|
【结 构 式】 
|
【分子编号】18964 【品名】4-bromobenzenesulfonyl chloride 【CA登记号】98-58-8 |
【 分 子 式 】C6H4BrClO2S 【 分 子 量 】255.51926 【元素组成】C 28.2% H 1.58% Br 31.27% Cl 13.87% O 12.52% S 12.55% |
合成路线1
该中间体在本合成路线中的序号：(A)The sulfonation of methyl N-trifluoroacetyldaunosaminide (I) with mesyl chloride or with 4-bromophenylsulfonyl chloride in pyridine gives the corresponding 4-O-mesyl derivative (II) or 4-O-(4-bromophenylsulfonyl) derivative (IIa); both compounds by reaction with NaI in refluxing butanone yield the 4-iodo compound (III). The hydrogenation of (III) with H2 over Pd/C in methanol, followed by hydrolysis with hot acetic acid yields 4-deoxy-N-trifluoroacetyldaunosaminide (IV), which is esterified with p-nitrobenzoyl chloride in pyridine affording the corresponding p-nitrobenzoyl ester (V). The reaction of (V) with dry HCl in methylene chloride gives 1,4-dideoxy-N-trifluoroacetyldanosaminide (VI), which is condensed with daunomycinone (VII) by means of silver trifluoromethylsulfonate in methylene chloride and hydrolyzed with NaOH to afford 4'-deoxy-daunomycine (VIII). The bromination of (VIII) with Br2 in methanol-dioxane gives 4'-deoxy-14-bromodaunomycine (IX), which is finally hydrolyzed with aqueous sodium formate.
| 【1】 Penco, S.; Arcamone, F.; Di Marco, A.; Novel antitumor glycosides of the anthracycline series and process for their preparation. FR 2325659 . |
| 【2】 Arcamone, F.; Penco, S.; Redaelli, S.; Hanessian, S.; Synthesis and antitumor activity of 4'-deoxydaunorubicin and 4'-deoxyadriamycin. J Med Chem 1976, 19, 1424-25. |
| 【3】 Robinson, C.P.; Prous, J.; Castaner, J.; ESORUBICIN HYDROCHLORIDE < Rec INNM; USAN >. Drugs Fut 1990, 15, 10, 986. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (A) | 18964 | 4-bromobenzenesulfonyl chloride | 98-58-8 | C6H4BrClO2S | 详情 | 详情 |
| (IIa) | 31180 | (2S,3S,4S,6R)-6-methoxy-2-methyl-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl 4-bromobenzenesulfonate | C15H17BrF3NO6S | 详情 | 详情 | |
| (I) | 30693 | 2,2,2-trifluoro-N-[(2S,3S,4S,6R)-3-hydroxy-6-methoxy-2-methyltetrahydro-2H-pyran-4-yl]acetamide | C9H14F3NO4 | 详情 | 详情 | |
| (II) | 31179 | (2S,3S,4S,6R)-6-methoxy-2-methyl-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl methanesulfonate | C10H16F3NO6S | 详情 | 详情 | |
| (III) | 31181 | 2,2,2-trifluoro-N-[(2S,3R,4S,6R)-3-iodo-6-methoxy-2-methyltetrahydro-2H-pyran-4-yl]acetamide | C9H13F3INO3 | 详情 | 详情 | |
| (IV) | 31182 | 2,2,2-trifluoro-N-[(2R,4R,6S)-2-hydroxy-6-methyltetrahydro-2H-pyran-4-yl]acetamide | C8H12F3NO3 | 详情 | 详情 | |
| (V) | 31183 | (2S,4R,6S)-6-methyl-4-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-2-yl 4-nitrobenzoate | C15H15F3N2O6 | 详情 | 详情 | |
| (VI) | 31184 | N-[(2S,4R,6S)-2-chloro-6-methyltetrahydro-2H-pyran-4-yl]-2,2,2-trifluoroacetamide | C8H11ClF3NO2 | 详情 | 详情 | |
| (VII) | 16223 | (8S,10S)-8-acetyl-6,8,10,11-tetrahydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | 21794-55-8 | C21H18O8 | 详情 | 详情 |
| (VIII) | 31185 | (8S,10S)-8-acetyl-10-[[(2S,4R,6S)-4-amino-6-methyltetrahydro-2H-pyran-2-yl]oxy]-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C27H29NO9 | 详情 | 详情 | |
| (IX) | 31186 | (8S,10S)-10-[[(2S,4R,6S)-4-amino-6-methyltetrahydro-2H-pyran-2-yl]oxy]-8-(2-bromoacetyl)-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C27H28BrNO9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)4-Bromobenzenesulfonyl chloride (I) was condensed with aminoisoxazole (II) in pyridine to afford sulfonamide (III). Subsequent Suzuki coupling of (III) to 4-tolylboronic acid (IV) under palladium catalysis provided biphenylsulfonamide (V), which was finally brominated with N-bromosuccinimide in cold CH2Cl2 to furnish the target bromoisoxazole.
