|
【结 构 式】 
|
【分子编号】10194 【品名】N-Phenylacetamide; Acetanilide 【CA登记号】103-84-4 |
【 分 子 式 】C8H9NO 【 分 子 量 】135.1656 【元素组成】C 71.09% H 6.71% N 10.36% O 11.84% |
合成路线1
该中间体在本合成路线中的序号：(I)A synthesis for [benzene-U-14C]-tiludronate has been described: The chlorination of [U-14C]-acetanilide (I) with tetrabutylammonium iodotetrachloride gives the corresponding 4-chloro derivative (II) (along with some of the 2-chloro isomer). The hydrolysis of (II) with concentrated HCl at 60 C yields the chloroaniline (III), which is converted to the corresponding diazonium salt (IV) with NaNO2 and HCl. The reaction of (IV) with ferric thiocyanate affords the labeled 4-chlorophenylthiocyanate (V), which is condensed with the lithium salt of methylenebis(phosphonic acid)tetraisopropyl ester (VI) in THF to yield 4-chlorophenylsulfanylmethylenebis(phosphonic acid)tetraisopropyl ester (VII). Finally, this compound is hydrolyzed with concentrated HCl or aqueous NaOH.
| 【1】 Ellames, G.J.; Burgos, A.; Synthesis of disodium [benzene-U-C-14]-(4-chlorophenylthio)methylene diphosphonate, [benzene-U-C-14]-tiludronate. J Label Compd Radiopharm 1995, 36, 11, 1071. |
| 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) | 10194 | N-Phenylacetamide; Acetanilide | 103-84-4 | C8H9NO | 详情 | 详情 |
| (I) | 44610 | C8H9NO | 详情 | 详情 | ||
| (II) | 10195 | N-(4-Chlorophenyl)acetamide | 539-03-7 | C8H8ClNO | 详情 | 详情 |
| (II) | 44611 | C8H8ClNO | 详情 | 详情 | ||
| (III) | 10196 | 4-Chlorobenzenaminium chloride | C6H7Cl2N | 详情 | 详情 | |
| (III) | 44612 | C6H7Cl2N | 详情 | 详情 | ||
| (IV) | 10197 | 4-Chlorobenzenediazonium chloride | C6H4Cl2N2 | 详情 | 详情 | |
| (IV) | 44613 | C6H7Cl2N | 详情 | 详情 | ||
| (V) | 10198 | 4-Chlorophenyl thiocyanate | 3226-37-7 | C7H4ClNS | 详情 | 详情 |
| (V) | 44614 | C7H4ClNS | 详情 | 详情 | ||
| (VI) | 10199 | [Bis(diisopropoxyphosphoryl)methyl]lithium | C13H29LiO6P2 | 详情 | 详情 | |
| (VII) | 10200 | Diisopropyl [(4-chlorophenyl)sulfanyl](diisopropoxyphosphoryl)methylphosphonate | C19H33ClO6P2S | 详情 | 详情 | |
| (VII) | 44615 | C19H33ClO6P2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The reduction of the ester function of (I) with LiAlH4 in THF gives (II). O-demethylation of (II) with EtSNa in DMF yields alcohol (III), which is then cyclized by Mitsunobu reaction with DEAD·Ph3P in THF to yield (IV). Displacement of the Br of (IV) by means of Zn(CN)2 and Pd(PPh3)4 in DMF affords cyano derivative (V), which is then converted into (VI) after debenzylation by treatment with HCl/EtOH and H2 over Pd/C. Finally (VI) is coupled with aldehyde (VII) by reductive amination in 1,2-dichloroethane in presence of NaBH(OAc)3.Alternatively the final product can be obtained by reaction of (VI) with chloro derivative (X) in CH3CN in presence of K2CO3 and KI. (X) can be obtained by acylation of acetanilide (VIII) with chloride (A) in 1,2-dichloroethane in presence of AlCl3 followed by treatment with TFA and Et3SiH.
