1-indanone -Drug Synthesis Database

【结构式】

【分子编号】23857

【品名】1-indanone

【CA登记号】83-33-0

【分子式】C₉H₈O

【分子量】132.16192

【元素组成】C 81.79% H 6.1% O 12.11%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(I)

The reaction of 1-indanone (I) with sodium azide in acetic acid/sulfuric acid gives the tetrahydroquinolone (II), which is reduced with LiAlH4 in THF, yielding the tetrahydroquinoline (III). The reaction of (III) with NaNO2 and sulfuric acid afords the N-nitroso derivative (IV), which is reduced wiith LiAlH4 in THF to the N-amino compound (V). The reaction of (V) with cyclohexane-1,3-dione (VI) gives the monohydrazone (VII), which is cyclized by means of HCl in refluxing acetic acid, yielding the tetracyclic compound (VIII). The reaction of (VIII) with dimethylamine and paraformaldehyde in hot acetic acid provides compound (IX), which is treated with 2-methylimidazole (X) in refluxing water to afford racemic cilansetron (XI). Finally, this racemate is submitted to optical resolution with di-p-toluyl-D-tartaric acid or D-pyroglutamic acid.

参考文献中间体

合成目标

【1】 Castaner, J.; Rabasseda, X.; Silvestre, J.S.; Graul, A.; Cilansetron. Drugs Fut 1999, 24, 5, 475.
【2】 Haeck, H.H.; Hamminga, D.; Van Wijngaarden, I.; Wouters, W. (Duphar International Research BV); New anellated indole derivs.. AU 8818414; EP 0297651; JP 1989022870; US 4939136 .
【3】 Verbeek, J.-M.; Van der Meij, P.F.C. (Duphar International Research BV); Process for the preparation of enantiomerically pure imidazolyl cpds.. EP 0768309 .
【4】 de Jonge, A.; Tulp, M.T.M.; Olivier, B.; Tipker, J.; van Hes, R.; Mol, F.; Hamminga, D.; Standaar, P.J.; Van Wijngaarden, I.; Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annelated indole derivatives. 1. J Med Chem 1993, 36, 23, 3693.

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)	23857	1-indanone	83-33-0	C₉H₈O	详情	详情
(II)	18553	3,4-dihydro-2(1H)-quinolinone	553-03-7	C₉H₉NO	详情	详情
(III)	23859	1,2,3,4-tetrahydroquinoline	635-46-1	C₉H₁₁N	详情	详情
(IV)	23860	1-nitroso-1,2,3,4-tetrahydroquinoline		C₉H₁₀N₂O	详情	详情
(V)	23861	3,4-dihydro-1(2H)-quinolinylamine; 3,4-dihydro-1(2H)-quinolinamine		C₉H₁₂N₂	详情	详情
(VI)	11244	1,3-Cyclohexanedione	504-02-9	C₆H₈O₂	详情	详情
(VII)	23863	3-[3,4-dihydro-1(2H)-quinolinylimino]cyclohexanone		C₁₅H₁₈N₂O	详情	详情
(VIII)	23864	5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one		C₁₅H₁₅NO	详情	详情
(IX)	23865	10-[(dimethylamino)methyl]-5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one		C₁₈H₂₂N₂O	详情	详情
(X)	15670	2-Methylimidazole; 2-Methyl-1H-imidazole	693-98-1	C₄H₆N₂	详情	详情
(XI)	23867	10-[(2-methyl-1H-imidazol-1-yl)methyl]-5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one		C₂₀H₂₁N₃O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Aldol condensation between 1-indanone (I) and glyoxylic acid (II) in the presence of H2SO4 afforded keto acid (III). Catalytic hydrogenation of (III) over Pd/C furnished 2-indanylacetic acid (IV).

参考文献中间体

合成目标

【1】 Arai, H.; Niwa, S.; Nishioka, H.; Yamanaka, T.; Torizuka, M.; Yoshinaga, K.; Kobayashi, N.; Ikeda, Y.; Tanaka, Y.; New potent prolyl endopeptidase inhibitors: Synthesis and structure-activity relationships of indan and tetralin derivatives and their analogues. J Med Chem 1994, 37, 13, 2071.

