ethyl 2-amino-4-methyl-5-(4-nitrophenyl)-3-thiophenecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】59516

【品名】ethyl 2-amino-4-methyl-5-(4-nitrophenyl)-3-thiophenecarboxylate

【CA登记号】

【分子式】C₁₄H₁₄N₂O₄S

【分子量】306.34224

【元素组成】C 54.89% H 4.61% N 9.14% O 20.89% S 10.47%

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：(III)

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.

参考文献中间体

合成目标

【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