|
【结 构 式】 
|
【分子编号】13467 【品名】Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride 【CA登记号】124-63-0 |
【 分 子 式 】CH3ClO2S 【 分 子 量 】114.55232 【元素组成】C 10.49% H 2.64% Cl 30.95% O 27.93% S 27.99% |
合成路线1
该中间体在本合成路线中的序号：(B)C-10213-Go has been synthesized from 1-methyl-2-mercaptoimidazole (I). When (I) is methylated with methyl iodide it gives the corresponding thiomethyl derivative (II). Nitration of (II) yields the nitro derivative (III). Oxidation of (III) with monoperphthalic acid gives the sulfone (IV). Condensation of (IV) with 1-methanesulfonyl-2-imidazolidinone (VI) in the presence of sodium hydride affords C-10213-Go.
| 【1】 Arya, V.P.; Satranidazole. Drugs Fut 1983, 8, 9, 797. |
| 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) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (A) | 34077 | 2-carboperoxybenzoic acid | C8H6O5 | 详情 | 详情 | |
| (I) | 18783 | 1-methyl-1H-imidazol-2-ylhydrosulfide; 1-methyl-1H-imidazole-2-thiol | 60-56-0 | C4H6N2S | 详情 | 详情 |
| (II) | 36225 | 1-methyl-2-(methylsulfanyl)-1H-imidazole; methyl 1-methyl-1H-imidazol-2-yl sulfide | C5H8N2S | 详情 | 详情 | |
| (III) | 36226 | methyl 1-methyl-5-nitro-1H-imidazol-2-yl sulfide; 1-methyl-2-(methylsulfanyl)-5-nitro-1H-imidazole | C5H7N3O2S | 详情 | 详情 | |
| (IV) | 36227 | 1-methyl-2-(methylsulfonyl)-5-nitro-1H-imidazole; methyl 1-methyl-5-nitro-1H-imidazol-2-yl sulfone | C5H7N3O4S | 详情 | 详情 | |
| (V) | 36228 | 2-imidazolidinone | 120-93-4 | C3H6N2O | 详情 | 详情 |
| (VI) | 36229 | 1-(methylsulfonyl)-2-imidazolidinone | 41730-79-4 | C4H8N2O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(B)The cyclization of 2,4-dichlorophenacyl bromide (I) with glycerol (II) gives cis-2-(2,4-dichlorophenyl)-2-bromomethyl-4-hydroxymethyl-1,3-dioxolane (III), which is then benzoylated with benzoyl chloride (A) yielding cis-2-(2,4-dichlorophenyl)-2-bromomethyl-4-benzoyloxymethyl-1,3-dioxolane (IV). The condensation of (IV) with 1H-imidazole (V) affords cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-4-benzoyloxymethyl-1,3-dioxolane (VI), which is then debenzoylated in basic medium giving cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-4-hydroxymethyl-1,3-dioxolane (VII). The reaction of (VII) with methanesulfonyl chloride (B) yields cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methanesulfonate (VIII). Finally, this compound is condensed with 1-acetyl-4-(4-hydroxyphenyl)piperazine (IX) by means of NaH in benzene - DMSO. Compound (IX) is obtained by reaction of 4-(1-piperazinyl)phenol dihydrobromide (X) with acetic anhydride by means of K2CO3 in refluxing acetic acid.
