isocyanato(trimethyl)silane; trimethylsilyl isocyanate -Drug Synthesis Database

【结构式】

【分子编号】19976

【品名】isocyanato(trimethyl)silane; trimethylsilyl isocyanate

【CA登记号】

【分子式】C₄H₉NOSi

【分子量】115.2071

【元素组成】C 41.7% H 7.87% N 12.16% O 13.89% Si 24.38%

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：

Benzocycloheptapyridine (I) was nitrated with NaNO3 and H2SO4 to afford (II) as the major isomer. Reduction of (II) with iron and CaCl2 gave amine (III), which was brominated to provide (IV). Removal of the amino group of (IV) was accomplished by diazotization, followed by reduction with hypophosphorous acid to give (V). Then, hydrolysis of the carbamate group in refluxing hydrochloric acid furnished piperidine (VI). Subsequent coupling of (VI) with N-Boc-piperidineacetic acid (VII) using EDC and HOBt yielded amide (VIII). After Boc deprotection of (VIII) with trifluoroacetic acid, piperidine (IX) was condensed with trimethylsilyl isocyanate to produce the corresponding urea. Finally, separation of the target (+)-atropoisomer was achieved by chiral chromatography.

参考文献中间体

合成目标

【1】 (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336): A very potent farnesyl protein transferase inhibitor as a novel antitumor agent. J Med Chem 1998, 41, 24, 4890.
【2】 Bishop, W.R.; Girijavallabhan, V.M.; Njoroge, F.G.; Bryant, M.S.; Nomeir, A.A.; Doll, R.J.; Ganguly, A.K.; Kirschmeier, P.; Liu, M.; Vibulbhan, B.; Atropisomeric trihalobenzocycloheptapyridine analogues provide stereoselective FPT inhibitors with antitumor activity. Bioorg Med Chem 1999, 7, 5, 861.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	19976	isocyanato(trimethyl)silane; trimethylsilyl isocyanate		C₄H₉NOSi	详情	详情
(I)	19338	ethyl 4-(3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate		C₂₂H₂₂BrClN₂O₂	详情	详情
(II)	19340	ethyl 4-(3-bromo-8-chloro-9-nitro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate		C₂₂H₂₁BrClN₃O₄	详情	详情
(III)	19341	ethyl 4-(9-amino-3-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate		C₂₂H₂₃BrClN₃O₂	详情	详情
(IV)	19342	ethyl 4-(9-amino-3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate		C₂₂H₂₂Br₂ClN₃O₂	详情	详情
(V)	19343	ethyl 4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate		C₂₂H₂₁Br₂ClN₂O₂	详情	详情
(VI)	19344	3,10-dibromo-8-chloro-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₉H₁₇Br₂ClN₂	详情	详情
(VII)	19346	1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid	157688-46-5	C₁₂H₂₁NO₄	详情	详情
(VIII)	25662	tert-butyl 4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxylate		C₃₁H₃₆Br₂ClN₃O₃	详情	详情
(IX)	25663	1-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-(4-piperidinyl)-1-ethanone		C₂₆H₂₈Br₂ClN₃O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

The cyclization of 2-(3-bromophenyl)ethyl alcohol (I) with ethyl 3,3-diethoxypropionate by means of TiCl4 in dichlromethane gives racemic 2-(6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)acetic acid ethyl ester (III), which is regioselectively hydrolyzed by means of Amano P-30 lipase in apH 7 buffer yielding 2-(6-bromo-3,4-dihydro-1H-2-benzopyran-1(S)-yl)acetic acid (IV). The condensation of (IV) with 1-(4-methoxyphenyl)piperazine (V) by means of diethyl cyanophosphate in dichloromethane affords the acylated piperazine (VI), which is reduced with the complex BH3.THF in THF to 6-bromo-1(S)-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-3,4-dihydro-1H-2-benzopyran (VII). The reaction of (VII) with trimethylsilyl isocyante (VIII) by means of BuLiDMF gives the crboxamide (IX), which is treated with di-tert-butyl dicarbonate and dimethylaminopyridine (DMAP) in dichloromethane to yield the N,N-bis(tert-butoxycarbonyl) derivative (X). Finally, this compound is treated with an excess of methylamine.

参考文献中间体

合成目标

【1】 Ennis, M.D.; Tenbrink, R.E. (Pharmacia & Upjohn AB); 1,6-Disubstd. isochromans for treatment of migraine headaches. EP 0836599; JP 1999509532; WO 9702259 .

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)	19969	2-(3-bromophenyl)-1-ethanol; 3-Bromophenethyl alcohol	28229-69-8	C₈H₉BrO	详情	详情
(II)	17901	Ethyl 3,3-diethoxypropanoate	10601-80-6	C₉H₁₈O₄	详情	详情
(III)	19971	ethyl 2-(6-bromo-3,4-dihydro-1H-isochromen-1-yl)acetate		C₁₃H₁₅BrO₃	详情	详情
(IV)	19972	ethyl 2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]acetate		C₁₃H₁₅BrO₃	详情	详情
(V)	16312	1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether	38212-30-5	C₁₁H₁₆N₂O	详情	详情
(VI)	19974	2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]-1-[4-(4-methoxyphenyl)-1-piperazinyl]-1-ethanone		C₂₂H₂₅BrN₂O₃	详情	详情
(VII)	19975	1-[2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]ethyl]-4-(4-methoxyphenyl)piperazine; 4-(4-[2-[(1S)-6-bromo-3,4-dihydro-1H-isochromen-1-yl]ethyl]-1-piperazinyl)phenyl methyl ether		C₂₂H₂₇BrN₂O₂	详情	详情
(VIII)	19976	isocyanato(trimethyl)silane; trimethylsilyl isocyanate		C₄H₉NOSi	详情	详情
(IX)	19977	(1S)-1-[2-[4-(4-methoxyphenyl)-1-piperazinyl]ethyl]-3,4-dihydro-1H-isochromene-6-carboxamide		C₂₃H₂₉N₃O₃	详情	详情
(X)	19978	1-[2-((1S)-6-[[bis(tert-butoxycarbonyl)amino]carbonyl]-3,4-dihydro-1H-isochromen-1-yl)ethyl]-4-(4-methoxyphenyl)piperazine		C₃₃H₄₅N₃O₇	详情	详情

Extended Information