1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone -Drug Synthesis Database

【结构式】

【分子编号】51596

【品名】1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone

【CA登记号】

【分子式】C₁₈H₁₈O₂

【分子量】266.33972

【元素组成】C 81.17% H 6.81% O 12.01%

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：(IV)

6-Methoxy-2-tetralone (I) was condensed with pyrrolidine (II) to produce enamine (III). Alkylation of (III) with benzyl bromide, followed by hydrolysis of the enamine function, furnished the 1-benzylnaphthalenone (IV). After formation of the chiral enamine (VI) with (S)-alpha-methylbenzylamine (V), enantioselective Michael addition of methyl vinyl ketone (VII) provided the (R)-diketone (VIII), which underwent ring closure to the phenanthrene derivative (IX) upon treatment with NaOMe. Methyl ether cleavage by using boron trichloride in the presence of tetrabutylammonium iodide afforded phenol (X). The conjugated ketone system of (X) was diastereoselectively reduced to the trans-phenanthrenone (XI) by means of lithium in liquid ammonia. Addition of the lithium acetylide of propyne (XII) to the ketone (XI) produced a diastereomeric mixture of carbinols from which the desired isomer (XIII) was isolated by flash chromatography. The phenol group of (XIII) was then converted to the aryl triflate (XIV) by reaction with trifluoromethanesulfonic anhydride and 2,6-lutidine.

参考文献中间体

合成目标

【1】 Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 .

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)	47506	6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone	2472-22-2	C₁₁H₁₂O₂	详情	详情
(II)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(III)	47507	methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine		C₁₅H₁₉NO	详情	详情
(IV)	51596	1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone		C₁₈H₁₈O₂	详情	详情
(V)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(VI)	51597	1-benzyl-6-methoxy-N-[(1S)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine; N-(1-benzyl-6-methoxy-3,4-dihydro-2-naphthalenyl)-N-[(1S)-1-phenylethyl]amine		C₂₆H₂₇NO	详情	详情
(VII)	30324	3-buten-2-one; methyl vinyl ketone	78-94-4	C₄H₆O	详情	详情
(VIII)	51598	(1R)-1-benzyl-6-methoxy-1-(3-oxobutyl)-3,4-dihydro-2(1H)-naphthalenone		C₂₂H₂₄O₃	详情	详情
(IX)	51599	(4aS)-4a-benzyl-7-methoxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone		C₂₂H₂₂O₂	详情	详情
(X)	51600	(4aS)-4a-benzyl-7-hydroxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone		C₂₁H₂₀O₂	详情	详情
(XI)	51601	(4aS,10aR)-4a-benzyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-2(1H)-phenanthrenone		C₂₁H₂₂O₂	详情	详情
(XII)	51602	1-Propyne		C₃H₄	详情	详情
(XIII)	51603	(2R,4aS,10aR)-4a-benzyl-2-(1-propynyl)-1,2,3,4,4a,9,10,10a-octahydro-2,7-phenanthrenediol		C₂₄H₂₆O₂	详情	详情
(XIV)	51604	(4bS,7R,8aR)-4b-benzyl-7-hydroxy-7-(1-propynyl)-4b,5,6,7,8,8a,9,10-octahydro-2-phenanthrenyl trifluoromethanesulfonate		C₂₅H₂₅F₃O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

6-Methoxy-2-tetralone (I) is converted into enamine (II) by treatment with pyrrolidine in toluene by azeotropic removal of water. Alkylation of (II) with benzyl bromide, followed by hydrolysis of the enamine, provides the 1-benzyl tetralone (III). This is then condensed with (S)-alpha-methylbenzylamine (IV), and the resultant imine (V) is treated with methyl vinyl ketone (VI) to furnish, after hydrolysis of the chiral auxiliary, the tricyclic ketone (VII). Rearrangement of (VII) in the presence of NaOMe results in the phenanthrenone (VIII). Cleavage of the methyl ether of (VIII) is accomplished by treatment with boron trichloride and tetrabutylammonium iodide to form phenol (IX). Reduction of enone (IX) with lithium metal in liquid ammonia leads to the saturated ketone (X). Finally, addition of the lithium acetylide of propyne (XI) to the ketone (X) affords the title carbinol adduct.

参考文献中间体

合成目标

【1】 Morgan, B.P.; Swick, A.G.; Hargrove, D.M.; LaFlamme, J.A.; Moynihan, M.S.; Carroll, R.S.; Martin, K.A.; Lee, E.; Decosta, D.; Bordner, J.; Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists. J Med Chem 2002, 45, 12, 2417.
【2】 Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 .

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)	47506	6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone	2472-22-2	C₁₁H₁₂O₂	详情	详情
(II)	47507	methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine		C₁₅H₁₉NO	详情	详情
(III)	51596	1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone		C₁₈H₁₈O₂	详情	详情
(IV)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(V)	61649	(1S)-N-[1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenylidene]-1-phenyl-1-ethanamine		C₂₆H₂₇NO	详情	详情
(VI)	30324	3-buten-2-one; methyl vinyl ketone	78-94-4	C₄H₆O	详情	详情
(VII)	61650	(1R)-1-benzyl-10-hydroxy-5-methoxy-10-methyltricyclo[7.3.1.0~2,7~]trideca-2,4,6-trien-13-one		C₂₂H₂₄O₃	详情	详情
(VIII)	51599	(4aS)-4a-benzyl-7-methoxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone		C₂₂H₂₂O₂	详情	详情
(IX)	51600	(4aS)-4a-benzyl-7-hydroxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone		C₂₁H₂₀O₂	详情	详情
(X)	51601	(4aS,10aR)-4a-benzyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-2(1H)-phenanthrenone		C₂₁H₂₂O₂	详情	详情
(XI)	51602	1-Propyne		C₃H₄	详情	详情

Extended Information