| 【1】 Heeres, J.; et al.; DE 2804096 . |
| 【2】 Blancafort, P.; Sweetman, A.J.; Castaner, J.; Serradell, M.N.; Ketoconazole. Drugs Fut 1979, 4, 7, 496. |
| 【3】 Backx, L.J.J.; Mostmans, J.H.; Heeres, J. (Janssen Pharmaceutica NV); 1-(1,3-Dioxolan-2-ylmethyl)-1H-imidazoles. US 4335125 . |
| 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) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (B) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (I) | 36408 | 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone | C8H5BrCl2O | 详情 | 详情 | |
| (II) | 13289 | Glycerine; Glycerin; Glycerol | 56-81-5 | C3H8O3 | 详情 | 详情 |
| (III) | 39602 | [(2S,4R)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methanol | C11H11BrCl2O3 | 详情 | 详情 | |
| (IV) | 30485 | [(2S,4S)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate; cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate | C18H15BrCl2O4 | 详情 | 详情 | |
| (V) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (VI) | 39603 | [(2S,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl benzoate | C21H18Cl2N2O4 | 详情 | 详情 | |
| (VII) | 39604 | [(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methanol | 170210-50-1 | C14H14Cl2N2O3 | 详情 | 详情 |
| (VIII) | 39605 | [(2S,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl methanesulfonate; cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl methanesulfonate | C15H16Cl2N2O5S | 详情 | 详情 | |
| (IX) | 29119 | 1-Acetyl-4-(4-hydoxyphenyl)piperazine; 1-[4-(4-hydroxyphenyl)-1-piperazinyl]-1-ethanone; N-Acetyl-4-(4-hydoxyphenyl)piperazine | 67914-60-7 | C12H16N2O2 | 详情 | 详情 |
| (X) | 39606 | 4-(1-piperazinyl)phenol; 1-(4-Hydroxyphenyl)piperazine | 56621-48-8 | C10H14N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The condensation of 2-fluoronitrobenzene (I) with cyclohexanol (II) by means of NaH gives 2-(cyclohexyloxy)nitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 2-(cyclohexyloxy)aniline (IV). The acylation of (IV) with methanesulfonyl chloride (V) in pyridine affords N-(2-cyclohexyloxy phenyl)methanesulfonamide (VI), which is finally nitrated with concentrated HNO3 in hot acetic acid.
| 【1】 Yoshikawa, K.; Ohuchi, Y.; Sekiuchi, K.; Saito, S.; Hatayama, K.; Sota, K. (Taisho Pharmaceutical Co., Ltd.); Sulfoanilide cpds. EP 0317332; JP 1990000268 . |
| 【2】 Yoshikawa, K.; Ohuchi, H.; Saito, H.; Nakajima, Y.; Hatayama, K.; Soda, H. (Taisho Pharmaceutical Co., Ltd.); Antiinflammatories, analgesics and antipyretics. JP 1990300122 . |
| 【3】 Prous, J.; Castaner, J.; Mealy, N.; NS-398. Drugs Fut 1993, 18, 7, 603. |
| 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) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 11306 | Cyclohexanol | 108-93-0 | C6H12O | 详情 | 详情 |
| (III) | 13465 | Cyclohexyl 2-nitrophenyl ether; 1-(Cyclohexyloxy)-2-nitrobenzene | C12H15NO3 | 详情 | 详情 | |
| (IV) | 13466 | 2-(Cyclohexyloxy)aniline; 2-(Cyclohexyloxy)phenylamine | C12H17NO | 详情 | 详情 | |
| (V) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (VI) | 13468 | N-[2-(Cyclohexyloxy)phenyl]methanesulfonamide | C13H19NO3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The acylation of aniline (I) with methanesulfonyl chloride (II) in pyridine gives the corresponding sulfonamide (III), which is submitted to a Friedel-Crafts condensation with succinic anhydride (IV) and AlCl3 in hot carbon disulfide to afford 4-[4-(methanesulfonyl)phenyl]-4-oxobutyric acid (V). The amidation of (V) with N-ethylheptylamine (VI) yields the corresponding amide (VII), which is finally reduced with LiAlH4 in THF and treated with an ethanolic solution of fumaric acid in order to precipitate the corresponding salt.
| 【1】 Stolle, W.T.; Stelzer, L.S.; Hester, J.B.; Perricone, S.C.; Hsi, R.S.P.; Synthesis of radiolabeled racemic and enantiomeric antiarrhythmic agents. J Label Compd Radiopharm 1994, 34, 10, 929. |
| 【2】 Robinson, C.; Robinson, K.; Castaner, J.; Ibutilide Fumarate. Drugs Fut 1996, 21, 9, 894. |
| 【3】 Hester, J.B. Jr. (Pharmacia Corp.); N-(Aminoalkylphenyl)sulfonamides their preparation and therapeutic use. EP 0164865; JP 1985239458; US 5155268 . |
| 【4】 Hester, J.B.; Gibson, J.K.; Cimini, M.G.; Emmert, D.E.; Locker, P.K.; Perricone, S.C.; Skaletzky, L.L.; Sykes, J.K.; West, B.E.; N-[(omega-Amino-1-hydroxyalkyl)phenyl]methanesulfonamide derivatives with Class III antiarrhythmic activity. J Med Chem 1991, 34, 1, 308-15. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (III) | 13699 | N-Phenylmethanesulfonamide; N-Phenyl methanesulfonamide | 1197-22-4 | C7H9NO2S | 详情 | 详情 |
| (IV) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (V) | 14625 | 4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutyric acid | C11H13NO5S | 详情 | 详情 | |
| (VI) | 14626 | N-ethyl-1-heptanamine; N-ethyl-N-heptylamine | C9H21N | 详情 | 详情 | |
| (VII) | 14627 | N-ethyl-N-heptyl-4-[4-[(methylsulfonyl)amino]phenyl]-4-oxobutanamide | C20H32N2O4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：Amine (I) was alkylated with 4-nitrophenethyl bromide (II) in refluxing isopropanol to yield the tertiary amine (III). Hydrogenation of the nitro group of (III) employing Pd/C afforded aniline (IV). Subsequent condensation of (IV) with methanesulfonyl chloride in the presence of Et3N produced the corresponding sulfonamide. The title compound was finally isolated as the hydrochloride salt.
