|
【结 构 式】 
|
【分子编号】13365 【品名】Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene 【CA登记号】108-86-1 |
【 分 子 式 】C6H5Br 【 分 子 量 】157.0097 【元素组成】C 45.9% H 3.21% Br 50.89% |
合成路线1
该中间体在本合成路线中的序号：(I)3-Phenoxypyridine can be prepared by two different ways: 1) By reaction of 3-hydroxypyridine (I) with bromobenzene (II) by means of KOH and copper bronze at 150 C. 2) By reaction of 3-iodopyridine (III) with phenol (IV) by means of KOH and copper bronze at 150 C. The monosulfate salt is prepared by treating 3-phenoxypyridine with H2SO4.
| 【1】 Renshaw, R.R.; Conn, R.C.; Quaternary deivation of pyridyl ethers. Onium Compound. XVI. J Am Chem Soc 1937, 59, 297-301. |
| 【2】 Butler, D.E. (Pfizer Inc.); 3-Phenoxypyridine monosulfate and a method for its production. BE 0861649; DE 2755016; ES 464922; FR 2392009; GB 1559918; JP 53077068; US 4128555 . |
| 【3】 Owen, R.T.; Castaner, J.; Serradell, M.N.; CI-844. Drugs Fut 1985, 10, 4, 279. |
合成路线2
该中间体在本合成路线中的序号：(VI)The reductive cleavage of 4-phenylazo-3-methyl-5-methylaminopyrazole (I) with H2 over RaNi in ethanol gives 4-amino-3-methyl-5-methylaminopyrazole (II), which is acylated with ethoxycarbonylacetyl chloride (III) in toluene yielding 4-(ethoxycarbonylacetylamino)-3-methyl-5-methylaminopyrazole (IV). The cyclization of (IV) by means of sodium ethoxide in ethanol affords 4,8-dihydro-3,8-dimethylpyrazolo[3,4b][1,4]diazepine-5,7(1H,6H) dione (V), which is finally phenylated by a treatment with powdered Cu and potassium acetate in refluxing bromobenzene
| 【1】 Rackur, G.; Hoffmann, I. (Aventis SA); 4-Aryl-5,6,7,8-tetrahydropyrazolo[3,4-b]-[1,5]diazepine-1H,4H-5,7-diones and medicaments containing same. DD 152936; DE 2932835; EP 0024038; EP 0050376; JP 5603977; US 4302468 . |
| 【2】 Castaner, J.; Prous, J.; Razobazam. Drugs Fut 1986, 11, 6, 465. |
| 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) | 24717 | N,3-dimethyl-4-[(E)-2-phenyldiazenyl]-1H-pyrazol-5-amine | C11H13N5 | 详情 | 详情 | |
| (II) | 24718 | N-(4-amino-3-methyl-1H-pyrazol-5-yl)-N-methylamine | C5H10N4 | 详情 | 详情 | |
| (III) | 13188 | ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride | 36239-09-5 | C5H7ClO3 | 详情 | 详情 |
| (IV) | 24720 | ethyl 3-[[3-methyl-5-(methylamino)-1H-pyrazol-4-yl]amino]-3-oxopropanoate | C10H16N4O3 | 详情 | 详情 | |
| (V) | 24721 | 3,8-dimethyl-4,8-dihydropyrazolo[3,4-b][1,4]diazepine-5,7(1H,6H)-dione | C8H10N4O2 | 详情 | 详情 | |
| (VI) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)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.
| 【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4
该中间体在本合成路线中的序号：(I)The reaction of bromobenzene (I) with 14CO2 by means of Mg in ether gives the corresponding benzoic acid (II), which is treated with SOCl2 and DMAP to yield the benzoyl chloride (III). The homologation of (III) with diazomethane in ether affords the phenacyl chloride (IV), which is enantioselectively reduced with borane and a chiral borolidine catalyst in THF to give (R)-2-chloro-1-phenylethanol (V). The cyclization of (V) by means of NaOH in ethyl ether yields the oxirane (VI), which by reaction with ammonia is converted into the (R)-2-amino-1-phenylethanol (VII). The condensation of (VII) with 4'-chlorobiphenyl-4-carboxylic acid (VIII) by means of CDI in DMF provides the amide (IX), which is cyclized to the oxazoline (X) by means of methanesulfonic anhydride and TEA in THF. Finally, this compound is condensed with imidazole (XI) by heating at 125 C.
