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【结 构 式】

【分子编号】17552

【品名】4-formylbenzonitrile; 4-Cyanobenzaldehyde

【CA登记号】105-07-7

【 分 子 式 】C8H5NO

【 分 子 量 】131.13384

【元素组成】C 73.27% H 3.84% N 10.68% O 12.2%
与该中间体有关的原料药合成路线共 16 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7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16

合成路线1

该中间体在本合成路线中的序号：(I)

Reaction of 4-cyanobenzaldehyde (I) with hydroxylamine sulfate in methanol gives 4-cyanobenzaldoxime (II). A 1,3-dipolar cycloaddition of (II) with isobutyl vinylacetate using N-chlorosuccinimide provides the racemic isoxazoline derivative (III). Treatment of (III) with lipase PS30 selectively converts the (R)-isomer to an optically pure acid (IV). Coupling of (IV) with methyl N2-(n-butyloxycarbonyl)-L-2,3-diaminopropionate (VI), which is derived from its corresponding commerically available acid (V), gives the intermediate (VII). Treatment of (VII) with HCl in methanol and ethyl acetate followed by ammonium acetate affords DMP 754 as a crystalline product. Saponification of DMP 754 using LiOH provides the corresponding acid (VIII).

参考文献 中间体
合成目标
【1】 Anzalone, L.; Storace, L. Ward, R.; Kauffman, G.S.; Zhang, L.-H.; Ma, P.; The chiral specific synthesis of DMP 754, a platelet GPIIb/IIIa antagonist. Tetrahedron Lett 1996, 37, 26, 4455-8.
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) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(II) 17553 4-[(hydroxyimino)methyl]benzonitrile C8H6N2O 详情 详情
(III) 17554 isobutyl 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate C16H18N2O3 详情 详情
(IV) 17555 2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid C12H10N2O3 详情 详情
(V) 17556 (2S)-3-amino-2-[(butoxycarbonyl)amino]propionic acid C8H16N2O4 详情 详情
(VI) 17557 methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate hydrochloride C9H19ClN2O4 详情 详情
(VII) 17558 methyl (2S)-2-[(butoxycarbonyl)amino]-3-([2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetyl]amino)propanoate C21H26N4O6 详情 详情
(VIII) 17559 (2S)-3-[[2-((5R)-3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[(butoxycarbonyl)amino]propionic acid C20H27N5O6 详情 详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Intermediate (XI) has been obtained as follows: Aldehyde (VII) was converted to the corresponding oxime (VIII) by treatment with hydroxylamine hydrochloride in pyridine. Dipolar cycloaddition of 3-butenoic acid (IX) with the nitrile oxide formed in situ by chlorination of oxime (VIII) and further elimination of HCl produced the racemic isoxazoline (X). Isolation of the required (R)-enantiomer (XI) was performed by chiral preparative HPLC on a Chiralpak AD column or, alternatively, through fractional crystallization of the diastereomeric cinchonidine salts.

参考文献 中间体
合成目标
【1】 Wityak, J.; et al.; Discovery of potent isoxazoline glycoprotein IIb/IIIa receptor antagonists. J Med Chem 1997, 40, 1, 50.
【2】 Wityak, J.; Sielecki, T.M.; Xue, C.-B.; et al.; Discovery of an orally active series of isoxazoline glycoprotein IIb/IIIa antagonists. J Med Chem 1997, 40, 13, 2064-84.
【3】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(Xb) 17555 2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid C12H10N2O3 详情 详情
(XI),(Xa) 33754 2-[(5S)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid C12H10N2O3 详情 详情
(VII) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(VIII) 17553 4-[(hydroxyimino)methyl]benzonitrile C8H6N2O 详情 详情
(IX) 33753 3-butenoic acid 625-38-7 C4H6O2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(V)

Oxime (VI) was prepared from 4-cyanobenzaldehyde (V) upon treatment with hydroxylamine-HCl and pyridine. The nitrile oxide generated from oxime (VI) and NaOCl underwent a dipolar cycloaddition to methyl butenoate (VII) to produce the racemic isoxazoline (VIII). After conversion of the nitrile group of (VIII) to imidate (IX), reaction with methanolic ammonia yielded amidine (X), which was protected with Boc2O to give (XI). Hydrolysis of the methyl ester of (XI) with LiOH provided carboxylic acid (XII), which was coupled to amine (IV) using TBTU to afford amide (XIII) as a diasteromeric mixture. After Boc group removal by acidic treatment yielding (XIV), its methyl ester group was hydrolyzed with LiOH to afford the corresponding acid. The diastereomeric mixture of carboxylic acids was finally separated by preparative chiral HPLC.

