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【结 构 式】 
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【分子编号】11969 【品名】N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine 【CA登记号】103-67-3 |
【 分 子 式 】C8H11N 【 分 子 量 】121.18208 【元素组成】C 79.29% H 9.15% N 11.56% |
合成路线1
该中间体在本合成路线中的序号：(I)1) The reaction of N-methyl-N-benzylamine (I) with isobutyraldehyde (II) and formaldehyde (III) in refluxing isopropanol, followed by hydrogenation with NaBH4 gives 3-(N-benzyl-N-methylamino)-2,2-dimethylpropanol (IV), which is condensed with diketene (V) in refluxing benzene to yield 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate (VI). Finally, this compound is submitted to cyclization with 2-fluoro-5-nitrobenzeldehyde (VII) (prepared by oxidation of 2-fluoro-5-nitrotoluene (VIII) with CrO3 in acetic ahydride-H2SO4) and methyl 3-aminocrotonate (IX) in refluxing isopropanol.
| 【1】 Yamaguchi, H.; Odamiya, Y.; Kanno, H.; Sunakawa, K. (Teijin Ltd.); 1,4-Dihydropyridine derivs., process for production thereof and pharmaceutical use thereof. EP 0128010; JP 1984222474; JP 1984227859; JP 1985104065; US 4578395 . |
| 【2】 Prous, J.; Castaner, J.; TC-81. Drugs Fut 1989, 14, 3, 239. |
| 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) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (II) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (IV) | 12110 | 3-[Benzyl(methyl)amino]-2,2-dimethyl-1-propanol | C13H21NO | 详情 | 详情 | |
| (V) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (VI) | 12112 | 3-[benzyl(methyl)amino]-2,2-dimethylpropyl 3-oxobutanoate | C17H25NO3 | 详情 | 详情 | |
| (VII) | 12108 | 2-Fluoro-5-nitrobenzaldehyde | 27996-87-8 | C7H4FNO3 | 详情 | 详情 |
| (VIII) | 20560 | 1-fluoro-2-methyl-4-nitrobenzene | 455-88-9 | C7H6FNO2 | 详情 | 详情 |
| (IX) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reductocondensation of naltrexone (I) with N-methylbenzylamine (II) by means of sodium cyanoborohydride in THF gives the N-benzyl-N-methylaminomorphinan derivative (III), which is debenzylated by hydrogenation with H2 over Pd/C in methanol yielding the methylaminomorphinan (IV). Finally, this compound is acylated with 3(E)-(3-furyl)acryloyl chloride and NaOH, Na2CO3 or triethylamine in methanol, THF or chloroform. Alternatively, methylaminomorphinan (IV) can also be obtained by direct reductocondensation of naltrexone (I) with methylamine by means of H2 over PtO2 in methanol.
| 【1】 Leeson, P.A.; Sorbera, L.A.; Castañer, J.; Nalfurafine Hydrochloride. Drugs Fut 2003, 28, 3, 237. |
| 【2】 Nagase, H.; et al.; Discovery of a structurally novel opioid kappa-agonist derived from 4,5-epoxymorphinan. Chem Pharm Bull 1998, 46, 2, 366. |
| 【3】 Nagase, H.; Hayakawa, J.; Kawamura, H.; Kawai, K.; Endoh, T. (Toray Industries, Inc.); Morphinan derivative and medicinal use. AU 686203; AU 7237394; EP 0663401 . |
| 【4】 Nagase, H.; Kawai, K.; Endo, T.; Ueno, S.; Negishi, Y. (Toray Industries, Inc.); Antitussive. EP 0657163; JP 1995503397; US 5739145; WO 9501178 . |
| 【5】 Nagase, H.; Kawai, K.; Kawamura, K.; Hayakawa, J.; Endo, T. (Toray Industries, Inc.); Morphinan deriv. and medicinal use. EP 0577847; EP 0846694; JP 1994509616; US 6277859; US 6323212; WO 9315081 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 | |
| (I) | 25079 | (1S,5R,13R,17S)-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one; Naltrexone | 16590-41-3 | C20H23NO4 | 详情 | 详情 |
| (II) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (III) | 25080 | (1S,5R,13R,14R,17S)-14-[benzyl(methyl)amino]-4-(cyclopropylmethyl)-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-triene-10,17-diol | C28H34N2O3 | 详情 | 详情 | |
| (IV) | 25081 | (1S,5R,13R,14R,17S)-4-(cyclopropylmethyl)-14-(methylamino)-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-triene-10,17-diol | C21H28N2O3 | 详情 | 详情 | |
| (V) | 25082 | (E)-3-(3-furyl)-2-propenoyl chloride | C7H5ClO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of N-(tert-butoxycarbonyl)-L-(2-naphthyl)alanine (I) with N-methylbenzyamine (II) by means of isobutyl chloroformate and NMM in dichloromethane gives the corresponding amide (III), which is deprotected with HCl in dioxane yielding (IV) with a free amino group. Finally, this compound is condensed with 1-[N-(2-nitrophenyl)carbamoyl]-L-proline (V) by means of HOBT and DCC in THF. The intermediate 1-[N-(2-nitrophenyl)carbamoyl]-L-proline (V) has been obtained by reaction of L-proline (VI) with 2-nitrophenyl isocyanate (VII) by means of NMM in THF/water.