| 【1】 Moenius, T.; et al.; C-14 labelling of NVPVID400 - a specific vitamin D-3-hydroxylase inhibitor. J Label Compd Radiopharm 1999, 42, 11, 1053. |
| 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) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (II) | 10202 | Benzoic acid | 65-85-0 | C7H6O2 | 详情 | 详情 |
| (III) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (IV) | 38669 | 2-chloro-1-phenyl-1-ethanone | 532-27-4 | C8H7ClO | 详情 | 详情 |
| (V) | 38670 | (1R)-2-chloro-1-phenyl-1-ethanol | 1674-30-2 | C8H9ClO | 详情 | 详情 |
| (VI) | 38671 | (2R)-2-phenyloxirane | C8H8O | 详情 | 详情 | |
| (VII) | 10173 | (1R)-2-Amino-1-phenyl-1-ethanol | 2549-14-6 | C8H11NO | 详情 | 详情 |
| (VIII) | 38672 | 4'-chloro[1,1'-biphenyl]-4-carboxylic acid | C13H9ClO2 | 详情 | 详情 | |
| (IX) | 38673 | 4'-chloro-N-[(2R)-2-hydroxy-2-phenylethyl][1,1'-biphenyl]-4-carboxamide | C21H18ClNO2 | 详情 | 详情 | |
| (X) | 38674 | (5S)-2-(4'-chloro[1,1'-biphenyl]-4-yl)-5-phenyl-4,5-dihydro-1,3-oxazole | C21H16ClNO | 详情 | 详情 | |
| (XI) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The Friedel Crafts condensation of fumaryl chloride (I) with bromobenzene (II) gives 1,2-bis(4-bromobenzoyl)ethylene (III), which is reduced with Zn and Ac-OH to yield 1,4-bis(4-bromophenyl)butane-1,4-dione (IV). The cyclization of (IV) in refluxing Ac2O affords 2,5-bis(4-bromophenyl)furan (V), which is treated with CNCu in refluxing quinoline to provide 2,5-bis(4-cyanophenyl)furan (VI). The reaction of (VI) with HCl in ethanol gives the bis imidate (VII), which is finally treated with O-methylhydroxylamine to yield the target bis O-methylamidooxime.
| 【3】 Tidwell, R.R.; Hall, J.E.; Kumar, A.; Dykstra, C.C.; Boykin, D.W.; Wilson, W.D.; Blagburn, B.L. (Auburn University; Georgia State University; University of North Carolina); Furan derivs. for inhibiting Pneumocystis carinii pneumonia, Giardia lamblia and Cryptosporidium parvum. WO 9615126 . |
| 【1】 Boykin, D.W.; et al.; Anti-pneumocystis activity of bis-amidoximes and bis-O-alkylamidoximes prodrugs. Bioorg Med Chem Lett 1996, 6, 24, 3017. |
| 【2】 Boykin, D.W.; et al.; 2,5-Bis[4-(N-alkylamidino)phenyl]furans as anti-Pneumocystis carinii agents. J Med Chem 1998, 41, 1, 124. |
| 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) | 57909 | Fumaryl chloride | 627-63-4 | C4H2Cl2O2 | 详情 | 详情 |
| (II) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (III) | 57910 | (E)-1,4-bis(4-bromophenyl)-2-butene-1,4-dione | C16H10Br2O2 | 详情 | 详情 | |
| (IV) | 35811 | 1,4-bis(4-bromophenyl)-1,4-butanedione | C16H12Br2O2 | 详情 | 详情 | |
| (V) | 35812 | 2,5-bis(4-bromophenyl)furan | C16H10Br2O | 详情 | 详情 | |
| (VI) | 35814 | 4-[5-(4-cyanophenyl)-2-furyl]benzonitrile | C18H10N2O | 详情 | 详情 | |
| (VII) | 35815 | ethyl 4-(5-[4-[ethoxy(imino)methyl]phenyl]-2-furyl)benzenecarboximidoate | C22H22N2O3 | 详情 | 详情 | |