| 【1】 Chan, M.F.; Kois, A.; Verner, E.J.; Raju, B.G.; Castillo, R.S.; Wu, C.; Okun, I.; Stavros, F.D.; Balaji, V.N.; The discovery and structure-activity relationships of nonpeptide, low molecular weight antagonists selective for the endothelin ETB receptor. Bioorg Med Chem 1998, 6, 12, 2301. |
| 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) | 18964 | 4-bromobenzenesulfonyl chloride | 98-58-8 | C6H4BrClO2S | 详情 | 详情 |
| (II) | 17834 | 3-methyl-5-isoxazolylamine; 3-methyl-5-isoxazolamine; 5-Amino-3-methylisoxazole | 14678-02-5 | C4H6N2O | 详情 | 详情 |
| (III) | 22375 | 4-bromo-N-(3-methyl-5-isoxazolyl)benzenesulfonamide | C10H9BrN2O3S | 详情 | 详情 | |
| (IV) | 15540 | 4-methylphenylboronic acid; p-Tolylboronic acid | 5720-05-8 | C7H9BO2 | 详情 | 详情 |
| (V) | 22377 | 4'-methyl-N-(3-methyl-5-isoxazolyl)[1,1'-biphenyl]-4-sulfonamide | C17H16N2O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：The bromosulfonate (XXI) has been obtained as follows: (S)-Lactic acid methyl ester (XXII) has been protected as its benzyloxymethyl ether (XXIII) according to Tetrahedron Lett 1980, 21: 1035. The reduction of (XXIII) with DIBAL yields the corresponding aldehyde (XXIV), which by a Grignard reaction with ethylmagnesium bromide in THF and chromatographic separation of the diastereoisomers (SiO2, hexane/ethyl acetate) affords 2(S)-(benzyloxymethoxy)-3(R)-pentanol (XXV). Finally, this compound is sulfonated to (XXI) with 4-bromobenzenesulfonyl chloride. Finally, compound (XX) is condensed with 2(S)-(benzyloxymethoxy)-3(R)-pentanol 4-bromobenzenesulfonate ester (XXI) by means of cesium carbonate in DMF, and deprotected with 6N HCl.