| 【1】 Audinot, V.; Dubuffet, T.; Newman-Tancredi, A.; Cussac, D.; Millan, M.J.; Lavielle, G.; Loutz, A.; Novel benzopyrano[3,4-c]pyrrole derivatives as potent and selective dopamine D3 receptor antagonists. Bioorg Med Chem Lett 1999, 9, 14, 2059. |
| 【2】 Lejeune, F.; Hautefaye, P.; Millan, M.; Dubuffet, T.; Lavielle, G. (ADIR et Cie.); Chromene derivs., process for their preparation and pharmaceutical compsns. containing them. EP 0887350; JP 1999071376; US 6090837 . |
| 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) | 33760 | methyl (3R,4S)-1-benzyl-4-(5-bromo-2-methoxyphenyl)-3-pyrrolidinecarboxylate | C20H22BrNO3 | 详情 | 详情 | |
| (II) | 33761 | [(3R,4S)-1-benzyl-4-(5-bromo-2-methoxyphenyl)pyrrolidinyl]methanol | C19H22BrNO2 | 详情 | 详情 | |
| (III) | 33762 | 2-[(3S,4R)-1-benzyl-4-(hydroxymethyl)pyrrolidinyl]-4-bromophenol | C18H20BrNO2 | 详情 | 详情 | |
| (IV) | 41665 | (3aS,9bR)-2-benzyl-8-bromo-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole | C18H18BrNO | 详情 | 详情 | |
| (V) | 41666 | (3aS,9bR)-2-benzyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-8-carbonitrile | C19H18N2O | 详情 | 详情 | |
| (VI) | 41667 | (3aS,9bR)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-8-carbonitrile | C12H12N2O | 详情 | 详情 | |
| (VII) | 41662 | N-[4-(2-oxoethyl)phenyl]acetamide | C10H11NO2 | 详情 | 详情 | |
| (VIII) | 10194 | N-Phenylacetamide; Acetanilide | 103-84-4 | C8H9NO | 详情 | 详情 |
| (IX) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (X) | 41663 | N-[4-(2-chloroacetyl)phenyl]acetamide | C10H10ClNO2 | 详情 | 详情 | |
| (XI) | 41664 | N-[4-(2-chloroethyl)phenyl]acetamide | C10H12ClNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Friedel-Crafts acylation of acetanilide (I) with propionyl chloride in the presence of AlCl3 afforded 4'-(acetamido)propiophenone (II). Subsequent Mannich reaction of (II) with dimethylamine hydrochloride and formaldehyde produced the aminoketone (III). Quaternization of the tertiary amine of (III) with MeI, followed by displacement of the resulting ammonium salt (IV) with KCN yielded the intermediate ketonitrile (V). In alternative procedure, nitrile (V) was prepared by acylation of acetanilide (I) with 3-chloro-2-methylpropionyl chloride, and further displacement of the resulting beta-chloroketone (VI) with KCN. Acid hydrolysis of both nitrile and acetamido groups of (V) provided ketoacid (VII), which was cyclized with hydrazine to give pyridazinone (VIII). Finally, acylation of the amino group of (VIII) by means of pyridine-2-carbonyl chloride furnished the title amide.
