5-iodo-1H-indole -Drug Synthesis Database

【结构式】

【分子编号】40983

【品名】5-iodo-1H-indole

【CA登记号】

【分子式】C₈H₆IN

【分子量】243.04685

【元素组成】C 39.53% H 2.49% I 52.21% N 5.76%

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：(VII)

5-Iodooxiindole (I) may be prepared by published procedures: 1) Treatment of p-iodoaniline (IV) with the Sandmeyer isonitrosoacetanilide Isatin synthesis, by condensation with chloral hydrate (A) and hydroxylamine followed by cyclization with concentrated sulfuric acid and hydrolysis with water yields isatin (V). The conversion of (V) to (I) may be conducted via the Wolf-Kishner reduction by treatment with hydrazine hydrate in ethanol at 20-80 C to give hydrazide (VI). The conversion from (VI) to (I) may be performed by treatment with sodium ethoxide in a suitable solvent such as ethanol at 0-80 C. 2) Iodoindole (VII) may be converted to the bromo derivative (VIII) by tretment with pyridinium perbromide in tert-butyl alcohol. The last step of the synthesis is the treatment of (VIII) with H2 over Pd/C in anhydrous ethanol, or by treatment with a solution of NH4Cl followed by treatment with activated zinc in THF. 3) Iodoaniline (IV) can be converted to the sulfanylderivative (IX) by treatment with tert-butyl hypochlorite, followed by treatment with ethyl methylthioacetate (B) and triethylamine in dichloromethane. Finally the conversion of (IX) to the desired product may be conducted by means of W-2 Raney-Ni in EtOH or by treatment with activated zinc in THF.

参考文献中间体

合成目标

【1】 McNutt, R.W. Jr.; Hunter, R.N. III; Jung, D.K.; Lackey, K.E.; Dickerson, S.; Harris, P.A.; Veal, J.M.; Peel, M.R. (Glaxo Group Ltd.); Benzylidene-1,3-dihydro-indol-2-one derivs. as receptor tyrosine kinase inhibitors, particularly of Raf kinases. EP 1003721; WO 9910325 .

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)	14018	2,2,2-Trichloro-1,1-ethanediol; Chloral hydrate	302-17-0	C₂H₃Cl₃O₂	详情	详情
(B)	40985	ethyl 2-(methylsulfanyl)-2-oxoacetate		C₅H₈O₃S	详情	详情
(I)	40979	5-iodo-1,3-dihydro-2H-indol-2-one		C₈H₆INO	详情	详情
(IV)	26393	4-iodoaniline; 4-iodophenylamine	540-37-4	C₆H₆IN	详情	详情
(V)	40981	5-iodo-1H-indole-2,3-dione	20780-76-1	C₈H₄INO₂	详情	详情
(VI)	40982	5-iodo-1H-indole-2,3-dione 3-hydrazone		C₈H₆IN₃O	详情	详情
(VII)	40983	5-iodo-1H-indole		C₈H₆IN	详情	详情
(VIII)	40984	3,3-dibromo-5-iodo-1,3-dihydro-2H-indol-2-one		C₈H₄Br₂INO	详情	详情
(IX)	40986	5-iodo-3-(methylsulfanyl)-1,3-dihydro-2H-indol-2-one		C₉H₈INOS	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The intermediate silyl sulfide (II) was prepared by palladium-catalyzed displacement of 5-bromo-1-methylindole (I) with potassium (triisopropylsilyl)sulfide. Alternatively, 5-iodoindole (III) was N-methylated with iodomethane and NaH, yielding 5-iodo-1-methylindole (IV), which was then reacted with potassium (triisopropylsilyl)sulfide to give (II). Condensation of silyl sulfide (II) with the aryl triflate (V) in the presence of CsF as the desilylating reagent furnished the diaryl sulfide (VI). Knoevenagel condensation of aldehyde (VI) with malonic acid (VII) gave rise to the cinnamic acid derivative (VIII). This was then coupled with ethyl isonipecotate (IX), producing amide (X). The ethyl ester of (X) was finally hydrolyzed with NaOH to yield the title sodium carboxylate salt.

参考文献中间体

合成目标

【1】 Reilly, E.B.; Liu, G.; Winn, M.; et al.; Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 4. Structure-activity relationships of substituents on the benzene ring of the cinnamide. J Med Chem 2001, 44, 25, 4393.
【2】 Jae, H.-S.; Pei, Z.; Staeger, M.A.; Gunawardana, I.W.; Winn, M.; Freeman, J.C.; Liu, G.; Link, J.; Boyd, S.A.; Zhu, G.-D.; Von Geldern, T.W.; Xin, Z.; Lynch, J.K.; Wang, S. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. WO 0059880 .
【3】 Lynch, J.K.; Link, J.; Zhu, G.-D.; Boyd, S.A.; Winn, M.; Pei, Z.; Gunawardana, I.W.; Liu, G.; Xin, Z.; Jae, H.-S.; Freeman, J.C.; Von Geldern, T.; Staeger, M.A. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. US 6110922; WO 0039081 .

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)	29521	5-bromo-1-methyl-1H-indole		C₉H₈BrN	详情	详情
(II)	53020	1-methyl-5-[(triisopropylsilyl)sulfanyl]-1H-indole; 1-methyl-1H-indol-5-yl triisopropylsilyl sulfide	n/a	C₁₈H₂₉NSSi	详情	详情
(III)	40983	5-iodo-1H-indole		C₈H₆IN	详情	详情
(IV)	53021	5-iodo-1-methyl-1H-indole	n/a	C₉H₈IN	详情	详情
(V)	52029	2,3-dichloro-4-formylphenyl trifluoromethanesulfonate		C₈H₃Cl₂F₃O₄S	详情	详情
(VI)	53022	2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]benzaldehyde	n/a	C₁₆H₁₁Cl₂NOS	详情	详情
(VII)	12963	Malonic acid	141-82-2	C₃H₄O₄	详情	详情
(VIII)	53023	(E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoic acid	n/a	C₁₈H₁₃Cl₂NO₂S	详情	详情
(IX)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(X)	53024	ethyl 1-((E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoyl)-4-piperidinecarboxylate	n/a	C₂₆H₂₆Cl₂N₂O₃S	详情	详情

Extended Information