| 【1】 Fromtling, R.A.; Castañer, J.; SCH-56592. Drugs Fut 1996, 21, 2, 160. |
| 【2】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0736030; JP 1997500658; US 5661151; US 5703079; WO 9517407 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18964 | 4-bromobenzenesulfonyl chloride | 98-58-8 | C6H4BrClO2S | 详情 | 详情 | |
| (XX) | 16351 | 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C32H32F2N8O3 | 详情 | 详情 | |
| (XXI) | 17074 | (1R,2S)-1-ethyl-2-[(heptyloxy)methoxy]propyl 4-bromobenzenesulfonate | C19H31BrO5S | 详情 | 详情 | |
| (XXII) | 17075 | propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate | 27871-49-4 | C4H8O3 | 详情 | 详情 |
| (XXIII) | 17076 | methyl (2S)-2-[(heptyloxy)methoxy]propanoate | C12H24O4 | 详情 | 详情 | |
| (XXIV) | 17077 | (2S)-2-[(heptyloxy)methoxy]propanal | C11H22O3 | 详情 | 详情 | |
| (XXV) | 17078 | (2S,3R)-2-[(heptyloxy)methoxy]-3-pentanol | C13H28O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)1) 4-(Benzyloxy)phenol (I) was protected as the silyl ether (II) by treatment with tert-butyldimethylsilyl chloride (TBDMS-Cl) in the presence of imidazole in DMF. Then, the benzyl group of (II) was removed by hydrogenolysis on Pd(OH)2/C to give 4-(tert-butyldimethylsilyloxy)phenol (III). This phenol was treated with NaH in DMF, and the resulting sodium phenoxide was alkylated with (S)-glycidyl 3-nitrobenzenesulfonate (IV) to provide epoxide (V) (1,2). Subsequent reaction of (V) with 4-aminophenethyl amine (VI) in refluxing MeOH gave the chiral phenoxypropanolamine (VII). Selective protection of the resultant secondary aliphatic amine with one equivalent of di-tert-butyl dicarbonate in THF afforded carbamate (VIII). Then, acylation of the aniline N atom with 4-bromobenzenesulfonyl chloride (IX) in the presence of pyridine gave sulfonamide (X). Finally, removal of both silyl ether and tert-butyl carbamate protecting groups using methanolic HCl provided the desired product.
| 【1】 Weber, A.E.; Mathvink, R.J.; Perkins, L.; Hutchins, J.E.; Candelore, M.R.; Tota, L.; Strader, C.D.; Wyvratt, M.J.; Fisher, M.H.; Potent, selective benzenesulfonamide agonists of the human beta3 adrenergic receptor. Bioorg Med Chem Lett 1998, 8, 9, 1101. |
| 【2】 Fisher, M.H.; Mathvink, R.J.; Ok, H.O.; Parmee, E.R.; Weber, A.E. (Merck & Co., Inc.); Substd. phenyl sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. CA 2114712; EP 0611003; JP 1995010827; US 5451677; WO 9418161 . |
| 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) | 18956 | 4-(Benzyloxy)phenol; 4-Benzyloxyphenol | 103-16-2 | C13H12O2 | 详情 | 详情 |
| (II) | 18957 | [4-(benzyloxy)phenoxy](tert-butyl)dimethylsilane; benzyl 4-[[tert-butyl(dimethyl)silyl]oxy]phenyl ether | C19H26O2Si | 详情 | 详情 | |
| (III) | 18958 | 4-[[tert-butyl(dimethyl)silyl]oxy]phenol | C12H20O2Si | 详情 | 详情 | |
| (IV) | 16259 | (2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate | 115314-14-2 | C9H9NO6S | 详情 | 详情 |
| (V) | 18960 | tert-butyl(dimethyl)[4-[(2S)oxiranylmethoxy]phenoxy]silane; tert-butyl(dimethyl)silyl 4-[(2S)oxiranylmethoxy]phenyl ether | C15H24O3Si | 详情 | 详情 | |
| (VI) | 18961 | 4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine | 13472-00-9 | C8H12N2 | 详情 | 详情 |
| (VII) | 18962 | (2S)-1-[(4-aminophenethyl)amino]-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-propanol | C23H36N2O3Si | 详情 | 详情 | |
| (VIII) | 18963 | tert-butyl 4-aminophenethyl[(2S)-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-hydroxypropyl]carbamate | C28H44N2O5Si | 详情 | 详情 | |
| (IX) | 18964 | 4-bromobenzenesulfonyl chloride | 98-58-8 | C6H4BrClO2S | 详情 | 详情 |
| (X) | 18965 | tert-butyl 4-[[(4-bromophenyl)sulfonyl]amino]phenethyl[(2S)-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-hydroxypropyl]carbamate | C34H47BrN2O7SSi | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)2) Alternatively, amine (VI) was selectively protected as the carbamate (XI) with di-tert-butyl dicarbonate. This compound was condensed with sulfonyl chloride (IX) and pyridine to afford sulfonamide (XII), and the Boc protecting group was then removed with trifluoroacetic acid to give the primary amine (XIII). Subsequent addition of (XIII) to epoxide (V) provided the phenoxypropanolamine (XIV), and the silyl group was finally eliminated with methanolic HCl.
