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【结 构 式】

【分子编号】16598

【品名】Formamide

【CA登记号】75-12-7

【 分 子 式 】CH3NO

【 分 子 量 】45.04096

【元素组成】C 26.67% H 6.71% N 31.1% O 35.52%
与该中间体有关的原料药合成路线共 7 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1

该中间体在本合成路线中的序号：(II)

The cyclization of methyl-5-(methylthio)anthranilate (I) with formamide (II) by heating at 190 C gives 6-(methylthio)-4(3H)-quinazolinone (III), which is condensed with methyl 3-chloroacrylate (IV) by means of NaH yielding methyl 3-[6-(methylthio)-4-oxo-4H-quinazolin-3-yl]-2-propenoate (V). Finally, this compound is hydrolyzed with refluxing 6N HCl. The same procedure of synthesis can also be performed from 5-(methylthio)anthranilic acid instead of methyl 5-(methylthio)anthranilate (I).

参考文献 中间体
合成目标
【1】 LeMahieu, R.A.; et al.; (E)-3-(4-Oxo-4H-quinazolin-3-yl=-2-propenoic acids, a new series of antiallergy agents. J Med Chem 1983, 26, 3, 420-423.
【2】 Lemahieu, R.A.; Nason, W.C. (Hoffmann-La Roche, Inc.); Trans-3-(4-oxo-4H-quinazolin-3-yl)-2-propenoic acid derivatives. EP 0023594; JP 8125167; US 4281127 .
【3】 Serradell, M.N.; Castaner, J.; Chu, S.S.; Tiacrilast. Drugs Fut 1985, 10, 2, 131.
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) 28939 methyl 2-amino-5-(methylsulfanyl)benzoate C9H11NO2S 详情 详情
(II) 16598 Formamide 75-12-7 CH3NO 详情 详情
(III) 28940 6-(methylsulfanyl)-4(3H)-quinazolinone C9H8N2OS 详情 详情
(IV) 28941 methyl (E)-3-chloro-2-propenoate C4H5ClO2 详情 详情
(V) 28942 methyl (E)-3-[6-(methylsulfanyl)-4-oxo-3(4H)-quinazolinyl]-2-propenoate C13H12N2O3S 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

The thiazolyl carbonate (XI) has been synthesized as follows: The reaction of formamide (XIV) with P2S5 in ethyl ether gives thioformamide (XV), which is cyclized with 2-chloro-3-oxopropionic acid ethyl ester (XVI) [obtained by condensation of ethyl chloroacetate (XVII) with ethyl formate (XVIII) by means of t-BuOK in THF] yielding thiazol-5-carboxylic acid ethyl ester (XIX). The reduction of (XIX) with LiAlH4 in THF affords 5-thiazolylmethanol (XX), which is then esterified with 4-nitrophenyl chloroformate (XXI) by means of 4-methylmorpholine (MPH) in dichloromethane to give the desired product (XI).

参考文献 中间体
合成目标
【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700.
【2】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 .
【3】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 .
【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 16595 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate 144163-97-3 C11H8N2O5S 详情 详情
(XIV) 16598 Formamide 75-12-7 CH3NO 详情 详情
(XV) 16599 Thioformamide CH3NS 详情 详情
(XVI) 16600 ethyl 2-chloro-3-oxopropanoate C5H7ClO3 详情 详情
(XVII) 16601 ethyl chloroacetate; ethyl 2-chloroacetate 105-39-5 C4H7ClO2 详情 详情
(XVIII) 16602 ethyl formate 109-94-4 C3H6O2 详情 详情
(XIX) 16603 ethyl 1,3-thiazole-5-carboxylate 32955-22-9 C6H7NO2S 详情 详情
(XX) 16604 1,3-thiazol-5-ylmethanol;5-thiazolylmethanol;Thiazole-5-methanol 38585-74-9 C4H5NOS 详情 详情
(XXI) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情

合成路线3

该中间体在本合成路线中的序号：

Condensation between p-fluorobenzaldehyde (I), p-toluenesulfinic acid (II) and formamide in the presence of camphorsulfonic acid afforded 4-fluorophenyltosylmethyl formamide (III). Subsequent dehydration of (III) by means of POCl3 and Et3N produced isonitrile (IV). Imine (VII) was prepared by condensation of pyridine-4-carboxaldehyde (V) with 1-Boc-4-aminopiperidine (VI) using MgSO4 as the dehydrating reagent. Dipolar cycloaddition of this imine with the anion of tosyl isonitrile (IV) generated the trisubstituted imidazole (VIII). Finally, acid cleavage of the Boc protecting group furnished the title compound.

参考文献 中间体
合成目标
【1】 Adams, J.L.; Gallagher, T.F.; Garigipati, R.S.; Boehm, J.C.; Sisko, J.; Peng, Z.-Q.; Lee, J.C.-L. (SmithKline Beecham plc); Certain 1,4,5-tri-substd. imidazole cpds. useful as cytokine. EP 0809499; JP 1998512555; US 5593992; WO 9621452 .
【2】 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16598 Formamide 75-12-7 CH3NO 详情 详情
(I) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(II) 25593 4-methylbenzenesulfinic acid C7H8O2S 详情 详情
(III) 25594 (4-fluorophenyl)[(4-methylphenyl)sulfonyl]methylformamide C15H14FNO3S 详情 详情
(IV) 25595 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide C15H12FNO2S 详情 详情
(V) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(VI) 28414 4-Amino-1-N-Boc-piperidine; tert-butyl 4-amino-1-piperidinecarboxylate; N-Boc-4-aminopiperidine 87120-72-7 C10H20N2O2 详情 详情
(VII) 34886 tert-butyl 4-[[(Z)-4-pyridinylmethylidene]amino]-1-piperidinecarboxylate C16H23N3O2 详情 详情
(VIII) 34887 tert-butyl 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-1-yl]-1-piperidinecarboxylate C24H27FN4O2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(A)

Ethylenediaminetetraacetic acid (EDTA) (I) on heating with formamide (A), afforded IGRF-154 (II). The latter compound was suspended in dimethylformamide (C), heated with morpholine (B) in ethanol and then refluxed with formalin. The final product crystallized on cooling.

参考文献 中间体
合成目标
【1】 Ren, Y.F.; et al.; An investigation of a new antineoplastic agent bimolane (AT-1727). Kexue Tongbao 1980, 23, 4, 189-190.
【2】 Ji Ru-Yun; Bimolane. Drugs Fut 1981, 6, 11, 667.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(A) 16598 Formamide 75-12-7 CH3NO 详情 详情
(I) 39018 2-[[2-[bis(carboxymethyl)amino]ethyl](carboxymethyl)amino]acetic acid C10H16N2O8 详情 详情
(II) 28033 4-[2-(3,5-dioxo-1-piperazinyl)ethyl]-2,6-piperazinedione C10H14N4O4 详情 详情
(C) 33491 Dimethylformamide 68-12-2 C3H7NO 详情 详情

合成路线5

该中间体在本合成路线中的序号：(XX)

　

参考文献 中间体
合成目标
【1】 Prakash SR, Cable SR, Correa ID, et al. 1995. Synthesis o{ isotopically labeled pyridoindolane 5-HT3 receptor antagonists J Label Comp Radiopluum, 36 (10): 993～1007
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) 14216 (5-Methyl-1H-imidazol-4-yl)methanol 29636-87-1 C5H8N2O 详情 详情
(XX) 16598 Formamide 75-12-7 CH3NO 详情 详情
(XXI) 66076 methyl 3-chloro-5-oxohexanoate 　 C7H11ClO3 详情 详情
(XXII) 66077 methyl 4-methyl-1H-imidazole-5-carboxylate 　 C6H8N2O2 详情 详情
(XXIII) 66078 (4-methyl-1H-imidazol-5-yl)methanol 　 C5H8N2O 详情 详情

合成路线6

该中间体在本合成路线中的序号：(VII)

　

参考文献 中间体
合成目标
【1】 Tung R. 2008. Preparation of 4-aminoquinazolines as EGFR and HER-2 inhibitors. PCT Int Appl WO 2008024439(Concert Pharmaceuticals Inc, USA).
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) 31326 5-bromo-2-furoic acid 585-70-6 C5H3BrO3 详情 详情
(II) 67215 N,O-dimethylhydroxylamine hydrochloride 　 C2H8NO.HCl 详情 详情
(III) 67216 5-bromo-N-methoxy-N-methylfuran-2-carboxamide 　 C7H8BrNO3 详情 详情
(IV) 52428 Bis(tributyltin); Hexabutyldistannane; Bis(tri-n-butyltin); Hexa-n-butylditin; Hexa-n-butyldistannane 813-19-4 C24H54Sn2 详情 详情
(V) 67217 N-methoxy-N-methyl-5-(tributylstannyl)furan-2-carboxamide 　 C19H35NO3Sn 详情 详情
(VI) 19964 5-Iodoanthranilic acid; 2-amino-5-iodobenzoic acid 5326-47-6 C7H6INO2 详情 详情
(VII) 16598 Formamide 75-12-7 CH3NO 详情 详情
(VIII) 67218 6-iodoquinazolin-4(1H)-one 16064-08-7 C8H5IN2O 详情 详情
(IX) 49875 4-chloro-6-iodoquinazoline 98556-31-1 C8H4ClIN2 详情 详情
(X) 67219 　 C10H9N.K 详情 详情
(XI) 67220 2-(2-bromoethyl)isoindoline-1,3-dione 　 C12H4D4BrNO2 详情 详情
(XII) 67221 iodomethane 　 CD3I 详情 详情
(XIII) 67222 2-(2-(methylthio)ethyl)isoindoline-1,3-dione 　 C11H4D7NO2S 详情 详情
(XIV) 13214 Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate 24424-99-5 C10H18O5 详情 详情
(XV) 67223 tert-butyl (2-(methylsulfonyl)ethyl)carbamate 　 C8H10D7NO4S 详情 详情
(XVI) 67224 2-(methylsulfonyl)ethanamine hydrochloride 　 C3H2D7NO2S.HCl 详情 详情
(XVII) 49872 1-Chloro-2-Hydroxy-5-Nitrobenzene; 2-Chloro-4-nitrophenol; 4-Nitro-2-chlorophenol; p-Nitro-o-chlorophenol 619-08-9 C6H4ClNO3 详情 详情
(XVIII) 17221 3-Fluorobenzyl bromide; 1-(bromomethyl)-3-fluorobenzene 456-41-7 C7H6BrF 详情 详情
(XIX) 49873 2-chloro-1-[(3-fluorobenzyl)oxy]-4-nitrobenzene; 2-chloro-4-nitrophenyl 3-fluorobenzyl ether C13H9ClFNO3 详情 详情
(XX) 49874 3-chloro-4-[(3-fluorobenzyl)oxy]phenylamine; 3-chloro-4-[(3-fluorobenzyl)oxy]aniline C13H11ClFNO 详情 详情
(XXI) 49876 N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-N-(6-iodo-4-quinazolinyl)amine; N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-6-iodo-4-quinazolinamine C21H14ClFIN3O 详情 详情
(XXII) 67225 5-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)-N-methoxy-N-methyltetrahydrofuran-2-carboxamide 　 C28H26ClFN4O4 详情 详情
(XXIII) 67226 5-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)tetrahydrofuran-2-carbaldehyde 　 C26H20DClFN3O3 详情 详情
(XXIV) 67227 tert-butyl ((5-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl)tetrahydrofuran-2-yl)methyl)(2-(methylsulfonyl)ethyl)carbamate 　 C34H27D9ClFN4O6S 详情 详情
(XXV) 67228 4-methylbenzenesulfonic acid 104-15-4 C7H8O3S 详情 详情

合成路线7

该中间体在本合成路线中的序号：(IX)

The intermediate 5-tert-butylimidazole-4-carbaldehyde (III) is prepared by reaction of ethyl pivaloyl acetate (VII) with sulfuryl chloride in chloroform to provide the 2-chloro derivative (VIII), which is cyclized with formamide (IX) in the presence of a trace of water in a sealed tube at 150 oC, affording ethyl 5-tert-butylimidazole-4-carboxylate (X). Reduction of ester (X) with LiAlH4 in THF gives alcohol (XI), which is finally oxidized to the target carbaldehyde (III) using MnO2 in acetone .

参考文献 中间体
合成目标
【1】 Hayashi, Y., Grodberg, J., Palladino, M. (Nereus Pharmaceuticals, Inc). Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins dehydrophenylahistins and analogs thereof. EP 1529044, JP 2006511534, WO 2004054498.
【2】 Palladino, M.A., Lloyd, G.K., Hayashi, Y., Nicholson, B. (Nereus Pharmaceuticals, Inc). Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof. EP 1711487, JP 2007520565, WO 2005077940.
【3】 Palladino, M., Lloyd, G.K., Hayashi, Y. (Nereus Pharmaceuticals, Inc). Analogs of dehydrophenylahistins and their therapeutic use. EP 1926724, US 2007078138, WO 2007035841.
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) 69002 5-tert-butylimidazole-4-carbaldehyde;5-(1,1-dimethylethyl)-1H-Imidazole-4-carboxaldehyde;4-(1,1-dimethylethyl)-1H-Imidazole-5-carboxaldehyde 714273-83-3 C8H12N2O 详情 详情
(VII) 69004 ethyl 4,4-dimethyl-3-oxopentanoate;Ethyl pivaloylacetate 17094-34-7 C9H16O3 详情 详情
(VIII) 69005 ethyl 2-chloro-4,4-dimethyl-3-oxopentanoate 　 C9H15ClO3 详情 详情
(IX) 16598 Formamide 75-12-7 CH3NO 详情 详情
(X) 69006 ethyl 5-(tert-butyl)-1H-imidazole-4-carboxylate 　 C10H16N2O2 详情 详情
(XI) 69007 (5-(tert-butyl)-1H-imidazol-4-yl)methanol 　 C8H14N2O 详情 详情
Extended Information