| (VIII) | 15455 | (aminooxy)methane; O-methylhydroxylamine | 67-62-9 | CH5NO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(X)The monosilylation of 2-butyl-2-ethylpropane-1,3-diol (I) with TBDMS-Cl and NaH in THF gives silyl ether (II), which is oxidized with NaIO4 and RuCl3 in CCl4/acetonitrile/water yielding silylated hexanoic acid (III).Elimination of the silyl group of (III) with tetrabutylammonium fluoride (TBAF) affords the hydroxyacid (IV), which is treated with refluxing 48% HBr to give the 2-(bromomethyl)-2-ethylhexanoic acid (V). The condensation of (V) with 2-amino-methoxythiophenol (VI) by means of triethylamine or pyrrolidine in DMF provides intermediate (VII), which is cyclized by means of p-toluenesulfonic acid in refluxing tetradecane to give the 1,5-benzothiazepinone (VIII). The reaction of (VIII) with N-bromosuccinimide (NBS) in dichloromethane yields the 7-bromo derivative (IX), which is treated with bromobenzene (X), K2CO3 and CuBr to afford the 5-phenylbenzothiazepinone (XI). The reduction of the carbonyl group of (XI) with LiAlH4 in ethyl ether gives the benzothiazepine (XII), which is then oxidized with OsO4 in THF/ tert-butanol yielding the S,S-dioxide (XIII). Finally, this compound is demethylated with AlBr3 and ethanethiol in dichloromethane.
| 【1】 Brieaddy, L.E.; Handlon, A.L.; Hodgson, G.L. Jr. (Glaxo Wellcome plc); Hypolipidemic benzothiazepines. EP 0792268; JP 1999500102; US 5998400; WO 9616051 . |
| 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) | 25871 | 2-butyl-2-ethyl-1,3-propanediol | 115-84-4 | C9H20O2 | 详情 | 详情 |
| (II) | 25872 | 2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-ethyl-1-hexanol | C15H34O2Si | 详情 | 详情 | |
| (III) | 25873 | 2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-ethylhexanoic acid | C15H32O3Si | 详情 | 详情 | |
| (IV) | 25874 | 2-ethyl-2-(hydroxymethyl)hexanoic acid | C9H18O3 | 详情 | 详情 | |
| (V) | 25875 | 2-(bromomethyl)-2-ethylhexanoic acid | C9H17BrO2 | 详情 | 详情 | |
| (VI) | 25876 | 2-amino-5-methoxyphenylhydrosulfide; 5-Methoxy-2-aminothiophenol;2-Mercapto-4-methoxyaniline;2-amino-5-methoxybenzenethiol；2-Amino-5-methoxy-1-benzenethiol | 6274-29-9 | C7H9NOS | 详情 | 详情 |
| (VII) | 25877 | 2-[[(2-amino-5-methoxyphenyl)sulfanyl]methyl]-2-ethylhexanoic acid | C16H25NO3S | 详情 | 详情 | |
| (VIII) | 25878 | 3-butyl-3-ethyl-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H23NO2S | 详情 | 详情 | |
| (IX) | 25879 | 7-bromo-3-butyl-3-ethyl-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H22BrNO2S | 详情 | 详情 | |
| (X) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (XI) | 25880 | 7-bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C22H26BrNO2S | 详情 | 详情 | |
| (XII) | 25881 | 7-bromo-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl methyl ether; 7-bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine | C22H28BrNOS | 详情 | 详情 | |
| (XIII) | 25882 | 7-bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1H-1lambda(6),5-benzothiazepine-1,1-dione | C22H28BrNO3S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Condensation of alpha-hydroxyhippuric acid (II) with bromobenzene (I) in methanesulfonic acid afforded the phenylglycine derivative (III). Further incorporation of the phosphonic acid was effected by palladium-catalyzed displacement of the bromide by diethyl phosphite to give (IV). Finally, acid hydrolysis of the benzamide and phosphite ester groups furnished the title compound.
