N-[2-(2-amino-1,3-thiazol-4-yl)ethyl]-2-(3,4,5-trimethoxyphenyl)acetamide -Drug Synthesis Database

【结构式】

【分子编号】35239

【品名】N-[2-(2-amino-1,3-thiazol-4-yl)ethyl]-2-(3,4,5-trimethoxyphenyl)acetamide

【CA登记号】

【分子式】C₁₆H₂₁N₃O₄S

【分子量】351.42656

【元素组成】C 54.68% H 6.02% N 11.96% O 18.21% S 9.12%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(X)

Michael addition of methyl vinyl ketone (II) to phthalimide (I) in the presence of NaOEt afforded phthalimido ketone (III). Bromination of (III) in MeOH, followed by acid hydrolysis of the resulting dimethyl ketal provided bromo ketone (IV). Cyclization of bromo ketone (IV) with thiourea (V) yielded the amino thiazole (VI) and further deprotection of the phthalimido group of (VI) in refluxing HBr furnished diamine (VII). 3,4,5-Trimethoxyphenylacetic acid (VIII) was converted to the corresponding acid chloride (IX) using oxalyl chloride, and subsequently coupled with amine (VII) under Schotten-Baumann conditions to give amide (X). Cyclization of (X) to the thiazolopyridine (XI) was effected by the Bischler-Napieralski procedure employing POCl3 in acetonitrile. The imine double bond of (XI) was then reduced by means of NaBH4, and the resulting compound was finally converted to the dihydrochloride salt.

参考文献中间体

合成目标

【1】 Shams, G.; Feller, D.R.; Zheng, W.; Konkar, A.A.; Miller, D.D.; Nikulin, V.I.; Vansal, S.S.; 2-Amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines: Novel selective beta3-adrenoceptor agonists. J Med Chem 1999, 42, 12, 2287.
【2】 Miller, D.D.; Feller, D.R. (Molecular Design International, Inc. ); beta3-Adrenoreceptor agonists, agonist compsns. and methods of using. EP 1023269; WO 9916752 .

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)	12376	Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione	85-41-6	C₈H₅NO₂	详情	详情
(II)	30324	3-buten-2-one; methyl vinyl ketone	78-94-4	C₄H₆O	详情	详情
(III)	35230	2-(3-oxobutyl)-1H-isoindole-1,3(2H)-dione		C₁₂H₁₁NO₃	详情	详情
(IV)	35231	2-(4-bromo-3-oxobutyl)-1H-isoindole-1,3(2H)-dione		C₁₂H₁₀BrNO₃	详情	详情
(V)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(VI)	35232	2-[2-(2-amino-1,3-thiazol-4-yl)ethyl]-1H-isoindole-1,3(2H)-dione		C₁₃H₁₁N₃O₂S	详情	详情
(VII)	35233	4-(2-aminoethyl)-1,3-thiazol-2-amine; 4-(2-aminoethyl)-1,3-thiazol-2-ylamine		C₅H₉N₃S	详情	详情
(VIII)	25349	2-(3,4,5-trimethoxyphenyl)acetic acid	937-52-0	C₁₁H₁₄O₅	详情	详情
(IX)	35238	2-(3,4,5-trimethoxyphenyl)acetyl chloride		C₁₁H₁₃ClO₄	详情	详情
(X)	35239	N-[2-(2-amino-1,3-thiazol-4-yl)ethyl]-2-(3,4,5-trimethoxyphenyl)acetamide		C₁₆H₂₁N₃O₄S	详情	详情
(XI)	35240	4-(3,4,5-trimethoxybenzyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-2-amine; 4-(3,4,5-trimethoxybenzyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-2-ylamine		C₁₆H₁₉N₃O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Condensation of 2-bromo-3'-methoxy-4-nitroacetophenone (I) with diethyl malonate affords the phenacylmalonate derivative (II). This is converted into the corresponding magnesium enolate and then acylated by 3,4,5-trimethoxyphenylacetyl chloride (III) to furnish the disubstituted malonate (IV). Intramolecular aldol condensation of diketone (IV) in the presence of Et3N leads to cyclopentenone (V). Subsequent hydrolysis and decarboxylation of the keto diester (V) under acidic conditions produces (VI). Finally, the nitro group of (VI) is reduced by means of zinc dust in AcOH to yield the title compound.

参考文献中间体

合成目标

【1】 Nam, N.-H.; Kim, Y.; You, Y.-J.; Hong, D.-H.; Kim, H.-M.; Ahn, B.-Z.; Synthesis, cytotoxicity and antitumor activity of 2,3-diarylcyclopent-2-ene-1-ones. Arch Pharmacal Res 2002, 25, 5, 600.
【2】 Nam, N.-H.; Kim, Y.; You, Y.-J.; Hong, D.-H.; Kim, H.-M.; Ahn, B.-Z.; Synthesis and anti-tumor activity of novel combretastatins: combretocyclopentenones and related analogues. Bioorg Med Chem Lett 2002, 12, 15, 1955.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	62318		C₉H₈BrNO₄	详情	详情
(II)	62319	diethyl 2-[2-(4-methoxy-3-nitrophenyl)-2-oxoethyl]malonate	C₁₆H₁₉NO₈	详情	详情
(III)	35239	N-[2-(2-amino-1,3-thiazol-4-yl)ethyl]-2-(3,4,5-trimethoxyphenyl)acetamide	C₁₆H₂₁N₃O₄S	详情	详情
(IV)	62320		C₂₇H₃₁NO₁₂	详情	详情
(V)	62321	diethyl 4-(4-methoxy-3-nitrophenyl)-2-oxo-3-(3,4,5-trimethoxyphenyl)-3-cyclopentene-1,1-dicarboxylate	C₂₇H₂₉NO₁₁	详情	详情
(VI)	62322		C₂₁H₂₁NO₇	详情	详情

Extended Information