| 【1】 Prashad, M.; et al.; Process development of (2-nitrophenylcarbamoyl)-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N-methylamide (SDZ NKT343). Org Process Res Dev 1999, 3, 6, 409. |
| 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) | 15061 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid; N-T-BOC-L-3-(2-NAPHTHYL)ALANINE | 58438-04-3 | C18H21NO4 | 详情 | 详情 |
| (II) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (III) | 15062 | tert-butyl N-[(1S)-2-[benzyl(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl]carbamate | C26H30N2O3 | 详情 | 详情 | |
| (IV) | 15063 | (2S)-2-amino-N-benzyl-N-methyl-3-(2-naphthyl)propanamide | C21H22N2O | 详情 | 详情 | |
| (V) | 32772 | (2S)-1-[(2-nitroanilino)carbonyl]-2-pyrrolidinecarboxylic acid | C12H13N3O5 | 详情 | 详情 | |
| (VI) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (VII) | 32771 | 1-isocyanato-2-nitrobenzene; 2-nitrophenyl isocyanate | 3320-86-3 | C7H4N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)Compound (XI) was condensed with methyl benzyl amine (XII) to furnish tertiary amine (XIII). The nitro group of (XIII) was then reduced with iron powder and HCl to afford amine (XIV). Subsequent acylation of (XIV) with isobutyric anhydride (XV) in the presence of Et3N produced amide (XVI). The title compound was then obtained by transesterification between (XVI) and titanium isopropoxide in isopropanol, followed by treatment with ethanolic HCl.
| 【1】 Cho, N.; Harada, M.; Imaeda, T.; Imada, T.; Matsumoto, H.; Hayase, Y.; Sasaki, S,; Furuya, S.; Suzuki, N.; Okubo, S.; Ogi, K.; Endo, S.; Onda, H.; Fujino, M.; Discovery of a novel, potent, and orally active no. J Med Chem 1998, 41, 22, 4190. |
| 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) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (XIII) | 23155 | ethyl 3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C32H27F2N3O5S | 详情 | 详情 | |
| (XIV) | 23156 | ethyl 2-(4-aminophenyl)-3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C32H29F2N3O3S | 详情 | 详情 | |
| (XV) | 22334 | 1-methylpropionic anhydride | 97-72-3 | C8H14O3 | 详情 | 详情 |
| (XVI) | 23158 | ethyl 3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-2-[4-(isobutyrylamino)phenyl]-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C36H35F2N3O4S | 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 synthesis of (R)-fluoxetine hydrochloride has been described: The condensation of acetophenone (I) with N-benzyl-N-methylamine (II) and formaldehyde by means of concentrated HCl in refluxing methanol gives 3-(N-benzyl-N-methylamino)propiophenone (III), which is asymmetrically reduced with H2 at 30 Atm. over [Rh(1,5-cyclooctadiene)Cl] and the chiral phosphine (2S,4S)-1-(N-methylcarbamoyl)-4-(dicyclohexylphosphino)-2-(diphenylphos phinomethyl)pyrrolidine in methanol yielding (R)-3-(N-benzyl-N-methylamino)-1-phenyl-1-propanol (IV). The debenzylation of (IV) with H2 over Pd/C in ethanol affords (R)-3-(methylamino)-1-phenyl-1-propanol (V), which is finally condensed with 1-chloro-4-(trifluoromethyl)benzene (VI) by means of NaH in dimethylacetamide.