参考文献 中间体
合成目标
【1】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 28133 methyl (2S)-3-amino-2-[[(3-methylphenyl)sulfonyl]amino]propanoate C11H16N2O4S 详情 详情
(V) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(VI) 17553 4-[(hydroxyimino)methyl]benzonitrile C8H6N2O 详情 详情
(VII) 28134 methyl 3-butenoate C5H8O2 详情 详情
(VIII) 28135 methyl 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate C13H12N2O3 详情 详情
(IX) 28136 methyl 2-(3-[4-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate C14H16N2O4 详情 详情
(X) 28137 methyl 2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate C13H15N3O3 详情 详情
(XI) 28138 methyl 2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetate C18H23N3O5 详情 详情
(XII) 28139 2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetic acid C17H21N3O5 详情 详情
(XIII) 28140 methyl (2S)-3-[[2-(3-[4-[[(tert-butoxycarbonyl)amino](imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[[(3-methylphenyl)sulfonyl]amino]propanoate C28H35N5O8S 详情 详情
(XIV) 28141 methyl (2S)-3-[[2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[[(3-methylphenyl)sulfonyl]amino]propanoate C23H27N5O6S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

Cycloaddition of sodium azide to 4-formylbenzonitrile (I) yielded tetrazole (II), which was protected with 2-phenylpropene (III) in the presence of methanesulfonic acid to give (IV). Subsequent condensation of (IV) with tert-butyl carbazate afforded hydrazone (V), which was further reduced to the benzylhydrazine (VI) employing NaBH3CN and p-toluenesulfonic acid. Opening of the trifluoroacetyl-protected epoxide (VII) with hydrazine (VI) gave hydrazinoalcohol (VIII). After hydrolysis of the trifluoroacetamide group of (VIII) with K2CO3, the resulting amine (IX) was coupled with N-methoxycarbonyl-L-tert-leucine (X) by means of EDC and HOBt to provide amide (XI).

参考文献 中间体
合成目标
【1】 Fassler, A.; Bold, G.; Capraro, H.-G.; Lang, M.; Khanna, S.C. (Novartis AG); Antivirally active heterocyclic azahexane derivs.. EP 0900210; JP 1999511177; US 5849911; WO 9740029 .
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) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(II) 28449 4-(2H-1,2,3,4-tetraazol-5-yl)benzaldehyde 74815-22-8 C8H6N4O 详情 详情
(III) 28450 1-isopropenylbenzene 98-83-9 C9H10 详情 详情
(IV) 28451 4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzaldehyde C17H16N4O 详情 详情
(V) 28452 tert-butyl 2-((Z)-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]phenyl]methylidene)-1-hydrazinecarboxylate C22H26N6O2 详情 详情
(VI) 28453 tert-butyl 2-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzyl]-1-hydrazinecarboxylate C22H28N6O2 详情 详情
(VII) 28454 2,2,2-trifluoro-N-[(1S)-1-[(2R)oxiranyl]-2-phenylethyl]acetamide C12H12F3NO2 详情 详情
(VIII) 28455 tert-butyl 2-[(2S,3S)-2-hydroxy-4-phenyl-3-[(2,2,2-trifluoroacetyl)amino]butyl]-2-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzyl]-1-hydrazinecarboxylate C34H40F3N7O4 详情 详情
(IX) 28456 tert-butyl 2-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzyl]-1-hydrazinecarboxylate C32H41N7O3 详情 详情
(X) 23447 (2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid C8H15NO4 详情 详情
(XI) 28457 tert-butyl (5S,6S,9S)-6-benzyl-9-(tert-butyl)-5-hydroxy-3-[4-[2-(1-methyl-1-phenylethyl)-2H-1,2,3,4-tetraazol-5-yl]benzyl]-8,11-dioxo-12-oxa-2,3,7,10-tetraazatridecan-1-oate C40H54N8O6 详情 详情

合成路线5

该中间体在本合成路线中的序号：(II)

Aldol condensation of 4-cyanobenzaldehyde (II) with 4-cyano-acetophenone (I) in methanolic NaOH furnished chalcone (III). Subsequent addition of bromine to (III) gave dibromide (IV). This was treated with NaOMe to produce the intermediate enol ether (V), which was then condensed with the ylide generated from trimethylsulfonium iodide and NaH to afford the 2,4-diarylfuran (VI). Acid-catalyzed addition of EtOH to (VI) provided the corresponding bis(imidate) (VII). Further reaction of (VII) with isopropylamine yielded the target amidine, which was isolated as the dihydrochloride salt.

