Liu, C.; Leftheris, K.; Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H. (Bristol-Myers Squibb Co.); Cpds. derived from an amine nucleus that are inhibitors of IMPDH enzyme. EP 1126843; US 6399773; WO 0025780 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 39658 　 C10H10N2O2 详情 详情
(VI) 23813 2,4,6-Trichloro-s-triazine; Cyanuric chloride; Trichlorocyanidine; Tricyanogen chloride; 2,4,6-Trichloro-1,3,5-triazine 108-77-0 C3Cl3N3 详情 详情
(VII) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(VIII) 53552 4,6-Dichloro-2-phenyltriazine 1700-02-3 C9H5Cl2N3 详情 详情
(IX) 53553 N-(4-chloro-6-phenyl-1,3,5-triazin-2-yl)-N-[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]amine; 4-chloro-N-[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]-6-phenyl-1,3,5-triazin-2-amine n/a C19H14ClN5O2 详情 详情
(X) 53554 2-(3-Pyridyl)ethylamine; 3-(2-Aminoethyl)pyridine 20173-24-4 C7H10N2 详情 详情

合成路线21

该中间体在本合成路线中的序号：(II)

Elesclomol can be prepared as follows. The precursor thiobenzoic acid N-methylhydrazide (III) can be obtained by either treatment of carboxymethyl dithiobenzoate (I) with methylhydrazine under alkaline conditions or by reaction of phenylmagnesium bromide (II) with carbon disulfide, followed by treatment with methylhydrazine. Then, dimerization of thiohydrazide (III) with malonic acid in the presence of DCC/HOBt, or with malonyl dichloride or malonic acid diphenyl ester, provides the target malonohydrazide derivative (1, 2). Conversion of elesclomol to different salts (including sodium, potassium, lithium, calcium, magnesium, ethanolamine and choline salts) has also been reported (3). Scheme 1.

参考文献 中间体
合成目标
【1】 Chen, S., Sun, L., Ono, M., Koya, K., Xia, Z.-Q. (SBR Pharmaceuticals Corp.). Synthesis of taxol enhancers. US 2003069225, US 6825235, WO 03006429.
【2】 Koya, K., Sun, L., Ono, M., Tatsuta, N., Wu, Y., Chen, S. (Synta Pharmaceuticals Corp.). Taxol enhancer compounds. EP 1406869, EP 1731148, JP 2004534848, US 2003119914, WO 03006430.
【3】 Kostik, E., Vaghefi, F., Liang, G. et al. (Synta Pharmaceuticals Corp.). EP 1781604, WO 2006009940.
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) 65625 2-(Benzothioylthio)acetic acid; S-(Thiobenzoyl)thioglycolic acid; Dithiobenzoic acid carboxymethyl ester 942-91-6 C9H8O2S2 详情 详情
(II) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(III) 65626 N-Methyl-N-thiobenzoylhydrazine; Thiobenzoic acid 1-methylhydrazide 21048-05-5 C8H10N2S 详情 详情
Extended Information