| 【1】 Berzsenyi, P.; Druga, A.; Pátfalusi, M.; Varga, I.; Rettegi, T.; Barlocco, D.; Moravcsik, I.; Mátyus, P.; Papp, G.; Varró, A.; Cignarella, G.; Simay, A. (Albert Szent-Györgyi Medical University ; Gyogyszerkutato Intezet Kft.); Novel antiarrhythmic cpds.. WO 9929655 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 | |
| (I) | 34749 | 1-(2,6-dimethylphenoxy)-N-methyl-2-propanamine; N-[2-(2,6-dimethylphenoxy)-1-methylethyl]-N-methylamine | C12H19NO | 详情 | 详情 | |
| (II) | 19191 | 1-(2-bromoethyl)-4-nitrobenzene | 5339-26-4 | C8H8BrNO2 | 详情 | 详情 |
| (III) | 34750 | 1-(2,6-dimethylphenoxy)-N-methyl-N-(4-nitrophenethyl)-2-propanamine; N-[2-(2,6-dimethylphenoxy)-1-methylethyl]-N-methyl-N-(4-nitrophenethyl)amine | C20H26N2O3 | 详情 | 详情 | |
| (IV) | 34751 | N-(4-aminophenethyl)-N-[2-(2,6-dimethylphenoxy)-1-methylethyl]-N-methylamine; 4-[2-[[2-(2,6-dimethylphenoxy)-1-methylethyl](methyl)amino]ethyl]aniline | C20H28N2O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)Compound can be prepared in two different ways: 1) By condensation of ampicilline (aminobenzylpenicilline) (I) with 1-chlorocarbonyl-2-oxo-3-mehylsulfonylimidazolidine (II) by means of NaOH in cool water or triethylamine in THF-water. 2) By condensation of 6-aminopenicillanic acid (III) with D-[(3-methylsulfonyl-2-oxoimidazolidin-1-yl)carbonylamino]phenylacetic acid (IV) by means of tetramethylchloroformamidinium chloride (A) and N-methylmorpholine (B) in methylene chloride - THF. The phenylacetic acid (IV) is obtained by condensation of D-phenylglycine (V) with 1-chlorocarbonyl-2-oxo-3-mehylsulfonylimidazolidine (II) by means of NaOH in dioxane - water. The acid chloride (II) is prepared by reaction of 2-imidazolidone (VI) with methanesulfonyl chloride (VII) in refluxing THF to give N-methylsulfonyl-2-imidazolidone (VIII), which is then condensed with phosgene by means of trimethylchlorosilane and triethylamine in dioxane.