参考文献 中间体
合成目标
【1】 Francesconi, I.; et al.; 2,4-Diphenyl furan diamidines as novel anti-pneumocystis carinii pneumonia agents. J Med Chem 1999, 42, 12, 2260.
【2】 Boykin, D.W.; Francesconi, I.; Tidwell, R.R.; Wilson, D.W. (Georgia State University; University of North Carolina); 2,4-Bis (4-amidino)phenyl furans as anti-Pneumocystis carinii agents. EP 0941991; GB 2334716; US 6008247 .
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) 25849 4-acetylbenzonitrile 1443-80-7 C9H7NO 详情 详情
(II) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(III) 25580 3-amino-2-methylpropanenitrile C4H8N2 详情 详情
(IV) 25851 4-[2,3-dibromo-3-(4-cyanophenyl)propanoyl]benzonitrile C17H10Br2N2O 详情 详情
(V) 25852 4-[(Z)-3-(4-cyanophenyl)-3-methoxy-2-propenoyl]benzonitrile C18H12N2O2 详情 详情
(VI) 25853 4-[4-(4-cyanophenyl)-2-furyl]benzonitrile C18H10N2O 详情 详情
(VII) 25854 ethyl 4-(4-[4-[ethoxy(imino)methyl]phenyl]-2-furyl)benzenecarboximidoate C22H22N2O3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

The condensation of 4-formylbenzonitrile (I) with N-methylhyddroxylamine (II) by means of Na2CO3 in dichloromethane gives the nitrone (III), which is cyclized with isobutyl 3-butenoate (IV) by heating at 100 C to afford the cis-isoxazolidinyl acetate (V) (along with some trans isomer) that is purified by chromatography. The hydrolysis of the ester (V) with LiOH in THF/water yields the free acid (VI), which is condensed with the diamino ester (VII) by means of PyBop and Et3N in DMF giving the intermediate (VIII). The treatment of (VII) with dry HCl in methanol/chloroform to convert the CN group into amidino yields derivative (IX), which is finally hydrolyzed to the free acid with aqueous HCl.

参考文献 中间体
合成目标
【1】 Confalone, P.N.; Jin, F.; Mousa, S.A.; Platelet glycoprotein IIb/IIIa receptor antagonists derived from isoxazolidines. Bioorg Med Chem Lett 1999, 9, 1, 55.
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) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(II) 12690 (Hydroxyamino)methane; N-Methylhydroxylamine 593-77-1 CH5NO 详情 详情
(III) 27637 4-[[methyl(oxo)-lambda(5)-azanylidene]methyl]benzonitrile C9H8N2O 详情 详情
(IV) 27638 isobutyl 3-butenoate 24342-03-8 C8H14O2 详情 详情
(V) 27639 isobutyl 2-[(3R,5S)-3-(4-cyanophenyl)-2-methylisoxazolidinyl]acetate C17H22N2O3 详情 详情
(VI) 27640 2-[(3R,5S)-3-(4-cyanophenyl)-2-methylisoxazolidinyl]acetic acid C13H14N2O3 详情 详情
(VII) 25970 methyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate C10H14N2O4S 详情 详情
(VIII) 27641 methyl (2S)-3-([2-[(3R,5S)-3-(4-cyanophenyl)-2-methylisoxazolidinyl]acetyl]amino)-2-[[(4-methyl-2-pyridinyl)sulfonyl]amino]propanoate C23H27N5O6S 详情 详情
(IX) 27642 methyl (2S)-3-[[2-((3R,5S)-3-[4-[amino(imino)methyl]phenyl]-2-methylisoxazolidinyl)acetyl]amino]-2-[[(3-methylphenyl)sulfonyl]amino]propanoate C24H31N5O6S 详情 详情

合成路线7

该中间体在本合成路线中的序号：(IV)

4-Formylbenzonitrile (IV) was converted to the aryl tetrazole (V) upon treatment with trimethylsilyl azide and dibutyltin oxide. Regioselective alkylation of tetrazole (V) with ethyl 5-bromovalerate (VI) afforded the (2-tetrazolyl)pentanoate (VII).

