2-nitropropane -Drug Synthesis Database

【结构式】

【分子编号】21819

【品名】2-nitropropane

【CA登记号】79-46-9

【分子式】C₃H₇NO₂

【分子量】89.09412

【元素组成】C 40.44% H 7.92% N 15.72% O 35.92%

与该中间体有关的原料药合成路线共 6 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6

合成路线1

该中间体在本合成路线中的序号：(IV)

By reaction of 3-(2-methyl-2-aminopropyl)indole (I) and 2-(2,3-epoxypropoxy)benzonitrile (II) by heating at 120-40 C followed by a treatment with HCl in ethanol. The starting products are obtained as follows: 1) The reaction of 3-(dimethylaminomethyl)indole (III) with 2-nitropropane (IV) by means of KOH gives 3-(2-methyl-2-nitropropyl)indole (V), which is then reduced with hydrazine and Raney-Ni in ethanol to yield (I). 2) The reaction of 2-hydroxybenzonitrile (VI) with epichlorohydrin (VII) by means of piperidine affords 2-(3-chloro-2-hydroxypropoxy)benzonitrile (VIII), which is epoxidized again to (II) by treatment with NaOH in hot THF-water.

参考文献中间体

合成目标

【1】 Kreighbaum, W.E.; et al.; Antihypertensive indole derivatives of phenoxypropanolamines with beta-adrenergic receptor antagonist and vasodilating activity. J Med Chem 1980, 23, 3, 285-289.
【2】 Weetman, D.F.; Castaner, J.; Bucindolol Hydrochloride. Drugs Fut 1981, 6, 7, 405.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10158	Piperidine	110-89-4	C₅H₁₁N	详情	详情
(I)	37566	2-(1H-indol-3-yl)-1,1-dimethylethylamine; 1-(1H-indol-3-yl)-2-methyl-2-propanamine		C₁₂H₁₆N₂	详情	详情
(II)	37567	2-(2-oxiranylmethoxy)benzonitrile		C₁₀H₉NO₂	详情	详情
(III)	37568	N,N-Dimethyl-1H-indole-3-methanamine;Gramine;N-(1H-indol-3-ylmethyl)-N,N-dimethylamine; 3-(dimethylaminomethyl)-indole[;]1H-indol-3-yl-N,N-dimethylmethanamine	87-52-5	C₁₁H₁₄N₂	详情	详情
(IV)	21819	2-nitropropane	79-46-9	C₃H₇NO₂	详情	详情
(V)	37569	3-(2-methyl-2-nitropropyl)-1H-indole		C₁₂H₁₄N₂O₂	详情	详情
(VI)	21990	2-hydroxybenzonitrile	611-20-1	C₇H₅NO	详情	详情
(VII)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
(VIII)	37570	2-(3-chloro-2-hydroxypropoxy)benzonitrile		C₁₀H₁₀ClNO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Condensation of aldehyde (I) with 2-nitropropane (II) using tert-butyldimethylsilyl chloride, tetrabutylammonium fluoride and triethylamine afforded a mixture of diastereomeric nitroaldol products (III). After separation by column chromatography, the desired isomer was protected as the tert-butyldimethylsilyl ether (IV). Deprotection of the benzoate ester of (IV) was carried out by reduction with diisobutylaluminum hydride to provide alcohol (V), which was then oxidized to the corresponding ketone (VI) with pyridinium chlorochromate. Wittig reaction of (VI) with phosphorane (VII) provided the bromomethylene compound (VIII).

参考文献中间体

合成目标

【1】 Oshida, J.; et al.; Synthesis and biological evaluation of 1alpha,24-dihydroxy-25-nitrovitamin D3. Bioorg Med Chem Lett 1999, 9, 3, 381.