| 【1】 Weber, A.E.; Mathvink, R.J.; Perkins, L.; Hutchins, J.E.; Candelore, M.R.; Tota, L.; Strader, C.D.; Wyvratt, M.J.; Fisher, M.H.; Potent, selective benzenesulfonamide agonists of the human beta3 adrenergic receptor. Bioorg Med Chem Lett 1998, 8, 9, 1101. |
| 【2】 Fisher, M.H.; Mathvink, R.J.; Ok, H.O.; Parmee, E.R.; Weber, A.E. (Merck & Co., Inc.); Substd. phenyl sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. CA 2114712; EP 0611003; JP 1995010827; US 5451677; WO 9418161 . |
| 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) | 18960 | tert-butyl(dimethyl)[4-[(2S)oxiranylmethoxy]phenoxy]silane; tert-butyl(dimethyl)silyl 4-[(2S)oxiranylmethoxy]phenyl ether | C15H24O3Si | 详情 | 详情 | |
| (VI) | 18961 | 4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine | 13472-00-9 | C8H12N2 | 详情 | 详情 |
| (IX) | 18964 | 4-bromobenzenesulfonyl chloride | 98-58-8 | C6H4BrClO2S | 详情 | 详情 |
| (XI) | 18966 | tert-butyl 4-aminophenethylcarbamate | C13H20N2O2 | 详情 | 详情 | |
| (XII) | 18967 | tert-butyl 4-[[(4-bromophenyl)sulfonyl]amino]phenethylcarbamate | C19H23BrN2O4S | 详情 | 详情 | |
| (XIII) | 18968 | N-[4-(2-aminoethyl)phenyl]-4-bromobenzenesulfonamide | C14H15BrN2O2S | 详情 | 详情 | |
| (XIV) | 18969 | 4-bromo-N-[4-(2-[[(2S)-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-hydroxypropyl]amino]ethyl)phenyl]benzenesulfonamide | C29H39BrN2O5SSi | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：Methyl (S)-lactate (XXVI) was protected as the benzyloxymethyl ether (XXVII) and subsequently reduced to aldehyde (XXVIII) with DIBAL in toluene at -78 C. Addition of ethylmagnesium bromide to this aldehyde (XXVIII) produced a diastereomeric mixture of carbinols. The required (2S,3R) isomer (XXIX) was isolated by column chromatography and then converted to brosylate ester (XXX) by reaction with 4-bromobenzenesulfonyl chloride. Nucleophilic displacement of the brosylate group of (XXX) by triazolone (XXV) produced the N-alkylated triazolone (XXXI). Then, acid cleavage of the benzyloxymethyl protec-ting group of (XXXI) provided alcohol (XXXII).
| 【1】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0773941; WO 9638443 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18964 | 4-bromobenzenesulfonyl chloride | 98-58-8 | C6H4BrClO2S | 详情 | 详情 | |
| (XXV) | 16351 | 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C32H32F2N8O3 | 详情 | 详情 | |
| (XXVI) | 17075 | propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate | 27871-49-4 | C4H8O3 | 详情 | 详情 |
| (XXVII) | 34845 | methyl (2S)-2-[(benzyloxy)methoxy]propanoate | C12H16O4 | 详情 | 详情 | |
| (XXVIII) | 34846 | (2S)-2-[(benzyloxy)methoxy]propanal | C11H14O3 | 详情 | 详情 | |
| (XXIX) | 34847 | (2S,3R)-2-[(benzyloxy)methoxy]-3-pentanol | C13H20O3 | 详情 | 详情 | |
| (XXX) | 34848 | (1R,2S)-2-[(benzyloxy)methoxy]-1-ethylpropyl 4-bromobenzenesulfonate | C19H23BrO5S | 详情 | 详情 | |
| (XXXI) | 34849 | 2-[(1S,2S)-2-[(benzyloxy)methoxy]-1-ethylpropyl]-4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C45H50F2N8O5 | 详情 | 详情 | |
| (XXXII) | 34850 | 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C37H42F2N8O4 | 详情 | 详情 |