参考文献 中间体
合成目标
【1】 Maw, G.N. (Pfizer Inc.); Anti-inflammatory piperazinyl-benzyl-tetrazole derivs. and intermediates thereof. EP 0983251; JP 2000513024; WO 9852929 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(V) 48159 4-(1H-1,2,3,4-tetraazol-5-yl)benzaldehyde C8H6N4O 详情 详情
(VI) 37151 ethyl 5-bromopentanoate 14660-52-7 C7H13BrO2 详情 详情
(VII) 48160 ethyl 5-[5-(4-formylphenyl)-2H-1,2,3,4-tetraazol-2-yl]pentanoate C15H18N4O3 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IV)

A related procedure for the synthesis of the precursor ethyl ester (XI) was also reported. The condensation between 4-formylbenzonitrile (IV), piperazine (III) and benzotriazole furnished the benzotriazolyl adduct (XII). Subsequent reaction of (XII) with the Grignard reagent (XIII) yielded the (diarylmethyl)piperazine (XIV). The cyano group of (XIV) was then converted to the tetrazole (XV) by treatment with trimethylsilyl azide and dibutyltin oxide. Alkylation of tetrazole (XV) with ethyl 5-bromovalerate (VI) gave rise to a mixture of 1-triazolyl (XVII) and 2-triazolylpentanoate (XVI). After desilylation of this mixture with tetraethylammonium fluoride, the desired 2-triazolyl derivative (XI) was isolated by column chromatography.

参考文献 中间体
合成目标
【1】 Maw, G.N. (Pfizer Inc.); Anti-inflammatory piperazinyl-benzyl-tetrazole derivs. and intermediates thereof. EP 0983251; JP 2000513024; WO 9852929 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 20690 (2R,5S)-1-allyl-2,5-dimethylpiperazine C9H18N2 详情 详情
(IV) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(VI) 37151 ethyl 5-bromopentanoate 14660-52-7 C7H13BrO2 详情 详情
(XI) 48163 ethyl 5-(5-[4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-hydroxyphenyl)methyl]phenyl]-2H-1,2,3,4-tetraazol-2-yl)pentanoate C30H40N6O3 详情 详情
(XII) 48164 4-[[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](1H-1,2,3-benzotriazol-1-yl)methyl]benzonitrile C23H26N6 详情 详情
(XIII) 20706 bromo(3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)magnesium C12H19BrMgOSi 详情 详情
(XIV) 48165 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)methyl]benzonitrile C29H41N3OSi 详情 详情
(XV) 48166 (2R,5S)-1-allyl-4-[(R)-(3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)[4-(1H-1,2,3,4-tetraazol-5-yl)phenyl]methyl]-2,5-dimethylpiperazine; 3-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl][4-(1H-1,2,3,4-tetraazol-5-yl)phenyl]methyl]phenyl tert-butyl(dimethyl)silyl ether C29H42N6OSi 详情 详情
(XVI) 48168 ethyl 5-(5-[4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)methyl]phenyl]-1H-1,2,3,4-tetraazol-1-yl)pentanoate C36H54N6O3Si 详情 详情
(XVII) 48167 ethyl 5-(5-[4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)methyl]phenyl]-2H-1,2,3,4-tetraazol-2-yl)pentanoate C36H54N6O3Si 详情 详情

合成路线9

该中间体在本合成路线中的序号：(VIII)

Amide (III) was prepared by acylation of L-methionine methyl ester (I) with 3-(chloromethyl)benzoyl chloride (II). Displacement of the halogen atom of (III) with LiN3 gave azide (IV), which was reduced to amine (V) by catalytic hydrogenation in the presence of Pd/C. Reductive coupling of (V) with protected imidazole-4-carboxaldehyde (VI) provided the (imidazolylmethyl)amine (VII), and a second reductive coupling of (VII) with benzaldehyde (VIII) furnished the trisubstituted amine (IX). The regioselective imidazole alkylation of (IX) with bromide (X), followed by trityl group deprotection with trifluoroacetic acid yielded (XI). Finally, the methyl ester group of (XI) was hydrolyzed with methanolic NaOH to afford the title carboxylic acid.

