ZK-34228, CGP-28237, -Drug Synthesis Database

【结构式】

【药物名称】ZK-34228, CGP-28237

【化学名称】5-Methylsulfonylamino-6-phenoxy-1-indanone

【CA登记号】75360-85-9

【分子式】C₁₆H₁₅NO₄S

【分子量】317.36625

【开发单位】Novartis (Originator), Schering AG (Originator)

【药理作用】Non-Steroidal Antiinflammatory Drugs

合成路线1 合成路线2 合成路线3

合成路线1

A) Synthesis of intermediate (VII): The acetylation of 5-aminoindane (I) with acetic anhydride gives N-(5-indanyl)acetamide (II), which is nitrated with HNO3 in glacial acetic acid yielding N-(6-nitro-5-indanyl)acetamide (III) and a small amount of the isomer (IV). The product (III) is hydrolyzed with HCl to 6-nitro-5-indanylamine (V). This nitroamine can also be obtained by nitration of 5-aminoindane (I). The Sandmeyer reaction of 6-nitro-5-indanylamine (V) with HNO2 and CuBr/NaBr in HBr gives 6-nitro-5-bromoindane (VI), which reacts with phenol in the presence of either K2CO3/ CuCl in pyridine (Method A) or t-BuOK in DMF (Method B) or t-BuOK/CuCl in tert-butanol (Method C) to yield 6-nitro-5-phenoxyindane (VII).

参考文献中间体

【1】 Ferrini, P.G.; Bottcher, I.; CGP-28237. Drugs Fut 1987, 12, 1, 9.
【2】 Schroder, E.; Lehmann, M.; Rufer, C.; Bottcher, I.; Non-steroidal antiinflammatory compounds. 6. Antii. Eur J Med Chem 1982, 17, 1, 35-42.
【3】 Rufer, C.; Bahlmann, F.; Schroder, E.; Bottcher, I.; Non-steroidal antiinflammatory compounds. 8. Antii. Eur J Med Chem 1982, 17, 1, 173-80.

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)	21473	5-indanamine; 2,3-dihydro-1H-inden-5-ylamine	24425-40-9	C₉H₁₁N	详情	详情
(II)	21474	N-(2,3-dihydro-1H-inden-5-yl)acetamide		C₁₁H₁₃NO	详情	详情
(III)	21475	N-(6-nitro-2,3-dihydro-1H-inden-5-yl)acetamide		C₁₁H₁₂N₂O₃	详情	详情
(IV)	21476	N-(4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide		C₁₁H₁₂N₂O₃	详情	详情
(V)	21477	6-nitro-2,3-dihydro-1H-inden-5-ylamine; 6-nitro-5-indanamine		C₉H₁₀N₂O₂	详情	详情
(VI)	21478	5-bromo-6-nitroindane		C₉H₈BrNO₂	详情	详情
(VII)	23070	6-nitro-2,3-dihydro-1H-inden-5-yl phenyl ether; 5-nitro-6-phenoxyindane		C₁₅H₁₃NO₃	详情	详情

合成路线2

1) Condensation of (VII) with tert-butoxybis(dimethylamino)methane followed by ozonolysis of the enamine (VIII) and reduction of the nitro group using Raney Ni yields 5-amino-6-phenoxy-1-indanone (X). In the last step the intermediate (X) is mesylated with mesyl chloride to give CGP 28237.

参考文献中间体

【1】 Ferrini, P.G.; Bottcher, I.; CGP-28237. Drugs Fut 1987, 12, 1, 9.
【2】 Schroder, E.; Lehmann, M.; Rufer, C.; Bottcher, I.; Non-steroidal antiinflammatory compounds. 6. Antii. Eur J Med Chem 1982, 17, 1, 35-42.
【3】 Rufer, C.; Bahlmann, F.; Schroder, E.; Bottcher, I.; Non-steroidal antiinflammatory compounds. 8. Antii. Eur J Med Chem 1982, 17, 1, 173-80.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(A)	21487	N-[tert-butoxy(dimethylamino)methyl]-N,N-dimethylamine	C₉H₂₂N₂O	详情	详情
(VII)	23070	6-nitro-2,3-dihydro-1H-inden-5-yl phenyl ether; 5-nitro-6-phenoxyindane	C₁₅H₁₃NO₃	详情	详情
(VIII)	23071	N,N-dimethyl-N-[(5-nitro-6-phenoxy-2,3-dihydro-1H-inden-1-ylidene)methyl]amine; N,N-dimethyl(5-nitro-6-phenoxy-2,3-dihydro-1H-inden-1-ylidene)methanamine	C₁₈H₁₈N₂O₃	详情	详情
(IX)	23072	5-nitro-6-phenoxy-1-indanone	C₁₅H₁₁NO₄	详情	详情
(X)	23073	5-amino-6-phenoxy-1-indanone	C₁₅H₁₃NO₂	详情	详情

合成路线3

2) Reduction of (VII) using Raney Ni gives 5-amino-6-phenoxyindane (XI), which is acetylated with acetic anhydride and oxidized with CrO3 to yield a mixture of indanones (XII) and (XIII). Chromatographic separation and hydrolysis of (XII) with HCl in ethanol gives 5-amino-6-phenoxy-1-indanone (X), which can be mesylated, as before, to CGP-28237.

参考文献中间体

【1】 Ferrini, P.G.; Bottcher, I.; CGP-28237. Drugs Fut 1987, 12, 1, 9.
【2】 Rufer, C.; Bahlmann, F.; Schroder, E.; Bottcher, I.; Non-steroidal antiinflammatory compounds. 8. Antii. Eur J Med Chem 1982, 17, 1, 173-80.
【3】 Schroder, E.; Lehmann, M.; Rufer, C.; Bottcher, I.; Non-steroidal antiinflammatory compounds. 6. Antii. Eur J Med Chem 1982, 17, 1, 35-42.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	23070	6-nitro-2,3-dihydro-1H-inden-5-yl phenyl ether; 5-nitro-6-phenoxyindane	C₁₅H₁₃NO₃	详情	详情
(X)	23073	5-amino-6-phenoxy-1-indanone	C₁₅H₁₃NO₂	详情	详情
(XI)	23075	6-phenoxy-2,3-dihydro-1H-inden-5-ylamine; 6-phenoxy-5-indanamine	C₁₅H₁₅NO	详情	详情
(XII)	23076	N-(1-oxo-6-phenoxy-2,3-dihydro-1H-inden-5-yl)acetamide	C₁₇H₁₅NO₃	详情	详情
(XIII)	23077	N-(3-oxo-6-phenoxy-2,3-dihydro-1H-inden-5-yl)acetamide	C₁₇H₁₅NO₃	详情	详情

Extended Information