| 【1】 Sakuraba, S.; Achiwa, K.; Efficient asymmetric hydrogenation of beta- and gamma-amino ketone derivatives leading to practical synthesis of fluoxetine and eprozinol. Chem Pharm Bull 1995, 43, 5, 748. |
| 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) | 10317 | Acetophenone | 98-86-2 | C8H8O | 详情 | 详情 |
| (II) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (III) | 11970 | 3-[Benzyl(methyl)amino]-1-phenyl-1-propanone; 3-(N-Benzyl-N-methylamino)propiophenone | 5409-62-1 | C17H19NO | 详情 | 详情 |
| (IV) | 11971 | (1R)-3-[Benzyl(methyl)amino]-1-phenyl-1-propanol | C17H21NO | 详情 | 详情 | |
| (V) | 11972 | (1R)-3-(Methylamino)-1-phenyl-1-propanol; (R)-3-Hydroxy-N-methyl-3-phenyl propylamine | 42142-52-9 | C10H15NO | 详情 | 详情 |
| (VI) | 11973 | 1-Chloro-4-(trifluoromethyl)benzene; 4-Chlorobenzotrifluoride | 98-56-6 | C7H4ClF3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)The selective protection of piperazine-2-carboxylic acid (I) with tert-butoxycarbonyl anhydride gives the carbamate (II), which is sulfonated with 4-methoxybenzenesulfonyl chloride (II) and triethylamine yielding the sulfonamide (IV). The esterification and simultaneous deprotection of (IV) with SOCl2 and methanol affords the methyl ester (V), which is treated with phosgene and N-benzyl-N-methylamine (VI) to afford the cyclic urea derivative (VII). Finally, this compound is treated with KOH and hydroxylamine in methanol to provide the target hydroxamic acid.
| 【1】 De, B.; Natchus, M.G.; Pikul, S.; Almstead, N.G.; Matthews, R.S.; Taiwo, Y.O.; Cheng, M. (The Procter & Gamble Co.); 1,4-Heterocyclic metalloprotease inhibitors. EP 0923563; EP 0925287; WO 9808825; WO 9808827 . |
| 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) | 25933 | 2-piperazinecarboxylic acid; Piperazine-2-carboxylic acid | C5H10N2O2 | 详情 | 详情 | |
| (II) | 25934 | 4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid | C10H18N2O4 | 详情 | 详情 | |
| (III) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (IV) | 25935 | 4-(tert-butoxycarbonyl)-1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylic acid | C17H24N2O7S | 详情 | 详情 | |
| (V) | 25936 | methyl 1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylate | C13H18N2O5S | 详情 | 详情 | |
| (VI) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (VII) | 25937 | methyl 4-[[benzyl(methyl)amino]carbonyl]-1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylate | C22H27N3O6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Treatment of ethyl acrylate (I) with N-benzylmethylamine (II) affords aminopropionate derivative (III), which is then subjected to Grignard reaction with 3-bromoflurobenzene (IV) by means of Mg and catalytic iodine in refluxing THF and crystallized as a hydrochloride salt by treatment with HCl to provide propylamino derivative (V). Alcohol (V) is converted into allylamine (VI) by elimination induced by heating with HCl/HOAc, and finally the target product is obtained by hydrogenation of (VI) catalyzed by Pd(OH)2/C in EtOH.