| 【1】 Koenig, H.B.; et al.; Penicillin compounds their production and their medicinal use. DE 2152968; FR 2157909; GB 1392850; JP 48049788; JP 48049911 . |
| 【2】 Koenig, H.B.; et al.; Penicillins their production and their medicinal use. DE 2152967; FR 2157908; GB 1392849; JP 48049787; JP 48049910 . |
| 【3】 Schroeck, W.; et al.; Penicillanic acids their production and their medicinal use. DE 2318955; ES 425197; FR 2225151; GB 1465355; JP 49135990 . |
| 【4】 Playle, A.C.; Castañer, J.; Mezlocillin. Drugs Fut 1977, 2, 9, 600. |
| 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) | 28928 | 4-methylmorpholine | 109-02-4 | C5H11NO | 详情 | 详情 |
| (A) | 40169 | N-[chloro(dimethylamino)methylene]-N-methylmethanaminium chloride | C5H12Cl2N2 | 详情 | 详情 | |
| (I) | 31107 | (2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid | 69-53-4 | C16H19N3O4S | 详情 | 详情 |
| (II) | 40167 | 3-(methylsulfonyl)-2-oxo-1-imidazolidinecarbonyl chloride | 41762-76-9 | C5H7ClN2O4S | 详情 | 详情 |
| (III) | 32631 | (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid; (+)-6-Aminopenicillanic acid; 6-APA | 551-16-6 | C8H12N2O3S | 详情 | 详情 |
| (IV) | 40168 | (2R)-2-([[3-(methylsulfonyl)-2-oxo-1-imidazolidinyl]carbonyl]amino)-2-phenylethanoic acid | C13H15N3O6S | 详情 | 详情 | |
| (V) | 40170 | (2R)-2-amino-2-phenylethanoic acid | C8H9NO2 | 详情 | 详情 | |
| (VI) | 36228 | 2-imidazolidinone | 120-93-4 | C3H6N2O | 详情 | 详情 |
| (VII) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (VIII) | 36229 | 1-(methylsulfonyl)-2-imidazolidinone | 41730-79-4 | C4H8N2O3S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)The intermediate dimesylate (VI) can be obtained as follows: The condensation of 2,3-dihydro-1,4-benzodioxin-5-amine (I) with ethyl bromoacetate (II) by means of Hunig's base and NaI in refluxing toluene gives the tertiary amine (III), which is reduced by means of LiAlH4 in THF to yield the diethanolamine (IV). Finally, this compound is esterified by means of mesyl chloride (V) to provide the desired dimesylate intermediate (VI). Alternatively, the diethanolamine (IV) can be obtained by direct condensation of 2,3-dihydro-1,4-benzodioxin-5-amine (I) with 2-chloroethanol (VII) by means of Hunig's base.
| 【1】 Jirkovsky, I.; Zeldis, J.; Chan, A.W.-Y.; Fiegelson, G.B. (Wyeth); Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines. WO 0378396 . |
| 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) | 22000 | 2,3-dihydro-1,4-benzodioxin-5-amine; 2,3-dihydro-1,4-benzodioxin-5-ylamine; 5-Amino-1,4-benzodioxane | 16081-46-2 | C8H9NO2 | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 64784 | ethyl 2-[2,3-dihydro-1,4-benzodioxin-5-yl(2-ethoxy-2-oxoethyl)amino]acetate | C16H21NO6 | 详情 | 详情 | |
| (IV) | 64785 | 2-[2,3-dihydro-1,4-benzodioxin-5-yl(2-hydroxyethyl)amino]-1-ethanol | C12H17NO4 | 详情 | 详情 | |
| (V) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (VI) | 64786 | 2-(2,3-dihydro-1,4-benzodioxin-5-yl{2-[(methylsulfonyl)oxy]ethyl}amino)ethyl methanesulfonate | C14H21NO8S2 | 详情 | 详情 | |
| (VII) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XV)The boronate intermediate (XI) is prepared by hydrolysis of methyl 6-bromo-2-naphthoate (XII) with LiOH in H2O/THF to give 6-bromo-2-naphthoic acid (XIII), which by Curtius rearrangement with DPPA and Et3N in DMF at 100 °C yields 6-bromo-2-naphthylamine (XIv). Sulfonylation of amine (XIv) with mesyl chloride (Xv) in pyridine provides the sulfonamido naphthalene (XvI), which finally undergoes borylation with bis(pinacolato)diboron in the presence of KOAc and combiPhos-Pd6 catalyst in refluxing toluene .