参考文献 中间体
合成目标
【1】 Ciccarone, T.M.; MacTough, S.C.; Williams, T.M.; et al.; Non-thiol 3-aminomethylbenzamide inhibitor of farnesyl-protein transferase. Bioorg Med Chem Lett 1999, 9, 14, 1991.
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) 17950 D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride 21691-49-6 C6H13NO2S 详情 详情
(II) 25107 3-(chloromethyl)benzoyl chloride 63024-77-1 C8H6Cl2O 详情 详情
(III) 33729 methyl (2S)-2-[[3-(chloromethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate C14H18ClNO3S 详情 详情
(IV) 33730 methyl (2S)-2-[[3-(azidomethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate C14H18N4O3S 详情 详情
(V) 33731 methyl (2S)-2-[[3-(aminomethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate C14H20N2O3S 详情 详情
(VI) 27712 1-trityl-1H-imidazole-4-carbaldehyde；1-Tritylimidazole-4-carboxaldehyde 33016-47-6 C23H18N2O 详情 详情
(VII) 33732 methyl (2S)-4-(methylsulfanyl)-2-[[3-([[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)benzoyl]amino]butanoate C37H38N4O3S 详情 详情
(VIII) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(IX) 33733 methyl (2S)-2-[[3-([(4-cyanobenzyl)[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)benzoyl]amino]-4-(methylsulfanyl)butanoate C45H43N5O3S 详情 详情
(X) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(XI) 33734 methyl (2S)-2-([3-[((4-cyanobenzyl)[[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl]amino)methyl]benzoyl]amino)-4-(methylsulfanyl)butanoate C34H34N6O3S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(III)

2,5-Bis(p-bromophenyl)furan (II) was prepared by cyclodehydration of diketone (I) in refluxing acetic anhydride. Displacement of both bromine atoms by copper(I) cyanide in boiling quinoline generated the dicyano derivative (V). Alternatively, furan (V) was prepared by addition of p-cyanobenzaldehyde (III) to divinyl sulfone (IV) in the presence of a thiazolium catalyst. After conversion of the cyano groups of (V) into bis-imidate (VI), reaccion with ethanolic ammonia furnished amidine (VII). The stable symmetrical carbonate (X) was obtained by reaction of p-fluorophenyl chloroformate (VIII) with p-fluorophenol (IX) in the presence of pyridine. Finally, reaction of the bis(amidine) compound (VII) with carbonate (X) yielded the title compound.

参考文献 中间体
合成目标
【1】 Kawada, A.; Aragane, Y.; Maeda, A.; Tezuka, T.; Heterocycl Commun 1996, 2, 2, 135-140.
【2】 Das, B.P.; Boykin, D.W.; Synthesis and antiprotozoal activity of 2,5-bis (4-guanylphenyl) furans. J Med Chem 1977, 20, 4, 531-536.
【3】 Rahmathullah, S.M.; et al.; Prodrugs for amidines: Synthesis and anti-Pneumocystis carinii activity of carbamates of 2,5-bis(4-amidinophenyl)furan. J Med Chem 1999, 42, 19, 3994.
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) 35811 1,4-bis(4-bromophenyl)-1,4-butanedione C16H12Br2O2 详情 详情
(II) 35812 2,5-bis(4-bromophenyl)furan C16H10Br2O 详情 详情
(III) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(IV) 35813 divinyl sulfone; dioxo(divinyl)-lambda(6)-sulfane 77-77-0 C4H6O2S 详情 详情
(V) 35814 4-[5-(4-cyanophenyl)-2-furyl]benzonitrile C18H10N2O 详情 详情
(VI) 35815 ethyl 4-(5-[4-[ethoxy(imino)methyl]phenyl]-2-furyl)benzenecarboximidoate C22H22N2O3 详情 详情
(VII) 35816 4-(5-[4-[amino(imino)methyl]phenyl]-2-furyl)benzenecarboximidamide C18H16N4O 详情 详情
(VIII) 35817 1-[(chlorocarbonyl)oxy]-4-fluorobenzene 38377-38-7 C7H4ClFO2 详情 详情
(IX) 19639 4-fluorophenol 371-41-5 C6H5FO 详情 详情
(X) 35818 bis(4-fluorophenyl) carbonate C13H8F2O3 详情 详情