| 【1】 Moe, S.; Mueller, A.; Balandrin, M. (NPS Pharmaceuticals, Inc.); Methods and cpds. for treating depression and other disorders. EP 1096926; WO 0002551 . |
| 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) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (II) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (III) | 48848 | ethyl 3-[benzyl(methyl)amino]propanoate | C13H19NO2 | 详情 | 详情 | |
| (IV) | 28002 | 1-bromo-3-fluorobenzene; 3-Bromofluorobenzene | 1073-06-9 | C6H4BrF | 详情 | 详情 |
| (V) | 48849 | 3-[benzyl(methyl)amino]-1,1-bis(3-fluorophenyl)-1-propanol | C23H23F2NO | 详情 | 详情 | |
| (VI) | 48850 | N-benzyl-N-[3,3-bis(3-fluorophenyl)-2-propenyl]-N-methylamine; N-benzyl-3,3-bis(3-fluorophenyl)-N-methyl-2-propen-1-amine | C23H21F2N | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IX)Cyclization of 1-(4-nitrophenyl)acetone (I) with ethyl 2-cyanoacetate (II) by means of NH4OAc, HOAc, S and diethylamine gives 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester (III), which is cyclized with phenyl isocyanate (IV) in pyridine to yield the thieno[2,3-d]pyrimidinedione derivative (V). Alkylation of compound (V) with 2,6-difluorobenzyl chloride (VI) by means of K2CO3 and KI in DMF affords the adduct (VII), which is brominated with NBS and AIBN in chlorobenzene to provide the bromomethyl derivative (VIII). Reaction of compound (VIII) with N-benzyl-N-methylamine (IX) by means of DIEA in DMF gives the tertiary amine (X), which by reduction of the nitro group with H2 over Pd/C in ethyl ether/formic acid yields the primary amine (XI). Finally, this compound is treated with CDI, O-methylhydroxylamine (XII) and TEA in dichloromethane.
| 【1】 Sorbera, L.A.; Castaner, J.; Leeson, P.A.; TAK-013. Drugs Fut 2003, 28, 2, 121-124. |
| 【5】 Suzuki, N.; Furuya, S.; Choh, N.; Nara, Y. (Takeda Chemical Industries, Ltd.); Thienopyrimidine cpds., their production and use. EP 1163244; JP 2001278884; JP 2001278885; US 6340682; WO 0056739 . |
| 【6】 Kimura, K.; Yamamoto, H.; Miki, S.; Kawakami, J.; Fukuoka, K. (Takeda Chemical Industries, Ltd.); Processes for the production of thienopyrimidine derivs.. EP 1266898; JP 2001316391; WO 0164683 . |
| 【2】 Suzuki, N.; Nara, Y.; Harada, M.; Endo, S.; Fujino, M.; Sasaki, S.; Furuya, S.; Cho, N.; Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: A highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor. J Med Chem 2003, 46, 1, 113. |
| 【3】 Sasaki, S.; Cho, N.; Nara, Y.; Harada, M.; Endo, S.; Furuya, S.; Fujino, M.; Suzuki, N.; Synthesis of orally active nonpeptide LHRH (GnRH) antagonists [II]: Discovery of the thieno[2,3-b]pyrimidine-2,4-dione derivative TAK-013. 22nd Symp Med Chem (Nov 27 2002, Shizuoka) 2002, Abst 2P-26. |
| 【4】 Harada, M.; Nara, Y.; Endo, S.; Suzuki, N.; Cho, N.; Fujino, M.; Sasaki, S.; Furuya, S.; Discovery of the thieno[2,3-d]pyrimidine-2,4-dione derivative TAK-013: Highly potent and orally active nonpeptide LHRH (GnRH) antagonist (II). 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 354. |
| 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) | 59515 | 1-(4-Nitrophenyl)-2-propanone; 4-Nitrophenylacetone | 5332-96-7 | C9H9NO3 | 详情 | 详情 |
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (III) | 59516 | ethyl 2-amino-4-methyl-5-(4-nitrophenyl)-3-thiophenecarboxylate | C14H14N2O4S | 详情 | 详情 | |
| (IV) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
| (V) | 59517 | 5-methyl-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione | C19H13N3O4S | 详情 | 详情 | |
| (VI) | 23150 | 2-(chloromethyl)-1,3-difluorobenzene | 697-73-4 | C7H5ClF2 | 详情 | 详情 |
| (VII) | 59518 | 1-(2,6-difluorobenzyl)-5-methyl-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione | C26H17F2N3O4S | 详情 | 详情 | |
| (VIII) | 59519 | 5-(bromomethyl)-1-(2,6-difluorobenzyl)-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione | C26H16BrF2N3O4S | 详情 | 详情 | |
| (IX) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (X) | 59520 | 5-{[benzyl(methyl)amino]methyl}-1-(2,6-difluorobenzyl)-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione | C34H26F2N4O4S | 详情 | 详情 | |
| (XI) | 59521 | 6-(4-aminophenyl)-5-{[benzyl(methyl)amino]methyl}-1-(2,6-difluorobenzyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione | C34H28F2N4O2S | 详情 | 详情 | |
| (XII) | 15455 | (aminooxy)methane; O-methylhydroxylamine | 67-62-9 | CH5NO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)Friedländer cyclization between 2-aminobenzophenone (I) and 2-oxobutyric acid (II) by means of NaOMe in MeOH gives carboxylic acid (III), which is then converted into the corresponding acid chloride (IV) by reaction with SOCl2 in CH2Cl2. Finally, the target product is obtained by reaction of (IV) with N-methylbenzylamine (V) by means of Et3N.