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)	23857	1-indanone	83-33-0	C₉H₈O	详情	详情
(II)	15618	2-Oxoacetic acid; Glyoxylic Acid	298-12-4	C₂H₂O₃	详情	详情
(III)	55611	2-(1-oxo-1,3-dihydro-2H-inden-2-ylidene)acetic acid		C₁₁H₈O₃	详情	详情
(IV)	21721	2-(2,3-dihydro-1H-inden-2-yl)acetic acid	37868-26-1	C₁₁H₁₂O₂	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 reduction of 1-indanone (I) with NaBH4 in methanol gives 1-indanol (II), which is brominated with Tms-Br in chloroform to yield 1-bromoindane (III) (1). The condensation of (III) with triethyl phosphonoacetate (IV) and NaH in DMF affords 2-(diethoxyphosphoryl)-2-(1-indanyl)acetic acid ethyl ester (V), which is treated with paraformaldehyde and K2CO3 in refluxing THF to provide 2-(1-indanyl)acrylic acid ethyl ester (VI). The hydrolysis of (VI) with NaOH in acetone/water gives the corresponding acrylic acid (VII), which is condensed with thioacetic acid (VIII) in refluxing chloroform to yield 3-(acetylsulfanyl)-2-(1-indanyl)propionic acid ethyl ester (IX) as a mixture of the two (R,R)+(S,S) and (R,S)+(S,R) racemates. These two racemates are easily separated by HPLC affording the desired (R,R)+(S,S)-(X) racemate. The condensation of (X) with L-tryptophan methyl ester (XI) by means of EDC and HOBT in THF/chloroform to provide a diastereomeric mixture (R,R,S)+(S,S,S) of compounds that is separated by HPLC to provide the desired (R,R,S) diastereomer (XII). Finally, this compound is hydrolyzed with NaOH in methanol/water to furnish the target tryptophan derivative.

参考文献中间体

合成目标

【1】 Inguimbert, N.; Roques, B.P.; Meudal, H.; Teffot, F.; Poras, H.; Fournié-Zaluski, M.-C.; Coric, P.; Toward an optimal joint recognition of the S1' subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP). J Med Chem 2002, 45, 7, 1477.
【2】 Roques, B.P.; Renard, P.; Scalbert, E.; Bennejean, C.; Fournie-Lazuski, M.-C.; Inguimbert, N.; Poras, H. (ADIR et Cie.; INSERM (Institut National de la Sante et de la Recherche Medicale)); Amino acid derivs. and use thereof as NEP, ACE and ECE inhibitors. FR 2805259; WO 0160822 .

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)	23857	1-indanone	83-33-0	C₉H₈O	详情	详情
(II)	53590	1-Hydroxyhydrindene; 1-Hydroxyindan; 1-Indanol	6351-10-6	C₉H₁₀O	详情	详情
(III)	53591	1-bromoindane	n/a	C₉H₉Br	详情	详情
(IV)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(V)	53592	ethyl 2-(diethoxyphosphoryl)-2-(2,3-dihydro-1H-inden-1-yl)acetate	n/a	C₁₇H₂₅O₅P	详情	详情
(VI)	53593	ethyl 2-(2,3-dihydro-1H-inden-1-yl)acrylate	n/a	C₁₄H₁₆O₂	详情	详情
(VII)	53594	2-(2,3-dihydro-1H-inden-1-yl)acrylic acid	n/a	C₁₂H₁₂O₂	详情	详情
(VIII)	12893	Ethanethioic S-acid		C₂H₄OS	详情	详情
(IX)	53595	3-(acetylsulfanyl)-2-(2,3-dihydro-1H-inden-1-yl)propanoic acid	n/a	C₁₄H₁₆O₃S	详情	详情
(X)	53596	(2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoic acid	n/a	C₁₄H₁₆O₃S	详情	详情
(XI)	30387	2-amino-6-isopropyl-4-pyrimidinol		C₇H₁₁N₃O	详情	详情
(XII)	53597	methyl (2S)-2-({(2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoyl}amino)-3-(1H-indol-3-yl)propanoate	n/a	C₂₆H₂₈N₂O₄S	详情	详情

合成路线4

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】 Boulton LT, Lennon IC, Bahar E 2006. Process for the synthesis of enantiomeric (propynylamino) indan derivatives by asymmetric reduction of indanones to chiral indanols and subsequent amination with propargylamine. US 2006199974（本专利属于Teva PMrmaceutical Industries Ltd, Israel)

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)	23857	1-indanone	83-33-0	C₉H₈O	详情	详情
(II)	53590	1-Hydroxyhydrindene; 1-Hydroxyindan; 1-Indanol	6351-10-6	C₉H₁₀O	详情	详情

Extended Information