bromo(isopropyl)magnesium -Drug Synthesis Database

【结构式】

【分子编号】33398

【品名】bromo(isopropyl)magnesium

【CA登记号】920-39-8

【分子式】C₃H₇BrMg

【分子量】147.29758

【元素组成】C 24.46% H 4.79% Br 54.25% Mg 16.5%

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：(II)

The synthesis of heptadeuterated flutamide has been reported: The reaction of deuterated isopropyl bromide (I) with Mg in THF gives the corresponding Grignard reagent (II), which is treated with CO2 yielding the deuterated isobutyric acid (III). The reaction of (III) with oxalyl chloride affords the expected acyl chloride (IV), which is finally condensed with 4-nitro-3-(trifluoromethyl)aniline (V).

参考文献中间体

合成目标

【1】 Passarella, D.; et al.; Synthesis of flutamide-d7 and its main metabolite-d6. J Label Compd Radiopharm 1999, 42, 3, 275.

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)	32658	2-bromopropane	75-26-3	C₃H₇Br	详情	详情
(II)	33398	bromo(isopropyl)magnesium	920-39-8	C₃H₇BrMg	详情	详情
(III)	33399	2-methylpropionic acid	79-31-2	C₄H₈O₂	详情	详情
(IV)	14932	isobutyryl chloride; 2-methylpropanoyl chloride	79-30-1	C₄H₇ClO	详情	详情
(V)	33400	4-nitro-3-(trifluoromethyl)phenylamine; 4-nitro-3-(trifluoromethyl)aniline; 3-Trifluoromethyl-4-nitroaniline	393-11-3	C₇H₅F₃N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(LIV)

Silylation of (L) by treatment with TBSOTf and 2,6-lutidine in CH2Cl2 furnishes (LI), whose benzyl group is removed by means of Na/NH3 in THF to yield (LII). Moffat oxidation of (LII) gives aldehyde (LIII), which is treated with isopropylmagnesium bromide (LIV) in THF to afford a mixture of adducts from which (LV) is chromatographically separated. Treatment of (LV) with TFA/H2O provides (LVI), which is then treated with O3 (DMS workup) and finally oxidized with HOSO2NH2, NaH2PO4 and NaClO2 to yield carboxylic acid (X).

参考文献中间体

合成目标

【1】 Chida, N.; et al.; Stereoselective total synthesis of (+)-lactacystin from D-glucose. Tetrahedron 1997, 53, 48, 16287.
【2】 Corey, E.J.; Li, W.-D.Z.; Total synthesis and biological activity of lactacystin, omuralide and analogs. Chem Pharm Bull 1999, 47, 1, 1.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	43590	(2R,3S,4R)-3-hydroxy-2-[(1S)-1-hydroxy-2-methylpropyl]-4-methyl-5-oxo-2-pyrrolidinecarboxylic acid		C₁₀H₁₇NO₅	详情	详情
(L)	43635	(3R,4S,5R)-5-[(benzyloxy)methyl]-4-hydroxy-3-methyl-5-vinyl-2-pyrrolidinone		C₁₅H₁₉NO₃	详情	详情
(LI)	43636	(3R,4S,5R)-5-[(benzyloxy)methyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-5-vinyl-2-pyrrolidinone		C₂₁H₃₃NO₃Si	详情	详情
(LII)	43637	(3R,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-(hydroxymethyl)-3-methyl-5-vinyl-2-pyrrolidinone		C₁₄H₂₇NO₃Si	详情	详情
(LIII)	43638	(2S,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-oxo-2-vinyl-2-pyrrolidinecarbaldehyde		C₁₄H₂₅NO₃Si	详情	详情
(LIV)	33398	bromo(isopropyl)magnesium	920-39-8	C₃H₇BrMg	详情	详情
(LV)	43639	(3R,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[(1S)-1-hydroxy-2-methylpropyl]-3-methyl-5-vinyl-2-pyrrolidinone		C₁₇H₃₃NO₃Si	详情	详情
(LVI)	43640	(3R,4S,5R)-4-hydroxy-5-[(1S)-1-hydroxy-2-methylpropyl]-3-methyl-5-vinyl-2-pyrrolidinone		C₁₁H₁₉NO₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XVIII)