| 【1】 Anzini, M.; et al.; Synthesis of 2-substituted 2,3-dihydro-9-phenyl-1H-pyrrolo[3,4-b]quinolin-3-ones as potential peripheral benzodiazepine-receptor ligands. Heterocycles 1994, 38, 1, 103. |
| 【2】 Manzoni, C.; Anzini, M.; Cappelli, A.; Giorgi, G.; Menziani, M.C.; Vomero, S.; De Benedetti, P.G.; Mapping the peripheral benzodiazepine receptor binding site by conformationally restrained derivatives of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195). J Med Chem 1997, 40, 18, 2910. |
| 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) | 21101 | (2-aminophenyl)(phenyl)methanone; 2-Aminobenzophenone | 2835-77-0 | C13H11NO | 详情 | 详情 |
| (II) | 48297 | 2-oxobutyric acid | 600-18-0 | C4H6O3 | 详情 | 详情 |
| (III) | 48298 | 3-methyl-4-phenyl-2-quinolinecarboxylic acid | C17H13NO2 | 详情 | 详情 | |
| (IV) | 48299 | 3-methyl-4-phenyl-2-quinolinecarbonyl chloride | C17H12ClNO | 详情 | 详情 | |
| (V) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XII)The cyclization of phenylacetone (I) with ethyl cyanoacetate (II) by means of HOAc and AcONH4 in refluxing benzene, followed by a treatment with sulfur in hot ethanol gives 2-amino-4-methyl-5-phenylthiophene-3-carboxylic acid ethyl ester (III). The condensation of (III) with diethyl ethoxymethylene malonate (IV) by heating at 120 C yields the adduct (V), which is submitted to a selective hydrolysis with KOH in hot ethanol to afford the carboxylic acid (VI). The cyclization of (VI) by means of PPE at 120 C provides the thienopyridine (VII), which is nitrated with NaNO3 and H2SO4 to give the 4-nitrophenyl derivative (VIII). The alkylation of the hydroxy-thienopyridine (VIII) with 2,6-difluorobenzyl chloride (IX) by means of NaH in DMF yields the benzylated thienopyridinone (X), which is brominated with NBS and AIBN in refluxing CCl4 to afford the bromomethyl derivative (XI). The condensation of (XI) with N-benzyl-N-methylamine (XII) by means of TEA in DMF provides the tertiary amine (XIII). The reduction of the nitro group of (XIII) by means of Fe and HCl in ethanol gives the 4-aminophenyl derivative (XIV), which is acylated with trifluoroacetic anhydride and TEA to yield the acetamide (XV). The reaction of (XV) with N,O-dimethylhydroxylamine (XVI) and TEA in CH2Cl2 affords the methoxyamide (XVII).