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)	21818	(4S,7aR)-7a-methyl-1-[(1R)-1-methyl-4-oxobutyl]octahydro-1H-inden-4-yl benzoate		C₂₂H₃₀O₃	详情	详情
(II)	21819	2-nitropropane	79-46-9	C₃H₇NO₂	详情	详情
(III)	21820	(4S,7aR)-1-[(1R)-4-hydroxy-1,5-dimethyl-5-nitrohexyl]-7a-methyloctahydro-1H-inden-4-yl benzoate		C₂₅H₃₇NO₅	详情	详情
(IV)	21821	(4S,7aR)-1-((1R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethyl-5-nitrohexyl)-7a-methyloctahydro-1H-inden-4-yl benzoate		C₃₁H₅₁NO₅Si	详情	详情
(V)	21822	(4S,7aR)-1-((1R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethyl-5-nitrohexyl)-7a-methyloctahydro-1H-inden-4-ol		C₂₄H₄₇NO₄Si	详情	详情
(VI)	21823	(7aR)-1-((1R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethyl-5-nitrohexyl)-7a-methyloctahydro-4H-inden-4-one		C₂₄H₄₅NO₄Si	详情	详情
(VIII)	21824	[[(1R,4R)-4-[(7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-(1-methyl-1-nitroethyl)pentyl]oxy](tert-butyl)dimethylsilane; (1R,4R)-4-[(7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-(1-methyl-1-nitroethyl)pentyl tert-butyl(dimethyl)silyl ether		C₂₅H₄₆BrNO₃Si	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

参考文献中间体

合成目标

【1】 Oshida, J.; et al.; Synthesis and biological evaluation of 1alpha,24-dihydroxy-25-nitrovitamin D3. Bioorg Med Chem Lett 1999, 9, 3, 381.

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)	21818	(4S,7aR)-7a-methyl-1-[(1R)-1-methyl-4-oxobutyl]octahydro-1H-inden-4-yl benzoate		C₂₂H₃₀O₃	详情	详情
(II)	21819	2-nitropropane	79-46-9	C₃H₇NO₂	详情	详情
(III)	21820	(4S,7aR)-1-[(1R)-4-hydroxy-1,5-dimethyl-5-nitrohexyl]-7a-methyloctahydro-1H-inden-4-yl benzoate		C₂₅H₃₇NO₅	详情	详情
(IV)	21828	(4S,7aR)-1-((1R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethyl-5-nitrohexyl)-7a-methyloctahydro-1H-inden-4-yl benzoate		C₃₁H₅₁NO₅Si	详情	详情
(V)	21829	(4S,7aR)-1-((1R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethyl-5-nitrohexyl)-7a-methyloctahydro-1H-inden-4-ol		C₂₄H₄₇NO₄Si	详情	详情
(VI)	21830	(7aR)-1-((1R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethyl-5-nitrohexyl)-7a-methyloctahydro-4H-inden-4-one		C₂₄H₄₅NO₄Si	详情	详情
(VII)	21831	(bromomethyl)(triphenyl)phosphonium bromide	1034-49-7	C₁₉H₁₇Br₂P	详情	详情
(VIII)	21832	(1S,4R)-4-[(7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-(1-methyl-1-nitroethyl)pentyl tert-butyl(dimethyl)silyl ether; [[(1S,4R)-4-[(7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-(1-methyl-1-nitroethyl)pentyl]oxy](tert-butyl)dimethylsilane		C₂₅H₄₆BrNO₃Si	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VII)

NPS-2143 can be obtained by coupling 2-chloro-6-[2(R)-oxiranylmethoxy]benzonitrile (I) with 1,1-dimethyl-2-(2-naphthyl)ethylamine (II) in ethanol at 50-60 C. Intermediates (I) and (II) can be obtained as follows: a) Treatment of 2-chloro-6-fluorobenzonitrile (III) with 18-crown-6 and potassium acetate in refluxing acetonitrile, followed by hydrolysis with NaOH in H2O provides 3-chloro-2-cyanophenol (IV), which is then condensed with 3-nitrobenzenesulfonic acid (2R)-2-oxiranylmethyl ester (V) in DMF by means of NaH to furnish 2-chloro-6-[2(R)-oxiranylmethoxy]benzonitrile (I). b) Treatment of 2-(aminomethyl)naphthalene (VI) with 2,4,6-triphenylpyrylium tetrafluoroborate in EtOH, followed by the reaction of the resulting compound dissolved in DMSO with the sodium salt obtained by treatment of 2-nitropropane (VII) with NaH in MeOH, gives the nitro derivative (VIII). Finally, reduction of the nitro group of (VIII) by hydrogenation over Ni Raney in EtOH yields 1,1,-dimethyl-2-(2-naphthyl)ethylamine (II).