The reaction of the methoxyamide (XVII) with isopropylmagnesium bromide (XVIII) in dioxane gives the isobutyryl derivative (XIX), which is deacylated by means of TFA in dichloromethane to yield the aromatic amine (XX). The acylation of (XX) with 1-acetoxycyclopropanecarbonyl chloride (XXI) by means of TEA in dichloromethane affords the corresponding amide (XXII), which is finally deacetylated by means of NaOH in MeOH to provide the target thienopyridinone derivative.

参考文献中间体

合成目标

【1】 Imada, T.; Fujino, M.; Suzuki, N.; Harada, M.; Kasai, S.; Sasaki, S.; Endo, S.; Hayase, Y.; Furuya, S.; Cho, N.; Discovery of the thieno[2,3-b]pyridin-4-one derivative TAK-810: Highly potent and orally active nonpeptide LHRH (GnRH) antagonist (I). 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 353.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	58693	3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-N-methoxy-N-methyl-4-oxo-2-{4-[(2,2,2-trifluoroacetyl)amino]phenyl}-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide		C₃₄H₂₉F₅N₄O₄S	详情	详情
(XVIII)	33398	bromo(isopropyl)magnesium	920-39-8	C₃H₇BrMg	详情	详情
(XIX)	58694	N-{4-[3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-5-isobutyryl-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide		C₃₅H₃₀F₅N₃O₃S	详情	详情
(XX)	58695	2-(4-aminophenyl)-3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-5-isobutyrylthieno[2,3-b]pyridin-4(7H)-one		C₃₃H₃₁F₂N₃O₂S	详情	详情
(XXI)	58696	1-(chlorocarbonyl)cyclopropyl acetate		C₆H₇ClO₃	详情	详情
(XXII)	58697	1-({4-[3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-5-isobutyryl-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl]anilino}carbonyl)cyclopropyl acetate		C₃₉H₃₇F₂N₃O₅S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XVIII)

Alternatively, the ethyl ester group of (XIII) is treated with N,O-dimethylhydroxylamine (XVI) and TEA as before to give the methoxyamide (XXIII), which is treated with isopropylmagnesium bromide (XVIII) in dioxane to yield the isobutyryl derivative (XXIV). The reduction of the nitro group of (XXIV) by means of Fe and HCl in ethanol affords the aromatic amine (XX), which is finally acylated with 1-hydroxycyclopropanecarboxylic acid (XXV) by means of BOP and DIEA in CH2Cl2 to provide the target thienopyridinone derivative.

参考文献中间体

合成目标

【1】 Suzuki, N.; Furuya, S.; Choh, N.; Imada, T. (Takeda Chemical Industries, Ltd.); Thienopyridine cpds., their production and use. EP 1090010; JP 2000219690; JP 2000219691; US 6262267; US 6329388; WO 0000493 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	23155	ethyl 3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₃₂H₂₇F₂N₃O₅S	详情	详情
(XVI)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(XVIII)	33398	bromo(isopropyl)magnesium	920-39-8	C₃H₇BrMg	详情	详情
(XX)	58695	2-(4-aminophenyl)-3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-5-isobutyrylthieno[2,3-b]pyridin-4(7H)-one		C₃₃H₃₁F₂N₃O₂S	详情	详情
(XXIII)	58698	3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-N-methoxy-N-methyl-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide		C₃₂H₂₈F₂N₄O₅S	详情	详情
(XXIV)	58699	3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-5-isobutyryl-2-(4-nitrophenyl)thieno[2,3-b]pyridin-4(7H)-one		C₃₃H₂₉F₂N₃O₄S	详情	详情
(XXV)	58700	1-Hydroxy-1-cyclopropanecarboxylic acid	17994-25-1	C₄H₆O₃	详情	详情

Extended Information