| 【1】 Bigge, C.F.; et al.; Exploration of phenyl-spaced 2-amino-(5-9)-phosphonoalkanoic acids as competitive N-methyl-D-aspartic acid antagonists. J Med Chem 1989, 32, 7, 1580-90. |
| 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) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (II) | 20606 | 2-(benzoylamino)-2-hydroxyacetic acid | 16555-77-4 | C9H9NO4 | 详情 | 详情 |
| (III) | 35750 | 2-(benzoylamino)-2-(4-bromophenyl)acetic acid | C15H12BrNO3 | 详情 | 详情 | |
| (IV) | 35751 | 2-(benzoylamino)-2-[4-(diethoxyphosphoryl)phenyl]acetic acid | C19H22NO6P | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The Friedel Crafts condensation of fumaryl chloride (I) with bromobenzene (II) gives 1,2-bis(4-bromobenzoyl)ethylene (III), which is reduced with Zn and Ac-OH to yield 1,4-bis(4-bromophenyl)butane-1,4-dione (IV). The cyclization of (IV) in refluxing Ac2O affords 2,5-bis(4-bromophenyl)furan (V) which is treated with CNCu in refluxing quinoline to provide 2,5-bis(4-cyanophenyl)furan (VI). The reaction of (VI) with HCl in ethanol gives the bis imidate (VII), which is finally treated with ammonia in ethanol to yield the target bis benzamidine.
| 【1】 Dann, O.; et al.; Trypanocidal diamidines with three isolated ring systems. Liebigs Ann Chem 1975, 1, 160. |
| 【2】 Das, B.P.; Boykin, D.W.; Synthesis and antiprotozoal activity of 2,5-bis (4-guanylphenyl) furans. J Med Chem 1977, 20, 4, 531-536. |
| 【3】 Boykin, D.W.; et al.; 2,5-Bis[4-(N-alkylamidino)phenyl]furans as anti-Pneumocystis carinii agents. J Med Chem 1998, 41, 1, 124. |
| 【4】 Boykin, D.W.; et al.; Anti-pneumocystis activity of bis-amidoximes and bis-O-alkylamidoximes prodrugs. Bioorg Med Chem Lett 1996, 6, 24, 3017. |
| 【5】 Niigata, K.; Murakami, M.; Kagami, S.; Fujikura, S.; Kojima, A.; Tachikawa, S.; Nozaki, J.; Takahashi, K. (Yamanouchi Pharmaceutical Co., Ltd.); Novel indene derivs. or their salts. JP 1977111580 . |
| 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) | 57909 | Fumaryl chloride | 627-63-4 | C4H2Cl2O2 | 详情 | 详情 |
| (II) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (III) | 57910 | (E)-1,4-bis(4-bromophenyl)-2-butene-1,4-dione | C16H10Br2O2 | 详情 | 详情 | |
| (IV) | 35811 | 1,4-bis(4-bromophenyl)-1,4-butanedione | C16H12Br2O2 | 详情 | 详情 | |
| (V) | 35812 | 2,5-bis(4-bromophenyl)furan | C16H10Br2O | 详情 | 详情 | |
| (VI) | 56856 | Copper (I) cyanide; Cuprous cyanide | 544-92-3 | CCuN | 详情 | 详情 |
| (VII) | 35814 | 4-[5-(4-cyanophenyl)-2-furyl]benzonitrile | C18H10N2O | 详情 | 详情 | |
| (VIII) | 35815 | ethyl 4-(5-[4-[ethoxy(imino)methyl]phenyl]-2-furyl)benzenecarboximidoate | C22H22N2O3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)Protection of isonipecotic acid (I) as the trifluoroacetamide (II), followed by treatment with thionyl chloride, afforded acid chloride (III). Friedel-Crafts reaction of acid chloride (III) with bromobenzene (IV) gave ketone (V), which was further protected as the ethylene ketal (VI). The trifluoroacetamide