5-indanamine; 2,3-dihydro-1H-inden-5-ylamine -Drug Synthesis Database

【结构式】

【分子编号】21473

【品名】5-indanamine; 2,3-dihydro-1H-inden-5-ylamine

【CA登记号】24425-40-9

【分子式】C₉H₁₁N

【分子量】133.19308

【元素组成】C 81.16% H 8.32% N 10.52%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(I)

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 leads to 6-nitro-5-bromoindane (VI), which reacts with 2,4-difluorophenol in the presence of KOC(CH3)3/CuCl in tert-butanol to yield 6-nitro-5-(2,4-difluorophenoxy)indane (VII). Starting from (VII), CGP-28238 can be prepared by two different routes: a) Condensation of (VII) with tert-butoxy-bis(dimethylamino)methane followed by ozonolysis of the enamine (VIII), and reduction of the nitro group using Raney-Ni and hydrazine hydrate yields 5-amino-6-(2,4-difluorophenoxy)-1-indanone (X). In the last step the intermediate (X) is mesylated with mesylchloride to give CGP-28238. b) Reduction of (VII) using Raney-Ni and hydrazine hydrate gives 5-amino-6-(2,4-difluorophenoxy)indane (XI), which is acetylated with acetic anhydride and oxidized with CrO3 to yield a mixture of indanone (XII) and (XIII). Chromatographic separation and hydrolysis of (XII) with HCl in ethanol gives 5-amino-6-(2,4-difluorophenoxy)-1-indanone (X), which can be mesylated, as before, to CGP-28238.

参考文献中间体

合成目标

【1】 Schroder, E.; Rufer, C.; Bottcher, I.; Kapp, J.-F. (Schering AG); Novel indanyl derivs., their preparation and use. EP 0056956; US 4375479 .
【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.
【4】 Wiesenberg, I.; Ferrini, P.G.; CGP-28238. Drugs Fut 1989, 14, 11, 1035.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	21486	2,4-difluorophenol	367-27-1	C₆H₄F₂O	详情	详情
(B)	21487	N-[tert-butoxy(dimethylamino)methyl]-N,N-dimethylamine		C₉H₂₂N₂O	详情	详情
(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)	21479	5-(2,4-difluorophenoxy)-6-nitroindane		C₁₅H₁₁F₂NO₃	详情	详情
(VIII)	21480	N-[[6-(2,4-difluorophenoxy)-5-nitro-2,3-dihydro-1H-inden-1-ylidene]methyl]-N,N-dimethylamine		C₁₈H₁₆F₂N₂O₃	详情	详情
(IX)	21481	6-(2,4-difluorophenoxy)-5-nitro-1-indanone		C₁₅H₉F₂NO₄	详情	详情
(X)	21482	5-amino-6-(2,4-difluorophenoxy)-1-indanone		C₁₅H₁₁F₂NO₂	详情	详情
(XI)	21483	6-(2,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-ylamine		C₁₅H₁₃F₂NO	详情	详情
(XII)	21484	N-[6-(2,4-difluorophenoxy)-1-oxo-2,3-dihydro-1H-inden-5-yl]acetamide		C₁₇H₁₃F₂NO₃	详情	详情
(XIII)	21485	N-[6-(2,4-difluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-5-yl]acetamide		C₁₇H₁₃F₂NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

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

合成目标

【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3

该中间体在本合成路线中的序号：(I)

The reaction of indan-5-amine (I) with acetic anhydride gives the acetamide (II), which is brominated with Br2 in acetic acid yielding the 6-bromo derivative (III). The reaction of (III) with CuCN in 1-methyl-2-pyrrolidone at 125 C affords the corresponding nitrile (IV), which is cyclized by means of H2O2 and NaOH in hot ethanol/water giving the tricyclic ketone (V). The reaction of (V) with chloromethyl pivalate (A) and potassium tert-butoxide in DMSO yields the pivaloyloxymethyl derivative (VI), which is oxidized with CrO3 and tert-butyl peroxide in dichloromethane affording the diketone (VII) (after chromatographic separation of the undesired regioisomer). The condensation of (VII) with N-(4-aminobenzoyl)-Lglutamic acid diethyl ester (VIII) by means of TsOH in refluxing DME gives the imino derivative (IX), which without isolation, is reduced to the secondary amine (X) (as a diastereomeric mixture) with NaBH3CN in methanol/acetic acid. The alkylation of the secondary amine group of (X) with propargyl bromide (XI) and CaCO3 in hot DMA yields the tertiary amine (XII), which is hydrolyzed and deprotected with first with NaOH in methanol/water, and then with aqueous HCl to provide the target compound as a diastereomeric mixture. Finally, this compound is resolved by a treatment with carboxypeptidase G2 and ZnCl2 in water that hydrolyzes selectively the undesired isomer.

