isonicotinoyl chloride -Drug Synthesis Database

【结构式】

【分子编号】27850

【品名】isonicotinoyl chloride

【CA登记号】39178-35-3

【分子式】C₆H₄ClNO

【分子量】141.5566

【元素组成】C 50.91% H 2.85% Cl 25.04% N 9.89% O 11.3%

与该中间体有关的原料药合成路线共 5 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1

该中间体在本合成路线中的序号：(II)

The acid chloride (II) of isonicotinic acid is prepared by reaction of oxalyl chloride (A) with the potassium salt of isonicotinic acid (I). The acylation of 1,3-dihydro-4-ethyl-2H-imidazol-2-one (III) with acid chloride (II) under Friedel-Crafts' conditions gives 1,3-dihydro-4-isonicotinoyl-5-ethyl-2H-imidazol-2-one.

参考文献中间体

合成目标

【1】 Dage, R.C.; Schnettler, R.A.; Palopoli, F.P.; 4-Aroyl-1,3-dihydro-2H-imidazol-2-ones, a new class of cardiotonic agents. Effect of 4-Pyridoyl substituents and related compounds. 186th ACS Natl Meet (Aug. 28 - Sept. 2, Washington, D.C.) 1983, Abst MEDI-84.
【2】 Schnettler, R.A.; Dage, R.C.; Grisar, J.M.; Palopoli, F.P.; 4-Pyridylimidazolones and method of use. EP 0059948; ES 8305352; ES 8402827; GB 2096600; US 4405628 .
【3】 Mannhold, R.; Piroximone. Drugs Fut 1984, 9, 12, 905.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	29841	Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride	79-37-8	C₂Cl₂O₂	详情	详情
(I)	34361	potassium isonicotinate		C₆H₄KNO₂	详情	详情
(II)	27850	isonicotinoyl chloride	39178-35-3	C₆H₄ClNO	详情	详情
(III)	34362	4-ethyl-1,3-dihydro-2H-imidazol-2-one		C₅H₈N₂O	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 N-alkylation of N-(tert-butoxycarbonyl)glycine (I) with benzyl bromide (II) by means of NaH in THF gives N-benzyl-N-(tert-butoxycarbonyl)glycine (III), which is condensed with 4-aminoacetophenone (IV) by means of isobutyl chloroformate and TEA in dichloromethane yielding the corresponding glycinamide (V). The cyclization of (V) with thiourea (VI) by means of I2 in refluxing isopropanol affords, after work up, the N-benzyl-glycinamide (VII), which is finally acylated with pyridine-4-carbonyl chloride by means of TEA and DMAP in dichloromethane.

参考文献中间体

合成目标

【1】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 .

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)	18066	N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid	4530-20-5	C₇H₁₃NO₄	详情	详情
(II)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(III)	27846	2-[benzyl(tert-butoxycarbonyl)amino]acetic acid		C₁₄H₁₉NO₄	详情	详情
(IV)	27847	1-(4-aminophenyl)-1-ethanone	99-92-3	C₈H₉NO	详情	详情
(V)	27848	tert-butyl 2-(4-acetylanilino)-2-oxoethyl(benzyl)carbamate		C₂₂H₂₆N₂O₄	详情	详情
(VI)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(VII)	27849	N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]-2-(benzylamino)acetamide		C₁₈H₁₈N₄OS	详情	详情
(VIII)	27850	isonicotinoyl chloride	39178-35-3	C₆H₄ClNO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The title compound was synthesized by acylation of 5,6-diethoxy-2-(methylthio)benzimidazole (I) with isonicotinoyl chloride (II) in the presence of triethylamine in chloroform.

参考文献中间体

合成目标

【1】 Brukstus, A.; Dauksas, V.; Garaliene, V.; Labanauskas, L.; Synthesis and positive inotropic effects of 1-acyl-5,6-diethoxy-2-methylthiobenzimidazoles. Arzneim-Forsch Drug Res 1998, 48, 12, 1137.