group of (VI) was then hydrolyzed to amine (VII) using K2CO3 in MeOH. Condensation of amine (VII) with N-Boc-4-piperidone (VIII) in the presence of titanium isopropoxide, and subsequent addition of diethylaluminum cyanide to the intermediate iminium salt, provided amino nitrile (IX). Treatment of (IX) with methylmagnesium bromide afforded the methyl derivative (X). Acid hydrolysis of the ketal and Boc groups of (X), followed by reprotection with Boc2O, furnished ketone (XI). Oxime formation in (XI) with O-ethyl hydroxylamine produced a 1.5:1 mixture of (E)- and (Z)-isomers, which were separated by silica gel chromatography. Previous equilibration of the mixture under acidic conditions favored the desired (Z)-isomer (XII). The Boc protecting group of (XII) was then removed by treatment with trifluoroacetic acid. The resultant piperidine (XIII) was finally coupled with 2,4-dimethylnicotinic acid N-oxide (XIV) using EDC and HOBt to furnish the title compound.
| 【1】 Palani, A.; et al.; Discovery of 4-[(Z)-(4-bromophenyl)-(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine N-oxide (SCH 351125). An orally bioavailable human CCR5 antagonist for the treatment of HIV infection. J Med Chem 2001, 44, 21, 3339. |
| 【2】 Palani, A.; et al.; Synthesis, SAR, and biological evaluation of oximino-piperidino-pieperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity. J Med Chem 2002, 45, 14, 3143. |
| 【3】 McCombie, S.W.; Clader, J.W.; Baroudy, B.M.; McKittrick, B.A.; Josien, H.B.; Tagat, J.R.; Vice, S.F.; Steensma, R.; Laughlin, M.A.; Miller, M.W.; Neustadt, B.R.; Palani, A. (Schering Corp.); Piperidine derivs. useful as CCR5 antagonists. EP 1175402; WO 0066559 . |
| 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) | 17402 | 4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid | 498-94-2 | C6H11NO2 | 详情 | 详情 |
| (II) | 51847 | 1-(2,2,2-trifluoroacetyl)-4-piperidinecarboxylic acid | C8H10F3NO3 | 详情 | 详情 | |
| (III) | 51848 | 1-(2,2,2-trifluoroacetyl)-4-piperidinecarbonyl chloride | C8H9ClF3NO2 | 详情 | 详情 | |
| (IV) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (V) | 51849 | 1-[4-(4-bromobenzoyl)-1-piperidinyl]-2,2,2-trifluoro-1-ethanone | C14H13BrF3NO2 | 详情 | 详情 | |
| (VI) | 51850 | 1-[4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]-1-piperidinyl]-2,2,2-trifluoro-1-ethanone | C16H17BrF3NO3 | 详情 | 详情 | |
| (VII) | 51851 | 4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]piperidine | C14H18BrNO2 | 详情 | 详情 | |
| (VIII) | 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 |
| (IX) | 51852 | C25H34BrN3O4 | 详情 | 详情 | ||
| (X) | 51853 | C25H37BrN2O4 | 详情 | 详情 | ||
| (XI) | 51854 | C23H33BrN2O3 | 详情 | 详情 | ||
| (XII) | 51855 | C25H38BrN3O3 | 详情 | 详情 | ||
| (XIII) | 51856 | C20H30BrN3O | 详情 | 详情 | ||