| 【1】 Imada, T.; Fujino, M.; Suzuki, N.; Harada, M.; Kasai, S.; Sasaki, S.; Endo, S.; Hayase, Y.; Furuya, S.; Cho, N.; Discovery of the thieno[2,3-b]pyridin-4-one derivative TAK-810: Highly potent and orally active nonpeptide LHRH (GnRH) antagonist (I). 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 353. |
| 【2】 Suzuki, N.; Furuya, S.; Choh, N.; Imada, T. (Takeda Chemical Industries, Ltd.); Thienopyridine cpds., their production and use. EP 1090010; JP 2000219690; JP 2000219691; US 6262267; US 6329388; WO 0000493 . |
| 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) | 23143 | 1-Phenylacetone; Methyl benzyl ketone; Benzyl methyl ketone; phenylacetone; Phenyl-2-propanone | 103-79-7 | C9H10O | 详情 | 详情 |
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (III) | 23145 | ethyl 2-amino-4-methyl-5-phenyl-3-thiophenecarboxylate | C14H15NO2S | 详情 | 详情 | |
| (IV) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (V) | 23147 | diethyl 2-([[3-(ethoxycarbonyl)-4-methyl-5-phenyl-2-thienyl]amino]methylene)malonate | C22H25NO6S | 详情 | 详情 | |
| (VI) | 23148 | 2-[[3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-propenyl]amino]-4-methyl-5-phenyl-3-thiophenecarboxylic acid | C20H21NO6S | 详情 | 详情 | |
| (VII) | 23149 | ethyl 4-hydroxy-3-methyl-2-phenylthieno[2,3-b]pyridine-5-carboxylate | C17H15NO3S | 详情 | 详情 | |
| (VIII) | 58691 | ethyl 4-hydroxy-3-methyl-2-(4-nitrophenyl)thieno[2,3-b]pyridine-5-carboxylate | C17H14N2O5S | 详情 | 详情 | |
| (IX) | 23150 | 2-(chloromethyl)-1,3-difluorobenzene | 697-73-4 | C7H5ClF2 | 详情 | 详情 |
| (X) | 23152 | ethyl 7-(2,6-difluorobenzyl)-3-methyl-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C24H18F2N2O5S | 详情 | 详情 | |
| (XI) | 23153 | ethyl 3-(bromomethyl)-7-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C24H17BrF2N2O5S | 详情 | 详情 | |
| (XII) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (XIII) | 23155 | ethyl 3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C32H27F2N3O5S | 详情 | 详情 | |
| (XIV) | 23156 | ethyl 2-(4-aminophenyl)-3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C32H29F2N3O3S | 详情 | 详情 | |
| (XV) | 58692 | ethyl 3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-4-oxo-2-{4-[(2,2,2-trifluoroacetyl)amino]phenyl}-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C34H28F5N3O4S | 详情 | 详情 | |
| (XVI) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (XVII) | 58693 | 3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-N-methoxy-N-methyl-4-oxo-2-{4-[(2,2,2-trifluoroacetyl)amino]phenyl}-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide | C34H29F5N4O4S | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VI)Partial demethylation of 2,4,5-trimethoxybenzaldehyde (I) with BCl3 gives 2-hydroxy-4,5-dimethoxybenzaldehyde (II), which is condensed with the sodium salt of p-tolylacetic acid (III) in boiling acetic anhydride to afford the coumarin derivative (IV). Benzylic halogenation of (IV) with N-bromosuccinimide in the presence of a catalytic amount of benzoyl peroxide yields bromide (V), which is finally condensed with N-methyl benzylamine (VI) to afford the desired compound.
| 【1】 Piazzi, L.; Rampa, A.; Bisi, A.; Gobbi, S.; Belluti, F.; Cavalli, A.; Bartolini, M..; Andrisano, V.; Valenti, P.; Recanatini, M.; 3-(4-{[Benzyl(methyl)amino]methyl}phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation: A dual function lead for Alzheimer's disease therapy. J Med Chem 2003, 46, 12, 2279. |
| 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) | 64839 | 2,4,5-trimethoxybenzaldehyde | C10H12O4 | 详情 | 详情 | |
| (II) | 64840 | 2-hydroxy-4,5-dimethoxybenzaldehyde | C9H10O4 | 详情 | 详情 | |
| (III) | 64841 | sodium 2-(4-methylphenyl)acetate | C9H9NaO2 | 详情 | 详情 | |
| (IV) | 64842 | 6,7-dimethoxy-3-(4-methylphenyl)-2H-chromen-2-one | C18H16O4 | 详情 | 详情 | |
| (V) | 64843 | 3-[4-(bromomethyl)phenyl]-6,7-dimethoxy-2H-chromen-2-one | C18H15BrO4 | 详情 | 详情 | |
| (VI) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |