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【结 构 式】

【分子编号】59515

【品名】1-(4-Nitrophenyl)-2-propanone; 4-Nitrophenylacetone

【CA登记号】5332-96-7

【 分 子 式 】C9H9NO3

【 分 子 量 】179.1754

【元素组成】C 60.33% H 5.06% N 7.82% O 26.79%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(I)

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
Extended Information