| (XIV) | 51857 | 3-carboxy-2,4-dimethyl-1-pyridiniumolate | C8H9NO3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XVIII)Selective mono-protection of 2,2-dibutyl-1,3-propanediol (X) using one equivalent of TBDMSCl and NaH in THF yields the TBDMS ether (XI), which is then oxidized by means of NaIO4 in the presence of a catalytic amount of RuCl3 in CCl4/acetonitrile/H2O, followed by desilylation with TBAF in THF to give the hydroxy acid (XII). Bromination of alcohol (XII) with concentrated HBr at reflux provides the bromo acid (XIII), which by condensation with 2-amino-5-methoxythiophenol (XIV) [prepared by hydrolysis of 2-amino-6-methoxybenzothiazole (XV) with KOH at reflux] by means of Et3N in DMF and subsequent cyclization using p-TsOH in refluxing tetradecane produces the 1,5-benzothiazepin-4-one derivative (XVI). Bromination of compound (XVI) with NBS in CH2Cl2 results in the 7-bromobenzothiazepinone (XVII), which is arylated with bromobenzene (XVIII) in the presence of CuBr and K2CO3 at reflux to afford the 5-phenylbenzothiazepinone derivative (XIX). Reduction of lactam (XIX) using AlH3 (generated in situ from LiAlH4 and H2SO4) in Et2O/THF followed by oxidation of the thioether moiety with NMMO and catalytic OsO4 in THF yields the sulfone (XX) , which is finally submitted to simultaneous bromide substitution and O-demethylation using MeSNa in the presence of NaBH4 in DMF at 120 °C .
| 【1】 Starke, I., Blomberg, D., Dahlstrom, M. (AstraZeneca AB; AstraZeneca plc). Chemical compounds. EP 1345918, JP 2004196815, JP 2004516285, US 2004067933, US 7192945, WO 2002050051. |
| 【2】 Brieaddy, L.E., Handlon, A.L., Hodgson, G.L. Jr. (GlaxoSmithKline plc). Hypolipidemic benzothiazepines., EP 0792268, JP 1999500102, US 5998400, WO 1996016051. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 25876 | 2-amino-5-methoxyphenylhydrosulfide; 5-Methoxy-2-aminothiophenol;2-Mercapto-4-methoxyaniline;2-amino-5-methoxybenzenethiol；2-Amino-5-methoxy-1-benzenethiol | 6274-29-9 | C7H9NOS | 详情 | 详情 |
| (I) | 68515 | 3,3-dibutyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide | C24H33NO3S2 | 详情 | 详情 | |
| (X) | 59709 | 2,2-dibutyl-1,3-propanediol;2,2-DIBUTYLPROPANE-1,3-DIOL;2-N-BUTYL-2-(HYDROXYMETHYL)-1-HEXANOL | 24765-57-9 | C11H24O2 | 详情 | 详情 |
| (XI) | 68522 | 2-butyl-2-(((tert-butyldimethylsilyl)oxy)methyl)hexan-1-ol | C17H38O2Si | 详情 | 详情 | |
| (XII) | 68523 | 2-butyl-2-(hydroxymethyl)hexanoic acid | C11H22O3 | 详情 | 详情 | |
| (XIII) | 59712 | 2-(bromomethyl)-2-butylhexanoic acid | C11H21BrO2 | 详情 | 详情 | |
| (XV) | 68524 | 2-amino-6-methoxybenzothiazole;6-Methoxy-2-aminobenzothiazole;6-Methoxy-2-benzothiazolamine | 1747-60-0 | C8H8N2OS | 详情 | 详情 |
| (XVI) | 68525 | 3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one | C18H27NO2S | 详情 | 详情 | |
| (XVII) | 68526 | 7-bromo-3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one | C18H26BrNO2S | 详情 | 详情 | |
| (XVIII) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (XIX) | 68527 | 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one | C24H30BrNO2S | 详情 | 详情 | |
| (XX) | 68528 | 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide | C24H30BrNO4S | 详情 | 详情 |