参考文献中间体

合成目标

【2】 Sheehan, D.; Del Mar, E.G.; Lago, M.A.; Southall, L.S.; Callahan, J.F.; Kotecha, N.R.; Thompson, M.; Barmore, R.M.; Keenan, R.M.; Van Wagenen, B.C. (GlaxoSmithKline Inc.; GlaxoSmithKline plc; NPS Pharmaceuticals, Inc.); Method of using calcilytic cpds.. US 6022894 .
【1】 del Fresno, M.; Doggrell, S.A.; Castaner, J.; NPS-2143. Drugs Fut 2002, 27, 2, 140.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	51708			C₂₃H₁₇BF₄O	详情	详情
(I)	51706	2-chloro-6-[(2R)oxiranylmethoxy]benzonitrile		C₁₀H₈ClNO₂	详情	详情
(II)	51710	1,1-dimethyl-2-(2-naphthyl)ethylamine; 2-methyl-1-(2-naphthyl)-2-propanamine		C₁₄H₁₇N	详情	详情
(III)	51704	2-Chloro-6-fluorobenzonitrile; 2-Fluoro-6-chlorobenzonitrile	668-45-1	C₇H₃ClFN	详情	详情
(IV)	51705	2-chloro-6-hydroxybenzonitrile		C₇H₄ClNO	详情	详情
(V)	16259	(2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate	115314-14-2	C₉H₉NO₆S	详情	详情
(VI)	51707	2-naphthylmethanamine; 2-naphthylmethylamine		C₁₁H₁₁N	详情	详情
(VII)	21819	2-nitropropane	79-46-9	C₃H₇NO₂	详情	详情
(VIII)	51709	2-(2-methyl-2-nitropropyl)naphthalene		C₁₄H₁₅NO₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(II)

By condensation of substituted nicotinamide (VI) with the carbazolyoxymethyl-oxirane (XII) in hot methanol/water. The intermediates the nicotinamide (VI) and the oxirane (XII) have been obtained as follows: 1.- Nicotinamide (VI): The reaction of 4-hydroxybenzyl alcohol (I) with 2-nitropropane (II) by means of potassium tert-butoxide in hot diglyme gives 4-(2-methyl-2-nitropropyl)phenol (III), which is reduced to the corresponding amino derivative (IV) with H2 over Pd/C in methanol/ethanol/acetic acid. Finally, this compound is condensed with 6-chloronicotinamide (V) by means of K2CO3 in dimethylacetamide/isooctane. 2.- Oxirane (XII): The reaction of phenylhydrazine (VII) with cyclohexane-1,3-dione (VIII) by means of NaHCO3 in isopropanol/water gives the monohydrazone (IX), which is cyclized with hotpolyphosphoric acid yielding the 4-hydroxycarbazole (X). Finally, this compound is condensed with the glycidyl 3-nitrophenylsulfonate (XI) by means of K2CO3 in refluxing acetone.

参考文献中间体

合成目标

【1】 Crowell, T.A.; Evrard, D.A.; Jones, C.D.; Muehl, B.S.; Rito, C.J.; Shuker, A.J.; Thorpe, A.J.; Thrasher, K.J. (Eli Lilly and Company); Carbazole analogues as selective B3 adrenergic agonists. EP 0827746; WO 9809625 .

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)	29474	4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol	623-05-2	C₇H₈O₂	详情	详情
(II)	21819	2-nitropropane	79-46-9	C₃H₇NO₂	详情	详情
(III)	29475	4-(2-methyl-2-nitropropyl)phenol		C₁₀H₁₃NO₃	详情	详情
(IV)	29476	4-(2-amino-2-methylpropyl)phenol	51706-55-9	C₁₀H₁₅NO	详情	详情
(V)	29477	6-chloronicotinamide	6271-78-9	C₆H₅ClN₂O	详情	详情
(VI)	29478	6-[4-(2-amino-2-methylpropyl)phenoxy]nicotinamide		C₁₆H₁₉N₃O₂	详情	详情
(VII)	11818	Phenyl hydrazine; 1-Phenylhydrazine	100-63-0	C₆H₈N₂	详情	详情
(VIII)	11244	1,3-Cyclohexanedione	504-02-9	C₆H₈O₂	详情	详情
(IX)	29479	3-hydroxy-2-cyclohexen-1-one N-phenylhydrazone		C₁₂H₁₄N₂O	详情	详情
(X)	29480	4-Hydroxycarbazole; 9H-carbazol-4-ol	52602-39-8	C₁₂H₉NO	详情	详情
(XI)	16259	(2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate	115314-14-2	C₉H₉NO₆S	详情	详情
(XII)	29481	9H-carbazol-4-yl (2S)oxiranylmethyl ether; 4-[(2S)oxiranylmethoxy]-9H-carbazole		C₁₅H₁₃NO₂	详情	详情

合成路线6

该中间体在本合成路线中的序号：(VI)

Preparation of the title compound has been reported by two procedures. Catalytic hydrogenation of benzofuran-4-carboxylic acid (I) over Pd/C afforded the dihydrobenzofuran (II). Carboxyl group reduction in (II) with LiAlH4 and further Swern oxidation of the resulting alcohol (III) furnished aldehyde (IV). Knoevenagel condensation of aldehyde (IV) with dimethyl malonate provided the benzylidenemalonate (V), which was converted to the key cyclopropane derivative (VII) upon treatment with 2-nitropropane (VI) and potassium tert-butoxide. Hydrolysis and decarboxylation of the malonate ester (VII) was performed using NaCN in hot DMSO to yield acid (VIIIa-b) as a diastereomeric mixture. Recrystallization of (VIIIa-b) from acetonitrile-water allowed the separation of the major (+/-)-trans-isomer, which was then resolved by preparative chiral HPLC. The desired (R,R)-isomer (IX) was finally coupled with guanidine (X) via activation with CDI

参考文献中间体

合成目标

【1】 Ahmad, S.; et al.; Arylcyclopropanecarboxyl guanidines as novel, potent, and selective inhibitors of the sodium hydrogen exchanger isoform-1. J Med Chem 2001, 44, 20, 3302.
【2】 Wu, S.C.; Atwal, K.S.; Dugar, S.; Ahmad, S. (Bristol-Myers Squibb Co.); Acyl guanidine sodium/proton exchange inhibitors and method. EP 1041980; JP 2001527042; US 6011059; WO 9933460 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIIa)	51881	(1R)-3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethylcyclopropanecarboxylic acid		C₁₄H₁₆O₃	详情	详情
(VIIIb)	51882	(1S)-3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethylcyclopropanecarboxylic acid		C₁₄H₁₆O₃	详情	详情
(I)	51875	1-benzofuran-4-carboxylic acid		C₉H₆O₃	详情	详情
(II)	51876	2,3-dihydro-1-benzofuran-4-carboxylic acid		C₉H₈O₃	详情	详情
(III)	51877	2,3-dihydro-1-benzofuran-4-ylmethanol		C₉H₁₀O₂	详情	详情
(IV)	51878	2,3-dihydro-1-benzofuran-4-carbaldehyde		C₉H₈O₂	详情	详情
(V)	51879	dimethyl 2-(2,3-dihydro-1-benzofuran-4-ylmethylene)malonate		C₁₄H₁₄O₅	详情	详情
(VI)	21819	2-nitropropane	79-46-9	C₃H₇NO₂	详情	详情
(VII)	51880	dimethyl 3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethyl-1,1-cyclopropanedicarboxylate		C₁₇H₂₀O₅	详情	详情
(IX)	51883	(1R,3R)-3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethylcyclopropanecarboxylic acid		C₁₄H₁₆O₃	详情	详情
(X)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情

Extended Information