| 【1】 Pratt, J.K., Betebenner, D., Flentge, C. et al. Aryl 1-uracil inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase: Uracil ring replacements. 244th ACS Natl Meet (August 19-23, Philadelphia) 2012, Abst MEDI 146. |
| 【2】 Wagner, R., Tufano, M.D., Stewart, K.D. et al. (Abbvie Bahamas Ltd.). Uracil or thymine derivative for treating hepatitis C. CN 101801935, CN 102746239, EP 2222646, JP 2010539186, US 2012213733, WO 2009039127. |
| 【3】 Flentge, C.A., Hutchinson, D.K., Betebenner, D.A. et al. (Abbott Laboratories). Anti-infective pyrimidines and uses thereof. CN 101842360, CN 102746240, EP 2203431, EP 2368882, EP 2639226, JP 2010539187, US 8188104, US 2012244119, US 8501238, WO 2009039134. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 67686 | N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide | C17H22BNO4S | 详情 | 详情 | |
| (XII) | 59539 | 6-Bromo-2-naphthoic acid methyl ester; Methyl 6-bromo-2-naphthoate | 33626-98-1 | C12H9BrO2 | 详情 | 详情 |
| (XIII) | 42564 | 6-Bromo-2-naphthoic acid；(6-Bromonaphthalen-2-yl)acetic acid;6-Bromo-2-naphthalenecarboxylic acid | 5773-80-8 | C11H7BrO2 | 详情 | 详情 |
| (XIV) | 55631 | 6-bromo-2-naphthalenamine; 6-bromo-2-naphthylamine | 7499-66-3 | C10H8BrN | 详情 | 详情 |
| (XV) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (XVI) | 67687 | N-(5-bromonaphthalen-1-yl)methanesulfonamide | C11H10BrNO2S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XXII)Chlorination of 2-chloro-5-nitrobenzenesulfonic acid (XIV) with SOCl2 in refluxing DMF gives the sulfonyl chloride (XV), which is converted to the corresponding sulfonamide (XVI) by treatment with NH4OH in toluene/THF. Amination of the chloro sulfonamide (XVI) with (NH4)2CO3 and NH4OH in the presence of CuSO4 at 118 °C leads to 2-amino-5-nitrobenzenesulfonamide (XVII). Alternatively, chlorination of 2-amino-5-nitrobenzenesulfonic acid (XVIII) using POCl3 in sulfolane at 110-120 °C provides the corresponding sulfonyl chloride (XIX), which is treated with NH4OH to yield sulfonamide (XVII). Reduction of the nitro moiety of compound (XVII) with H2 over Pd/C in the presence of MsOH in EtOH/H2O at 55 °C affords 2,5-diaminobenzenesulfonamide mesylate (XX), which can also be obtained by chloride substitution in 2-chloro-5-nitrobenzenesulfonamide (XVI) with benzylamine by means of Et3N in acetonitrile at 92 °C, followed by hydrogenolysis of the resulting 2-(benzylamino)-5-nitrobenzenesulfonamide (XXI) over Pd/C in the presence of MsOH in THF/EtOH/H2O. Selective N-sulfonylation of diamine (XX) with methanesulfonyl chloride (XXII) and pyridine in CH2Cl2 or acetonitrile gives rise to 2-amino-5-(methylsulfonamido)benzenesulfonamide (XXIII), which is then condensed with either methyl malonyl chloride (XXIV) in THF or ethyl malonyl chloride (XXV) in DMF/Et2O or DMA , yielding amides (XXVI) or (XXVII). Finally, carbamoyl sulfonamides (XXVI) and (XXVII) are cyclized and simultaneously hydrolyzed by treatment with NaOH (XII) .
| 【1】 Tran, C.V., Ruebsam, F., Murphy, D.E. et al. (Anadys Pharmaceuticals, Inc.). 5,6-Dihydro-1H-pyridin-2-one compounds. CA 2682584, EP 2129224, JP 2010523586, US 2010034773, US 7939524, US 8101800, US 2012130068, US 8236948, WO 2008124450. |
| 【2】 Dragovich, P.S., Thompson, P.A., Ruebsam, F. (Anadys Pharmaceuticals, Inc.). A method of inhibiting hepatitis C virus by combination of a 5,6-dihydro-1H-pyridin-2-one and one or more additional antiviral compounds. EP 2346329, US 2011229438, WO 2010042834. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 68662 | 2-(7-(methylsulfonamido)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)acetic acid | C10H11N3O6S2 | 详情 | 详情 | |
| (XIV) | 68665 | 2-chloro-5-nitrobenzenesulfonic acid;2-Chloro-5-nitrobenzene sulfonic acid;p-Nitrochlorobenzene-o-sulfonic acid;2-chloro-5-nitro-Benzenesulfonic acid;2-chloro-5-nitrobenzenesulphonic acid | 96-73-1 | C6H4ClNO5S | 详情 | 详情 |