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)	30848	5,6-diethoxy-2-(methylsulfanyl)-1H-benzimidazole; 5-ethoxy-2-(methylsulfanyl)-1H-benzimidazol-6-yl ethyl ether		C₁₂H₁₆N₂O₂S	详情	详情
(II)	27850	isonicotinoyl chloride	39178-35-3	C₆H₄ClNO	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IX)

Friedel-Crafts acylation of acetanilide (I) with propionyl chloride in the presence of AlCl3 afforded 4'-(acetamido)propiophenone (II). Subsequent Mannich reaction of (II) with dimethylamine hydrochloride and formaldehyde produced the aminoketone (III). Quaternization of the tertiary amine of (III) with MeI, followed by displacement of the resulting ammonium salt (IV) with KCN yielded the intermediate ketonitrile (V). In alternative procedure, nitrile (V) was prepared by acylation of acetanilide (I) with 3-chloro-2-methylpropionyl chloride, and further displacement of the resulting alpha-chloroketone (VI) with KCN. Acid hydrolysis of both nitrile and acetamido groups of (V) provided ketoacid (VII), which was cyclized with hydrazine to give pyridazinone (VIII). Finally, acylation of the amino group of (VIII) by means of pyridine-4-carbonyl chloride furnished the title amide.

参考文献中间体

合成目标

【1】 Liu, C.M.; et al.; Synthesis and platelet aggregation inhibitory activity of 6-(4'-substituted acylaminophenyl)-4,5-dihydro-3-(2H)-pyridazinones. Acta Pharm Sin 1999, 34, 1, 23.

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)	10194	N-Phenylacetamide; Acetanilide	103-84-4	C₈H₉NO	详情	详情
(II)	29198	N-(4-propionylphenyl)acetamide		C₁₁H₁₃NO₂	详情	详情
(III)	29199	N-[4-[3-(dimethylamino)-2-methylpropanoyl]phenyl]acetamide		C₁₄H₂₀N₂O₂	详情	详情
(IV)	29200	3-[4-(acetamido)phenyl]-N,N,N,2-tetramethyl-3-oxo-1-propanaminium iodide		C₁₅H₂₃IN₂O₂	详情	详情
(V)	29201	N-[4-(3-cyano-2-methylpropanoyl)phenyl]acetamide		C₁₃H₁₄N₂O₂	详情	详情
(VI)	29202	N-[4-(3-chloro-2-methylpropanoyl)phenyl]acetamide		C₁₂H₁₄ClNO₂	详情	详情
(VII)	29203	4-(4-aminophenyl)-3-methyl-4-oxobutyric acid		C₁₁H₁₃NO₃	详情	详情
(VIII)	29204	6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone		C₁₁H₁₃N₃O	详情	详情
(IX)	27850	isonicotinoyl chloride	39178-35-3	C₆H₄ClNO	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VI)

The acylation of N-[4-(4-aminophenyl)-2-thiazolyl]carbamic acid tert-butyl ester (I) with bromoacetyl bromide (II) gives the bromoacetamide (III), which is then condensed with (S)-alpha-methylbenzylamine (IV) to yield the glycinamide derivative (V). The acylation of (V) with 4-pyridylcarbonyl chloride affords the protected precursor (VI), which is finally deprotected to provide the target BILS 179 BS.

参考文献中间体

合成目标

【1】 Crute, J.J.; et al.; Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat Med 2002, 8, 4, 386.
【2】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 .
【3】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Crute, J.J.; Thavonekham, B.; Grygon, C. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Antiherpes virus cpds. and methods for their preparation and use. US 6288091 .

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)	54066	tert-butyl 4-(4-aminophenyl)-1,3-thiazol-2-ylcarbamate	n/a	C₁₄H₁₇N₃O₂S	详情	详情
(II)	14005	2-Bromoacetyl bromide; Bromoacetyl bromide	598-21-0	C₂H₂Br₂O	详情	详情
(III)	54067	tert-butyl 4-{4-[(2-bromoacetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate	n/a	C₁₆H₁₈BrN₃O₃S	详情	详情
(IV)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(V)	54068	tert-butyl 4-{4-[(2-{[(1S)-1-phenylethyl]amino}acetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate	n/a	C₂₄H₂₈N₄O₃S	详情	详情
(VI)	27850	isonicotinoyl chloride	39178-35-3	C₆H₄ClNO	详情	详情
(VII)	54069	tert-butyl 4-{4-[(2-{isonicotinoyl[(1S)-1-phenylethyl]amino}acetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate	n/a	C₃₀H₃₁N₅O₄S	详情	详情

Extended Information