合成路线11

该中间体在本合成路线中的序号：(I)

4-Formylbenzonitrile (I) was converted to oxime (II) by treatment with hydroxylamine hydrochloride in pyridine-ethanol. Chlorination of the oxime with NaOCl, followed by dehydrohalogenation of the intermediate imidoyl chloride and dipolar cycloaddition to vinylacetic acid (III) produced the racemic isoxazoline (IV). The cyano group of (IV) was then converted to amidine (V) by formation of the corresponding imidate and subsequent treatment with methanolic ammonia. After protection of the amidine function of (V) as the Boc-derivative, ester hydrolysis employing LiOH yielded carboxylic acid (VI). Methyl 2-piperidine acetate (VIII) was obtained by catalytic hydrogenation of 2-pyridylacetic acid (VII) in the presence of MeOH and HCl. Coupling of acid (VI) with the racemic methyl 2-piperidineacetate (VIII) in the presence of O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoborate (TBTU) furnished a diastereomeric mixture of amides (IX). Cleavage of the Boc group of (IX) by means of either trifluoroacetic acid or methanolic HCl provided amidine (X). Finally, basic hydolysis of the methyl ester of (X) gave rise to the title compound.

参考文献 中间体
合成目标
【1】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 .
【2】 Olson, R.E.; Wityak, J.; Wexler, R.R.; Sielecki, T.M.; Mous, S.A.; Liu, J.; Thoolen, M.; Ring constrained analogues of beta-alanine-containing GPIIb/IIIa receptor antagonists. Bioorg Med Chem Lett 2000, 10, 5, 449.
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) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(II) 17553 4-[(hydroxyimino)methyl]benzonitrile C8H6N2O 详情 详情
(III) 33753 3-butenoic acid 625-38-7 C4H6O2 详情 详情
(IV) 40752 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid C12H10N2O3 详情 详情
(V) 28137 methyl 2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate C13H15N3O3 详情 详情
(VI) 28139 2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetic acid C17H21N3O5 详情 详情
(VII) 35366 2-(2-pyridinyl)acetic acid 16179-97-8 C7H7NO2 详情 详情
(VIII) 40753 methyl 2-(2-piperidinyl)acetate C8H15NO2 详情 详情
(IX) 40750 methyl 2-(1-[2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetyl]-2-piperidinyl)acetate C25H34N4O6 详情 详情
(X) 40751 methyl 2-[1-[2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]-2-piperidinyl]acetate C20H26N4O4 详情 详情

合成路线12

该中间体在本合成路线中的序号：(I)

4-Formylbenzonitrile (I) was converted to oxime (II) by treatment with hydroxylamine hydrochloride in pyridine-ethanol. Chlorination of the oxime with NaOCl, followed by dehydrohalogenation of the intermediate imidoyl chloride and dipolar cycloaddition to vinylacetic acid (III) produced the racemic isoxazoline (IV). The cyano group of (IV) was then converted to amidine (V) by formation of the corresponding imidate and subsequent treatment with methanolic ammonia. After protection of the amidine function of (V) as the Boc-derivative, ester hydrolysis employing LiOH yielded carboxylic acid (VI) (1). Coupling of acid (VI) with the racemic ethyl 2-piperidineacetate (VII) in the presence of O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoborate (TBTU) furnished a diastereomeric mixture of amides (VIII). The Boc group of (VIII) was finally cleaved by means of trifluoroacetic acid.

参考文献 中间体
合成目标
【1】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 .
【2】 Olson, R.E.; Wityak, J.; Wexler, R.R.; Sielecki, T.M.; Mous, S.A.; Liu, J.; Thoolen, M.; Ring constrained analogues of beta-alanine-containing GPIIb/IIIa receptor antagonists. Bioorg Med Chem Lett 2000, 10, 5, 449.
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) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(II) 17553 4-[(hydroxyimino)methyl]benzonitrile C8H6N2O 详情 详情
(III) 33753 3-butenoic acid 625-38-7 C4H6O2 详情 详情
(IV) 40752 2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid C12H10N2O3 详情 详情
(V) 28137 methyl 2-(3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate C13H15N3O3 详情 详情
(VI) 28139 2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetic acid C17H21N3O5 详情 详情
(VII) 40754 ethyl 2-(2-piperidinyl)acetate C9H17NO2 详情 详情
(VIII) 40755 ethyl 2-(1-[2-[3-(4-[amino[(tert-butoxycarbonyl)imino]methyl]phenyl)-4,5-dihydro-5-isoxazolyl]acetyl]-2-piperidinyl)acetate C26H36N4O6 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VI)