| (XV) | 43034 | 2-chloro-5-nitrobenzenesulfonyl chloride;2-Chloro-5-nitro-benzenesulfonyl chloride;2-Chloro-5-nitrophenylsulfonyl chloride;6-Chloro-3-nitrobenzenesulfonyl chloride | 4533-95-3 | C6H3Cl2NO4S | 详情 | 详情 |
| (XVI) | 43035 | 2-chloro-5-nitrobenzenesulfonamide | 96-72-0 | C6H5ClN2O4S | 详情 | 详情 |
| (XVII) | 68666 | 2-amino-5-nitrobenzenesulfonamide | C6H7N3O4S | 详情 | 详情 | |
| (XVIII) | 68668 | 2-amino-5-nitrobenzenesulfonic acid | 96-75-3 | C6H6N2O5S | 详情 | 详情 |
| (XIX) | 68667 | 2-amino-5-nitrobenzene-1-sulfonyl chloride | C6H5ClN2O4S | 详情 | 详情 | |
| (XX) | 68669 | 2,5-diaminobenzenesulfonamide mesylate;2,5-diaminobenzenesulfonamide methanesulfonate | C6H9N3O2S.CH4O3S | 详情 | 详情 | |
| (XXI) | 68670 | 2-(benzylamino)-5-nitrobenzenesulfonamide | C13H13N3O4S | 详情 | 详情 | |
| (XXII) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (XXIII) | 68671 | 2-amino-5-(methylsulfonamido)benzenesulfonamide | C7H11N3O4S2 | 详情 | 详情 | |
| (XXIV) | 50272 | Malonic acid monomethyl ester chloride; Methyl (chloroformyl)acetate; Methyl malonyl chloride ;Methyl 3-chloro-3-oxopropionate | 37517-81-0 | C4H5ClO3 | 详情 | 详情 |
| (XXV) | 13188 | ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride | 36239-09-5 | C5H7ClO3 | 详情 | 详情 |
| (XXVI) | 68672 | methyl 3-((4-(methylsulfonamido)-2-sulfamoylphenyl)amino)-3-oxopropanoate | C11H15N3O7S2 | 详情 | 详情 | |
| (XXVII) | 68673 | ethyl 3-((4-(methylsulfonamido)-2-sulfamoylphenyl)amino)-3-oxopropanoate | C12H17N3O7S2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XIV)Reaction of 2-aminobenzyl alcohol (I) with acetone in aqueous AcOH affords 2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine, which is reduced with LiAlH4 in THF, producing 2-(isopropylamino)benzyl alcohol (II). After oxidation of alcohol (II) to the corresponding benzaldehyde (III) by means of MnO2 in toluene at 117 °C, Knoevenagel condensation with Meldrum’s acid (IV) in the presence of AcOH and ethylenediamine in MeOH gives 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (V) . Chlorination of acid (V) with SOCl2 in toluene at 95 °C and subsequent coupling of the resulting acid chloride with N-Boc-endo-3-aminotropane (VI) in the presence of NaOH in toluene/water affords the corresponding amide (VII). Deprotection of the N-Boc-tropane derivative (VII) by means of TFA in CH2Cl2 furnishes the corresponding amine TFA salt (VIII) (1-9), which is then N-alkylated with 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol (IX) [prepared by condensation of (S)-epichlorohydrin (X) with Nmethylbenzylamine in hexane and subsequent hydrogenolysis of the obtained benzylamine derivative (XI) in the presence of Pd(OH)2/C and Boc2O in EtOAc] in the presence of DIEA in MeOH at 80 °C to give the N-Boc-methylamine derivative (XII). Deprotection of this compound by means of TFA in CH2Cl2 and N-sulfonylation of the obtained free amine (XIII) with methanesulfonyl chloride (XIV) in the presence of DBU in CH2Cl2 then affords velusetrag. Alternatively, reaction of amine (VIII) with N-[(S)-glycidyl]-N-methylmethanesulfonamide (XV) [prepared by alkylation of N-methylmethanesulfonamide (XVI) with (S)-epichlorohydrin (XVII) using aqueous NaOH] in the presence of NaOH in MeOH yields velusetrag . N-Boc-endo-3-aminotropane (VI) is prepared by hydrolysis of 2,5-dimethoxytetrahydrofuran (XVIII) with aqueous HCl, followed by Mannich reaction of the resulting succinaldehyde with BnNH2 and 1,3-acetonedicarboxylic acid (XIX) in the presence of HCl in H2O to give N-benzyl-8-azabicyclo[3.2.1]octan-3-one (XX). Treatment of this compound with H2 over Pd(OH)2/C and Boc2O in EtOAc yields N-Boc-8-azabicyclo[3.2.1]octan-3-one (XXI), which is then converted to the desired amine (VI) by reductive amination with HCOONH4 in the presence of Pd/C in MeOH/H2O .