参考文献中间体

合成目标

【1】 Bavetsias, V.; Matusiak, Z.; Melin, C.; Neidle, S.; Marriott, J.H.; Boyle, F.T.; Jackman, A.L.; Chemoenzymatic preparation of the novel antifolate thymidylate synthase inhibitor N-(4-{N-[(6S)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}-benzoyl)-L-glutamic acid and its glutamyl cleavage product. J Chem Soc - Perkins Trans I 1999, 11, 1495.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	16166	chloromethyl pivalate	18997-19-8	C₆H₁₁ClO₂	详情	详情
(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)	31073	N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide		C₁₁H₁₂BrNO	详情	详情
(IV)	31074	N-(6-cyano-2,3-dihydro-1H-inden-5-yl)acetamide		C₁₂H₁₂N₂O	详情	详情
(V)	31075	2-methyl-3,6,7,8-tetrahydro-4H-cyclopenta[g]quinazolin-4-one		C₁₂H₁₂N₂O	详情	详情
(VI)	31076	(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate		C₁₈H₂₂N₂O₃	详情	详情
(VII)	31077	(2-methyl-4,6-dioxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate		C₁₈H₂₀N₂O₄	详情	详情
(VIII)	31078	diethyl (2S)-2-[(4-aminobenzoyl)amino]pentanedioate; Diethyl N-(4-aminobenzoyl)-L-glutamate	13726-52-8	C₁₆H₂₂N₂O₅	详情	详情
(IX)	31079	diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-ylidene)amino]benzoyl]amino)pentanedioate		C₃₄H₄₀N₄O₈	详情	详情
(X)	31080	diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl]amino)pentanedioate		C₃₄H₄₂N₄O₈	详情	详情
(XI)	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(XII)	31081	diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioate		C₃₇H₄₄N₄O₈	详情	详情
(XIII)	31082	(2S)-2-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioic acid		C₂₇H₂₆N₄O₆	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

5-Aminoindan (I) was acetylated, and the resulting anilide (II) was brominated in HOAc to afford (III). Displacement of the bromine of (III) with CuCN in N-methylpyrrolidinone at 125 C furnished nitrile (IV), which was cyclized to the desired quinazolinone derivative (V) upon treatment with sodium hydroperoxide. Protection of the NH group of (V) was achieved by alkylation with chloromethyl pivaloate yielding (VI). Benzylic bromination of (VI) with N-bromosuccinimide in the presence of benzoyl peroxide gave bromide (VII). This was condensed with diethyl p-aminobenzoyl-L-glutamate (VIII) by means of CaCO3 to produce adduct (IX). Further alkylation of (IX) with propargyl bromide (X) using CaCO3 provided propargyl amine (XI). Hydrolysis of the ethyl esters and pivaloyloxymethyl protecting group of (XI) with NaOH afforded (XII). The glutamic acid moiety of (XII) was then removed by enzimatic hydrolysis with carboxypeptidase G2 to furnish intermediate (XIII).

参考文献中间体

合成目标

【1】 Bavetsias, V.; Boyle, F.T.; Hennequin, L.F.A.; Marriott, J.H. (AstraZeneca plc; BTG plc); Anti-cancer cpds. containing cyclopentaquinazoline ring. EP 0758328; GB 2290082; JP 1997512812; US 5747499; WO 9530673 .
【2】 Jackman, A.L.; Melin, C.; Bavetsias, V.; Matusiak, Z.S.; Marriott, J.H.; Kimbel, C.; Boyle, F.T.; Design and synthesis of cyclopenta[g]quinazoline-based antifolates as inhibitors of thymidylate synthase and potential antitumor agents. J Med Chem 2000, 43, 10, 1910.

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)	31073	N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide		C₁₁H₁₂BrNO	详情	详情
(IV)	31074	N-(6-cyano-2,3-dihydro-1H-inden-5-yl)acetamide		C₁₂H₁₂N₂O	详情	详情
(V)	31075	2-methyl-3,6,7,8-tetrahydro-4H-cyclopenta[g]quinazolin-4-one		C₁₂H₁₂N₂O	详情	详情
(VI)	31076	(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate		C₁₈H₂₂N₂O₃	详情	详情
(VII)	41348	(6-bromo-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate		C₁₈H₂₁BrN₂O₃	详情	详情
(VIII)	31078	diethyl (2S)-2-[(4-aminobenzoyl)amino]pentanedioate; Diethyl N-(4-aminobenzoyl)-L-glutamate	13726-52-8	C₁₆H₂₂N₂O₅	详情	详情
(IX)	31080	diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl]amino)pentanedioate		C₃₄H₄₂N₄O₈	详情	详情
(X)	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(XI)	31081	diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioate		C₃₇H₄₄N₄O₈	详情	详情
(XII)	31082	(2S)-2-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioic acid		C₂₇H₂₆N₄O₆	详情	详情
(XIII)	41349	4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoic acid		C₂₂H₁₉N₃O₃	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Boyle, F.; Crook, J.W.; Matusiak, Z.S. (AstraZeneca plc; BTG plc); Tricyclic cpds. with pharmaceutical activity. EP 0667864; GB 2272217; JP 1996505838; US 5789417; WO 9411354 .

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)	31073	N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide		C₁₁H₁₂BrNO	详情	详情
(IV)	31074	N-(6-cyano-2,3-dihydro-1H-inden-5-yl)acetamide		C₁₂H₁₂N₂O	详情	详情
(V)	31075	2-methyl-3,6,7,8-tetrahydro-4H-cyclopenta[g]quinazolin-4-one		C₁₂H₁₂N₂O	详情	详情
(VI)	31076	(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate		C₁₈H₂₂N₂O₃	详情	详情
(VII)	41348	(6-bromo-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-3-yl)methyl pivalate		C₁₈H₂₁BrN₂O₃	详情	详情
(VIII)	31078	diethyl (2S)-2-[(4-aminobenzoyl)amino]pentanedioate; Diethyl N-(4-aminobenzoyl)-L-glutamate	13726-52-8	C₁₆H₂₂N₂O₅	详情	详情
(IX)	31080	diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)amino]benzoyl]amino)pentanedioate		C₃₄H₄₂N₄O₈	详情	详情
(X)	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(XI)	31081	diethyl (2S)-2-([4-[(3-[[(2,2-dimethylpropanoyl)oxy]methyl]-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioate		C₃₇H₄₄N₄O₈	详情	详情
(XII)	31082	(2S)-2-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)pentanedioic acid		C₂₇H₂₆N₄O₆	详情	详情
(XIII)	41349	4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoic acid		C₂₂H₁₉N₃O₃	详情	详情

Extended Information