| 【1】 Liu, C.M.; et al.; Synthesis and platelet aggregation inhibitory activity of 6-(4'-substituted acylaminophenyl)-4,5-dihydro-3-(2H)-pyridazinones. Acta Pharm Sin 1999, 34, 1, 23. |
| 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) | 10194 | N-Phenylacetamide; Acetanilide | 103-84-4 | C8H9NO | 详情 | 详情 |
| (II) | 29198 | N-(4-propionylphenyl)acetamide | C11H13NO2 | 详情 | 详情 | |
| (III) | 29199 | N-[4-[3-(dimethylamino)-2-methylpropanoyl]phenyl]acetamide | C14H20N2O2 | 详情 | 详情 | |
| (IV) | 29200 | 3-[4-(acetamido)phenyl]-N,N,N,2-tetramethyl-3-oxo-1-propanaminium iodide | C15H23IN2O2 | 详情 | 详情 | |
| (V) | 29201 | N-[4-(3-cyano-2-methylpropanoyl)phenyl]acetamide | C13H14N2O2 | 详情 | 详情 | |
| (VI) | 29202 | N-[4-(3-chloro-2-methylpropanoyl)phenyl]acetamide | C12H14ClNO2 | 详情 | 详情 | |
| (VII) | 29203 | 4-(4-aminophenyl)-3-methyl-4-oxobutyric acid | C11H13NO3 | 详情 | 详情 | |
| (VIII) | 29204 | 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone | C11H13N3O | 详情 | 详情 | |
| (IX) | 29205 | 2-pyridinecarbonyl chloride | C6H4ClNO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Friedel-Crafts acylation of acetanilide (I) with propionyl chloride in the presence of AlCl3 afforded 4'-(acetamido)propiophenone (II). Subsequent Mannich reaction of (II) with dimethylamine hydrochloride and formaldehyde produced the aminoketone (III). Quaternization of the tertiary amine of (III) with MeI, followed by displacement of the resulting ammonium salt (IV) with KCN yielded the intermediate ketonitrile (V). In alternative procedure, nitrile (V) was prepared by acylation of acetanilide (I) with 3-chloro-2-methylpropionyl chloride, and further displacement of the resulting alpha-chloroketone (VI) with KCN. Acid hydrolysis of both nitrile and acetamido groups of (V) provided ketoacid (VII), which was cyclized with hydrazine to give pyridazinone (VIII). Finally, acylation of the amino group of (VIII) by means of pyridine-4-carbonyl chloride furnished the title amide.
| 【1】 Liu, C.M.; et al.; Synthesis and platelet aggregation inhibitory activity of 6-(4'-substituted acylaminophenyl)-4,5-dihydro-3-(2H)-pyridazinones. Acta Pharm Sin 1999, 34, 1, 23. |
| 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) | 10194 | N-Phenylacetamide; Acetanilide | 103-84-4 | C8H9NO | 详情 | 详情 |
| (II) | 29198 | N-(4-propionylphenyl)acetamide | C11H13NO2 | 详情 | 详情 | |
| (III) | 29199 | N-[4-[3-(dimethylamino)-2-methylpropanoyl]phenyl]acetamide | C14H20N2O2 | 详情 | 详情 | |
| (IV) | 29200 | 3-[4-(acetamido)phenyl]-N,N,N,2-tetramethyl-3-oxo-1-propanaminium iodide | C15H23IN2O2 | 详情 | 详情 | |
| (V) | 29201 | N-[4-(3-cyano-2-methylpropanoyl)phenyl]acetamide | C13H14N2O2 | 详情 | 详情 | |
| (VI) | 29202 | N-[4-(3-chloro-2-methylpropanoyl)phenyl]acetamide | C12H14ClNO2 | 详情 | 详情 | |
| (VII) | 29203 | 4-(4-aminophenyl)-3-methyl-4-oxobutyric acid | C11H13NO3 | 详情 | 详情 | |
| (VIII) | 29204 | 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone | C11H13N3O | 详情 | 详情 | |
| (IX) | 27850 | isonicotinoyl chloride | 39178-35-3 | C6H4ClNO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Friedel-Crafts acylation of acetanilide (I) with 2-chloropropionyl chloride (II) in the presence of AlCl3 provided ketone (III). The chlorine atom of (III) was then displaced with dimethylamine to afford amino ketone (IV), which was reduced to alcohol (V) using NaBH4 in MeOH. Treatment of alcohol (V) with carbonyl diimidazole furnished the imidazolyl derivative (VI). The acetamido group of (VI) was then hydrolyzed with 3N HCl to give aniline (VII). This compound was converted to isothiocyanate (VIII) by treatment with thiophosgene and NaOH. Alternatively, aniline (VII) was treated with carbon disulfide and NaOH and then with iodomethane to give the bis(methylthio)methyleneamino derivative (IX). The condensation of either (VIII) or (IX) with 2-aminothiophenol (X) produced the target benzothiazole (XI) as a mixture of isomers. Then, separation of the diastereoisomers by column chromatography, followed by resolution by chiral HPLC, furnished the title (S,S)-isomer.