Velusetrag can be converted to its salts, including hydrochloride, citrate,adipate, phosphate, sulfate, tartrate, malate, hydrobromide and mesylate, by treatment with the respective acids .
| 【1】 Marquess, D., Fatheree, P.R., Turner, D.S., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. EP 1735304, JP 2007535546, JP 2008174569, US 2005228014, US 2007281970, US 7375114, US 7728006, WO 2005100350. |
| 【2】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2007270457, US 7592355. |
| 【3】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4, receptor agonists. US 2008176895, US 7763637. |
| 【4】 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. US 2008255187, US 7534889. |
| 【5】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2010285519. |
| 【6】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolone-carboxamide compounds as 5-HT4 receptor agonists. US 2010311979. |
| 【7】 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. EP 1807422, JP 2008518965, US 2006100236, US 7399862, WO 2006052640. |
| 【8】 Fatheree, P.R., Turner, S.D., Goldblum, A., Chao, R., Genov, D. (Theravance, Inc.). Crystalline form of a quinolinone-carboxamide compound. EP 1874766, JP 2008535848, US 2006229332, US 7728004, WO 2006108127. |
| 【9】 Genov, D., Lee, J., Liu, J. (Theravance, Inc.). Process for preparing intermediates to 5-HT4 receptor agonist compounds. EP 1984362, JP 2009526852, US 2007191355, WO 2007097976. |
| 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) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (II) | 36334 | [2-(isopropylamino)phenyl]methanol；2-(isopropylamino)benzyl alcohol;(2-(isopropylamino)phenyl)methanol | C10H15NO | 详情 | 详情 | |
| (III) | 36335 | 2-(isopropylamino)benzaldehyde | C10H13NO | 详情 | 详情 | |
| (IV) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (V) | 36333 | 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid | C13H13NO3 | 详情 | 详情 | |
| (VI) | 68799 | (1R,3r,5R)-tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate | C12H22N2O2 | 详情 | 详情 | |
| (VII) | 68803 | (1R,3R)-tert-butyl 3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate | C25H33N3O4 | 详情 | 详情 | |
| (VIII) | 68804 | N-((1R,3R)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate | C20H25N3O2.C2HF3O2 | 详情 | 详情 | |
| (IX) | 68807 | 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol;(S)-tert-butyl (3-chloro-2-hydroxypropyl)(methyl)carbamate | C9H18ClNO3 | 详情 | 详情 | |
| (X) | 13917 | (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin | 67843-74-7 | C3H5ClO | 详情 | 详情 |
| (XI) | 68808 | (S)-1-(benzyl(methyl)amino)-3-chloropropan-2-ol | C11H16ClNO | 详情 | 详情 | |
| (XII) | 68805 | tert-butyl ((S)-2-hydroxy-3-((1R,3R,5S)-3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octan-8-yl)propyl)(methyl)carbamate | C29H42N4O5 | 详情 | 详情 | |
| (XIII) | 68806 | N-((1R,3R,5S)-8-((R)-2-hydroxy-3-(methylamino)propyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate | C24H34N4O3.C2HF3O2 | 详情 | 详情 | |
| (XIV) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (XV) | 68802 | N-[(S)-glycidyl]-N-methylmethanesulfonamide;(S)-N-methyl-N-(oxiran-2-ylmethyl)methanesulfonamide | C5H11NO3S | 详情 | 详情 | |
| (XVI) | 67859 | N-methylmethanesulfonamide | 1184-85-6 | C2H7NO2S | 详情 | 详情 |
| (XVII) | 13917 | (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin | 67843-74-7 | C3H5ClO | 详情 | 详情 |
| (XVIII) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (XIX) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (XX) | 68801 | (1R,5R)-8-benzyl-8-azabicyclo[3.2.1]octan-3-one;N-benzyl-8-azabicyclo[3.2.1]octan-3-one | C14H17NO | 详情 | 详情 | |
| (XXI) | 68800 | N-Boc-8-azabicyclo[3.2.1]octan-3-one | C12H19NO3 | 详情 | 详情 |