Reaction of piperonyloyl chloride (I) with N,O-dimethylhydroxylamine gives rise to the Weinreb amide (II). This is then condensed with the lithium anion of 2-picoline (III) to produce ketone (IV). Nitrosation of (IV) with NaNO2/HCl leads to keto oxime (V). Subsequent cyclization of (V) with p-formylbenzonitrile (VI) in the presence of ammonium acetate in AcOH affords the N-hydroxy imidazole (VII), which is further reduced to the triaryl imidazole (VIII) by means of triethyl phosphite in DMF. The cyano group of (VIII) is then hydrolyzed under acidic conditions to provide carboxylic acid (IX). After activation of (IX) as the corresponding acid chloride (X), treatment with ammonium hydroxide in THF yields the target carboxamide (1,2).

参考文献 中间体
合成目标
【1】 Callahan, J.F.; Burgess, J.L.; Fornwald, J.A.; Gaster, L.M.; Harling, J.D.; Harrington, F.P.; Heer, J.; Kwon, C.; Lehr, R.; Mathur, A.; Olson, B.A.; Weinstock, J.; Laping, N.J.; Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5). J Med Chem 2002, 45, 5, 999.
【2】 Callahan, J.F.; Burgess, J.L. (GlaxoSmithKline Inc.); Triarylimidazoles. EP 1169317; JP 2002541253; US 6465493; WO 0061576 .
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) 28821 1,3-benzodioxole-5-carbonyl chloride 20850-43-5 C8H5ClO3 详情 详情
(II) 64530 N-methoxy-N-methyl-1,3-benzodioxole-5-carboxamide C10H11NO4 详情 详情
(III) 17590 2-methylpyridine; 2-picoline 109-06-8 C6H7N 详情 详情
(IV) 64531 1-(1,3-benzodioxol-5-yl)-2-(2-pyridinyl)-1-ethanone C14H11NO3 详情 详情
(V) 64532 1-(1,3-benzodioxol-5-yl)-2-(2-pyridinyl)-1,2-ethanedione 2-oxime C14H10N2O4 详情 详情
(VI) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(VII) 64533 4-[4-(1,3-benzodioxol-5-yl)-1-hydroxy-5-(2-pyridinyl)-1H-imidazol-2-yl]benzonitrile C22H14N4O3 详情 详情
(VIII) 64534 4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzonitrile C22H14N4O2 详情 详情
(IX) 64535 4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzoic acid C22H15N3O4 详情 详情
(X) 64536 4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzoyl chloride C22H14ClN3O3 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VII)

Metalation of 1-trityl-4-iodoimidazole (VI) with ethylmagnesium bromide, followed by addition to 4-cyanobenzaldehyde (VII) gives rise to the carbinol (VIII), which is further reduced to the diaryl methane (IX) employing triibutyltin hydride in the presence of AIBN. Trimethylaluminium-catalyzed coupling between nitrile (IX) and amine (V) provides amidine (X). The N-trityl group of (X) is finally removed under acidic conditions to furnish the title compound.

参考文献 中间体
合成目标
【1】 Tom, W.; Aslanian, R.; West, R.; Shih, N.-Y.; Piwinski, J.J.; She, S.; Williams, S.M.; Design and synthesis of novel dual histamine H1/H3 receptor antagonists based on the H1 receptor antagonist chlorpheniramine. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 63.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 57813 3-(4-chlorophenyl)-3-(2-pyridinyl)propylamine; 3-(4-chlorophenyl)-3-(2-pyridinyl)-1-propanamine C14H15ClN2 详情 详情
(VI) 30216 4-iodo-1-trityl-1H-imidazole C22H17IN2 详情 详情
(VII) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(VIII) 57814 4-[hydroxy(1-trityl-1H-imidazol-4-yl)methyl]benzonitrile C30H23N3O 详情 详情
(IX) 57815 4-[(1-trityl-1H-imidazol-4-yl)methyl]benzonitrile C30H23N3 详情 详情
(X) 57816 N-[3-(4-chlorophenyl)-3-(2-pyridinyl)propyl]-4-[(1-trityl-1H-imidazol-4-yl)methyl]benzenecarboximidamide C44H38ClN5 详情 详情

合成路线15

该中间体在本合成路线中的序号：(VI)

2-Bromo-3-methylpyridine (I) is converted to the corresponding N-oxide (II) by treatment with m-chloroperbenzoic acid in CH2Cl2. Reaction of N-oxide (II) with trimethylsilyl cyanide and dimethylcarbamoyl chloride gives rise to the 2-cyanopyridine (III). Subsequent radical bromination of (III) using NBS and AIBN affords the bromomethyl pyridine (IV). Lithiation of 1-methyl-2-(triethylsilyl)imidazole (V), followed by condensation with 4-cyanobenzaldehyde (VI), provides carbinol (VII). This is then condensed with bromide (IV) in the presence of Ag2O to give ether (VIII). 5-Bromo-2,2-difluorobenzodioxole (IX) is lithiated with butyllithium in cold Et2O and subsequently treated with triisopropyl borate to afford, after aqueous work-up, the arylboronic acid (X). Finally, Mitsunobu coupling between boronic acid (X) and the bromopyridine (VIII) provides the title compound.

参考文献 中间体
合成目标
【1】 Wang, L.; Hasvold, L.; Tong, Y.; et al.; Discovery of potent and orally active farnesyltransferase inhibitors. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 129.
【2】 Sham, H.L.; Rockway, T.W.; Li, T.; Mantei, R.A.; Li, Q.; Lin, N.-H.; Wang, L.; Wang, W.; Wang, X.; Sullivan, G.M.; Wang, G.T.; Gwaltney, S.L. II; Claiborne, A.K.; Hasvold, L.A.; Tong, Y. (Abbott Laboratories Inc.); Farnesyltransferase inhibitors. US 2002115640; WO 0274747 .
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) 57602 2-Bromo-3-methylpyridine; 2-Bromo-3-picoline 3430-17-9 C6H6BrN 详情 详情
(II) 57603 2-bromo-3-methyl-1-pyridiniumolate C6H6BrNO 详情 详情
(III) 57604 6-bromo-5-methyl-2-pyridinecarbonitrile C7H5BrN2 详情 详情
(IV) 57605 6-bromo-5-(bromomethyl)-2-pyridinecarbonitrile C7H4Br2N2 详情 详情
(V) 57606 1-methyl-5-(triethylsilyl)-1H-imidazole C10H20N2Si 详情 详情
(VI) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(VII) 57607 4-[hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzonitrile C12H11N3O 详情 详情
(VIII) 57608 6-bromo-5-{[(4-cyanophenyl)(1-methyl-1H-imidazol-5-yl)methoxy]methyl}-2-pyridinecarbonitrile C19H14BrN5O 详情 详情
(IX) 57609 5-Bromo-2,2-difluoro-1,3-benzodioxole；4-Bromo-1,2-[(difluoromethylene)dioxy]benzene 33070-32-5 C7H3BrF2O2 详情 详情
(X) 57610 2,2-difluoro-1,3-benzodioxol-5-ylboronic acid C7H5BF2O4 详情 详情

合成路线16

该中间体在本合成路线中的序号：(IX)

Lithiation of 1-methylimidazole (VII), followed by quenching with triethylchlorosilane provides the 2-silyl imidazole (VIII). After metalation of (VIII) with tert-butyllithium, condensation with 4-cyanobenzaldehyde (IX) gives rise to the carbinol (X). Finally, coupling between alcohols (VI) and (X) in the presence of p-toluenesulfonic acid in refluxing toluene leads to the desired ether adduct.

参考文献 中间体
合成目标
【1】 Hasvold, L.A.; et al.; Design and synthesis of pyridone farnesyltransferase inhibitors. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 126.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 60862 5-(3-chlorophenyl)-6-(hydroxymethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile C13H9ClN2O2 详情 详情
(VII) 38630 1-methyl-1H-imidazole 616-47-7 C4H6N2 详情 详情
(VIII) 60863 1-methyl-2-(tripropylsilyl)-1H-imidazole C13H26N2Si 详情 详情
(IX) 17552 4-formylbenzonitrile; 4-Cyanobenzaldehyde 105-07-7 C8H5NO 详情 详情
(X) 60864 4-[hydroxy(1-methyl-1H-imidazol-2-yl)methyl]benzonitrile C12H11N3O 详情 详情
Extended Information