| 【1】 Venet, M.; Van Wauwe, J.; Mabire, D.; Sanz, G.; Poignet, H.; Wouters, J.; Synthesis of R116010, a retinoic acid (RA) metabolism inhibitor with antitumoral effects. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PC-60. |
| 【2】 Venet, M.G.; Mabire, D.J.-P.; Lacrampe, J.F.A.; Sanz, G.C. (Janssen Pharmaceutica NV); N-[4-(heteroarylmethyl)phenyl]-heteroarylamines. EP 0907650; JP 2000503670; US 6124330; WO 9749704 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 46351 | N-[4-[(1R,2S)-2-(dimethylamino)-1-hydroxypropyl]phenyl]acetamide | C13H20N2O2 | 详情 | 详情 | |
| (Vb) | 46352 | N-[4-[(1S,2S)-2-(dimethylamino)-1-hydroxypropyl]phenyl]acetamide | C13H20N2O2 | 详情 | 详情 | |
| (VIa) | 46353 | N-[4-[(1R,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]acetamide | C16H22N4O | 详情 | 详情 | |
| (VIb) | 46354 | N-[4-[(1S,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]acetamide | C16H22N4O | 详情 | 详情 | |
| (VIIa) | 46355 | N-[(1S,2R)-2-(4-aminophenyl)-2-(1H-imidazol-1-yl)-1-methylethyl]-N,N-dimethylamine; 4-[(1R,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]aniline | C14H20N4 | 详情 | 详情 | |
| (VIIb) | 46356 | N-[(1S,2S)-2-(4-aminophenyl)-2-(1H-imidazol-1-yl)-1-methylethyl]-N,N-dimethylamine; 4-[(1S,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]aniline | C14H20N4 | 详情 | 详情 | |
| (VIIIa) | 46357 | (1R,2S)-1-(1H-imidazol-1-yl)-1-(4-isothiocyanatophenyl)-N,N-dimethyl-2-propanamine; N-[(1S,2R)-2-(1H-imidazol-1-yl)-2-(4-isothiocyanatophenyl)-1-methylethyl]-N,N-dimethylamine | C15H18N4S | 详情 | 详情 | |
| (VIIIb) | 46358 | N-[(1S,2S)-2-(1H-imidazol-1-yl)-2-(4-isothiocyanatophenyl)-1-methylethyl]-N,N-dimethylamine; (1S,2S)-1-(1H-imidazol-1-yl)-1-(4-isothiocyanatophenyl)-N,N-dimethyl-2-propanamine | C15H18N4S | 详情 | 详情 | |
| (IXa) | 46359 | 1-[(1R,2S)-1-(4-[[bis(methylsulfanyl)methylene]amino]phenyl)-2-(dimethylamino)propyl]-1H-imidazole | C17H24N4S2 | 详情 | 详情 | |
| (IXb) | 46360 | 1-[(1S,2S)-1-(4-[[bis(methylsulfanyl)methylene]amino]phenyl)-2-(dimethylamino)propyl]-1H-imidazole | C17H24N4S2 | 详情 | 详情 | |
| (XIa) | 46361 | N-[4-[(1R,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]-1,3-benzothiazol-2-amine; N-(1,3-benzothiazol-2-yl)-N-[4-[(1R,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]amine | C21H23N5S | 详情 | 详情 | |
| (XIb) | 46362 | N-[4-[(1S,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]-1,3-benzothiazol-2-amine; N-(1,3-benzothiazol-2-yl)-N-[4-[(1S,2S)-2-(dimethylamino)-1-(1H-imidazol-1-yl)propyl]phenyl]amine | C21H23N5S | 详情 | 详情 | |
| (I) | 10194 | N-Phenylacetamide; Acetanilide | 103-84-4 | C8H9NO | 详情 | 详情 |
| (II) | 12926 | 2-Chloropropanoyl chloride; 2-Chloropropionyl chloride | 7623-09-8 | C3H4Cl2O | 详情 | 详情 |
| (III) | 46349 | N-[4-(2-chloropropanoyl)phenyl]acetamide | C11H12ClNO2 | 详情 | 详情 | |
| (IV) | 46350 | N-[4-[2-(dimethylamino)propanoyl]phenyl]acetamide | C13H18N2O2 | 详情 | 详情 | |
| (X) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |