3-bromobenzonitrile -Drug Synthesis Database

【结构式】

【分子编号】26573

【品名】3-bromobenzonitrile

【CA登记号】6952-59-6

【分子式】C₇H₄BrN

【分子量】182.0195

【元素组成】C 46.19% H 2.22% Br 43.9% N 7.7%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(V)

The Skraup reaction of 4-bromoaniline (I) with acetone and iodine afforded dihydroquinoline (II), which was protected as the tert-butyl carbamate (III) with Boc2O in the presence of n-BuLi. Lithium-halogen exchange in (III), followed by treatment with trimethyl borate provided boronic acid (IV). Subsequent Suzuki coupling of (IV) with 3-bromobenzonitrile (V) using tetrakis(triphenylphosphine)-palladium produced the 6-arylquinoline (VI). The Boc group of (VI) was finally removed with trifluoroacetic acid to furnish the title compound.

参考文献中间体

合成目标

【1】 Pooley, C.L.F.; Edwards, J.P.; Goldman, M.E.; Wang, M.-W.; Marschke, K.B.; Crombie, D.L.; Jones, T.K.; Discovery and preliminary SAR studies of a novel, nonsteroidal progesterone receptor antagonist phamacophore. J Med Chem 1998, 41, 18, 3461.
【2】 Jones, T.K.; Goldman, M.E.; Pooley, C.L.F.; Winn, D.T.; Edwards, J.E.; West, S.J.; Tegley, C.M.; Zhi, L.; Hamann, L.G.; Farmer, L.J.; Davis, R.J. (Ligand Pharmaceuticals, Inc.); Steroid receptor modulator cpds. and methods. EP 0800519; JP 1998510840; US 5688808; US 5688810; US 5693646; US 5693647; US 5696127; US 5696130; US 5696133; WO 9619458 .

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)	22531	4-Bromoaniline; 4-Bromophenylamine	106-40-1	C₆H₆BrN	详情	详情
(II)	26570	6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline		C₁₂H₁₄BrN	详情	详情
(III)	26571	tert-butyl 6-bromo-2,2,4-trimethyl-1(2H)-quinolinecarboxylate		C₁₇H₂₂BrNO₂	详情	详情
(IV)	26572	1-(tert-butoxycarbonyl)-2,2,4-trimethyl-1,2-dihydro-6-quinolinylboronic acid		C₁₇H₂₄BNO₄	详情	详情
(V)	26573	3-bromobenzonitrile	6952-59-6	C₇H₄BrN	详情	详情
(VI)	26574	tert-butyl 6-(3-cyanophenyl)-2,2,4-trimethyl-1(2H)-quinolinecarboxylate		C₂₄H₂₆N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Hydrolysis of 3-bromobenzonitrile (I) by means of sodium perborate leads to amide (II). Subsequent Suzuki coupling of 3-bromobenzamide (II) with 3-methoxyphenylboronic acid (III) furnishes the biphenyl compound (IV). The methyl ether group of (IV) is then cleaved employing BBr3 to yield phenol (V). This is finally coupled with cyclohexyl isocyanate (VI) to produce the title carbamate.

参考文献中间体

合成目标

【1】 Kathuria, S.; Gaetani, S.; Fegley, D.; Valiño, M.; Duranti, A.; Tontini, A.; Mor, M.; Tarzia, G.; La Rana, G.; Calignano, A.; Giustino, A.; Tattoli, M.; Palmery, M.; Cuomo, V.; Piomelli, D.; Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 2003, 9, 1, 76.

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)	26573	3-bromobenzonitrile	6952-59-6	C₇H₄BrN	详情	详情
(II)	63206	3-bromobenzamide		C₇H₆BrNO	详情	详情
(III)	29426	3-methoxyphenylboronic acid	10365-98-7	C₇H₉BO₃	详情	详情
(IV)	63207	3'-methoxy[1,1'-biphenyl]-3-carboxamide		C₁₄H₁₃NO₂	详情	详情
(V)	63208	3'-hydroxy[1,1'-biphenyl]-3-carboxamide		C₁₃H₁₁NO₂	详情	详情
(VI)	18108	1-isocyanatocyclohexane; cyclohexyl isocyanate	3173-53-3	C₇H₁₁NO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XVI)

Intermediates (II) and (IV) are prepared as follows. Alkylation of the sodium enolate of methyl 3-bromophenylacetate (VII) with 4-chlorobenzyl bromide (VIII) in cold THF followed by methyl ester hydrolysis with LiOH in aqueous acetonitrile affords 2-(m-bromophenyl)-3-(p-chlorophenyl)propionic acid (IX), which is converted to the corresponding Weinreb amide (X) by chlorination with oxalyl chloride and subsequent treatment with N,O-dimethylhydroxylamine. Addition of methylmagnesium bromide to the methoxyamide (X) gives the 3,4-diaryl-2-butanone (XI), which is then reduced using NaBH4 or LiBH(s-Bu)3 (L-selectride) to provide alcohol (XIIa) as the major diastereoisomer. After conversion of alcohol (XIIa) to the corresponding mesylate, displacement with NaN3 in hot DMF leads to azide (XIII), which is reduced by catalytic hydrogenation in the presence of PtO2 and Boc2O to afford the Boc-protected amine (XIV). Then, palladium-catalyzed substitution of the aryl bromide (XIV) with zinc cyanide yields the nitrile (XV), which is deprotected to (IIa) using HCl in EtOAc (2, 3). Similarly, coupling between 3-bromobenzonitrile (XVI) and isopropenyl acetate (XVII) in the presence of Pd2(dba)3 and 2-(dicyclohexylphosphino)-2’-(dimethylamino)biphenyl (DCPDMAB) gives 1-(m-cyanophenyl)acetone (XVIII), which is alkylated with 3-chlorobenzyl chloride (XIX) in the presence of cesium hydroxide and tetrabutylammonium iodide to yield the diarylbutanone (XX). Reduction of ketone (XX) with lithium tri(sec-butyl)borohydride produces alcohol (XXI), which is converted to the Boc-protected amine (XV) by mesylation followed by displacement with NaN3, and then reduction of the resulting azide (XXII) by catalytic hydrogenation in the presence of PtO2 and Boc2O (1). The ketonitrile (XX) is alternatively produced by palladium-catalyzed cyanuration of aryl bromide (XI) with either zinc cyanide or potassium ferrocyanide. The intermediate enol tosylate (IV) can be obtained by treatment of (XX) with sodium tert-butoxide and p-toluenesulfonic anhydride (5, 6). Preparation of the enantiomerically pure amine (IIb) can be accomplished by resolution at the stage of the diarylpropionic acid (IX) or, in a more efficient method, by dynamic kinetic resolution of (XI) via stereoselective hydrogenation to (XIIb) in the presence of the chiral Ru catalyst [(S)-xyl-BINAP]-[(S)-DAIPEN]RuCl2 and excess potassium tert-butoxide (4). Scheme 2.

参考文献中间体

合成目标

【1】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides. CA 2478183, EP 1496838, JP 2005519958, JP 2006257090, US 2004058820, US 6972295, WO 03077847.
【2】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides active at the cannabinoid-1 receptor. WO 2004048317.
【3】 Lin, L.S., Lanza, T.J. Jr., Jewell, J.P. et al. Discovery of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J Med Chem 2006, 49(26): 7584-7.
【4】 Chen, C., Frey, L.F., Shultz, S. et al. Catalytic, enantioselective synthesis of taranabant, a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. Org Proc Res Devel 2007, 11(3): 616-23.
【5】 Campos, K.R., Klapars, A., McWilliams, J.C. et al. (Merck & Co., Inc.). Formation of tetra-substituted enamides and stereoselective reduction thereof. WO 2006017045.
【6】 Weissman, S.A. (Merck & Co., Inc.). Cyanation of aromatic halides. US 2006106223.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIIa)	65595			C₁₆H₁₆BrClO	详情	详情
(XIIb)	65596			C₁₆H₁₆BrClO	详情	详情
(Iia)	65586	3-[(1RS,2RS)-2-Amino-1-[(4-Chlorophenyl)Methyl]Propyl]Benzonitrile		C₁₇H₁₇ClN₂	详情	详情
(Iib)	65587	3-[(1S,2S)-2-Amino-1-[(4-Chlorophenyl)Methyl]Propyl]Benzonitrile	732982-66-0	C₁₇H₁₇ClN₂	详情	详情
(IV)	65582	(R )-(-)-4-Penten-2-ol	64584-92-5	C₅H₁₀O	详情	详情
(VII)	50901	methyl 2-(3-bromophenyl)acetate	150529-73-0	C₉H₉BrO₂	详情	详情
(VIII)	16481	1-(bromomethyl)-4-chlorobenzene	622-95-7	C₇H₆BrCl	详情	详情
(IX)	65592			C₁₅H₁₂BrClO₂	详情	详情
(X)	65593			C₁₇H₁₇BrClNO₂	详情	详情
(XI)	65594	3-(3-Bromophenyl)-4-(4-Chlorophenyl)Butan-2-One	848310-98-5	C₁₆H₁₄BrClO	详情	详情
(XIII)	65597			C₁₆H₁₅BrClN₃	详情	详情
(XIV)	65598			C₂₁H₂₅BrClNO₂	详情	详情
(XV)	65599			C₂₂H₂₅ClN₂O₂	详情	详情
(XVI)	26573	3-bromobenzonitrile	6952-59-6	C₇H₄BrN	详情	详情
(XVII)	21178	isopropenyl acetate	108-22-5	C₅H₈O₂	详情	详情
(XVIII)	65600	(3-Cyanophenyl)Acetone		C₁₀H₉NO	详情	详情
(XIX)	10356	1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride	104-83-6	C₇H₆Cl₂	详情	详情
(XX)	65601			C₁₇H₁₄ClNO	详情	详情
(XXI)	65602			C₁₇H₁₆ClNO	详情	详情
(XXII)	65603			C₁₇H₁₅ClN₄	详情	详情

Extended Information