1-Fluoro-4-isocyanatobenzene; 4-Fluorophenyl isocyanate -Drug Synthesis Database

【结构式】

【分子编号】17977

【品名】1-Fluoro-4-isocyanatobenzene; 4-Fluorophenyl isocyanate

【CA登记号】1195-45-5

【分子式】C₇H₄FNO

【分子量】137.1133032

【元素组成】C 61.32% H 2.94% F 13.86% N 10.22% O 11.67%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(XIII)

2-nitroaniline (III) was prepared by reaction of an excess of cyclohexylamine (II) with either 2-chloronitrobenzene (Ia) in the presence of CuI and K2CO3 at 150 C or 2-fluoronitrobenzene (Ib) in chloroform. Catalytic hydrogenation gave phenylenediamine (IV), which was selectively alkylated on the primary N atom with bromoacetylpyrrolidine (V) in the presence of K2CO3 in DMF. Condensation of the resulting (VI) with the malonic acid dichloride (VII) yielded benzodiazepine (VIII). Hydrazone function was then reduced with zinc dust in acetic acid to provide amine (IX). Separation of the racemic mixture was performed by treatment with the chiral carbonic acid derivative (X), followed by chromatographic separation to give the desired (S)-isomer (XI). Cleavage of the carbamate group of (XI) was effected by hydrogenolysis to afford chiral amine (XII). The target urea was then prepared by reaction of (XII) with 4-fluorophenylisocyanate (XIII) in dichloromethane.

参考文献中间体

合成目标

【1】 Bailey, N.; et al.; Novel 1,5-benzodiazepindione gastrin/CCKB antagonists. Bioorg Med Chem Lett 1997, 7, 3, 281.
【2】 Finch, H.; Shah, P.; Carr, R.A.E. (Glaxo Wellcome plc); 1,5-Benzodiazepine derivs. having CCK and/or gastrin antagonistic activity. US 5585376; US 5646140; WO 9424149; WO 9424151 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Ia)	17964	(2-chlorophenyl)(oxo)-lambda(5)-azanolate		C₆H₅ClNO₂	详情	详情
(Ib)	17965	(2-fluorophenyl)(oxo)-lambda(5)-azanolate		C₆H₅FNO₂	详情	详情
(II)	17966	cyclohexanamine; cyclohexyl amine; cyclohexylamine	108-91-8	C₆H₁₃N	详情	详情
(III)	17967	[2-(cyclohexylamino)phenyl](oxo)-lambda(5)-azanolate		C₁₂H₁₇N₂O₂	详情	详情
(IV)	17968	N-(2-aminophenyl)-N-cyclohexylamine; N(1)-cyclohexyl-1,2-benzenediamine		C₁₂H₁₈N₂	详情	详情
(V)	17969	2-bromo-1-(1-pyrrolidinyl)-1-ethanone		C₆H₁₀BrNO	详情	详情
(VI)	17970	2-[2-(cyclohexylamino)anilino]-1-(1-pyrrolidinyl)-1-ethanone		C₁₈H₂₇N₃O	详情	详情
(VII)	17971	2-(2-phenylhydrazono)malonoyl dichloride		C₉H₆Cl₂N₂O₂	详情	详情
(VIII)	17972	1-cyclohexyl-5-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-1,5-benzodiazepine-2,3,4(5H)-trione 3-(N-phenylhydrazone)		C₂₇H₃₁N₅O₃	详情	详情
(IX)	17973	3-amino-1-cyclohexyl-5-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione		C₂₁H₂₈N₄O₃	详情	详情
(X)	17974	4-nitrophenyl (1S)-1-phenylethyl carbonate		C₁₅H₁₃NO₅	详情	详情
(XI)	17975	(1S)-1-phenylethyl (3R)-1-cyclohexyl-2,4-dioxo-5-[2-oxo-2-(1-pyrrolidinyl)ethyl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-ylcarbamate		C₃₀H₃₆N₄O₅	详情	详情
(XII)	17976	(3R)-3-amino-1-cyclohexyl-5-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione		C₂₁H₂₈N₄O₃	详情	详情
(XIII)	17977	1-Fluoro-4-isocyanatobenzene; 4-Fluorophenyl isocyanate	1195-45-5	C₇H₄FNO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

The N-protection of 4-(2-aminoethyl)phenol (I) with benzyl chloroformate gives the N-benzyloxycarbonyl derivative (II), which is condensed with 1-methyl-1-(trichloromethyl)ethanol (III) by means of NaOH in acetone yielding the phenoxyisobutyric acid (IV). The deprotection of the amino group of (IV) by hydrogenation over Pd/C affords the ethylamino derivative (V), which is reprotected with 9-fluorenylmethoxycarbonyl protecting group to provide carbamate (VI). The acid group of (VI) is then coupled to a Sasrin polystyrene resin giving the N-protected resin (VII), which is deprotected with piperidine affording resin (VIII) with a free amino group, which is condensed with heptanoic acid (A) by means of DIC and HOBT to give the amide (IX). The reduction of the carbonyl group amide (IX) with BH3/THF yields the heptylamine (X), which is condensed with 4-fluorophenyl isocyanate (XI) to afford the urea (XII). Finally, this compound is treated with trifluoroacetic acid to eliminate the polystyrene resin and isolate the target compound. Alternatively, the heptylamine (X) can also be obtained directly by reductocondensation of the free amino group of the resin (VIII) with heptanal (B) by means of NaBH3CN.

参考文献中间体

合成目标

【1】 Brown, P.J.; et al.; Generation of secondary alkyl amines on solid support by borane reduction. Application to the parallel synthesis of PPAR ligands. Synthesis 1997, 7, 778.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	13580	1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate	1885-14-9	C₇H₅ClO₂	详情	详情
(B)	25714	octanal	124-13-0	C₈H₁₆O	详情	详情
(A)	35032	heptanoic acid	111-14-8	C₇H₁₄O₂	详情	详情
(I)	19988	4-(2-Aminoethyl)phenol; Tyramine	51-67-2	C₈H₁₁NO	详情	详情
(II)	25974	benzyl 4-hydroxyphenethylcarbamate		C₁₆H₁₇NO₃	详情	详情
(III)	25975	1,1,1-trichloro-2-methyl-2-propanol	57-15-8	C₄H₇Cl₃O	详情	详情
(IV)	25976	2-[4-(2-[[(benzyloxy)carbonyl]amino]ethyl)phenoxy]-2-methylpropionic acid		C₂₀H₂₃NO₅	详情	详情
(V)	25977	2-[4-(2-aminoethyl)phenoxy]-2-methylpropionic acid		C₁₂H₁₇NO₃	详情	详情
(VI)	25978	2-[4-(2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]ethyl)phenoxy]-2-methylpropionic acid		C₂₇H₂₇NO₅	详情	详情
(VII)	25978	2-[4-(2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]ethyl)phenoxy]-2-methylpropionic acid		C₂₇H₂₇NO₅	详情	详情
(VIII)	25977	2-[4-(2-aminoethyl)phenoxy]-2-methylpropionic acid		C₁₂H₁₇NO₃	详情	详情
(IX)	25979	2-[4-[2-(heptanoylamino)ethyl]phenoxy]-2-methylpropionic acid		C₁₉H₂₉NO₄	详情	详情
(X)	25980	2-[4-[2-(heptylamino)ethyl]phenoxy]-2-methylpropionic acid		C₁₉H₃₁NO₃	详情	详情
(XI)	17977	1-Fluoro-4-isocyanatobenzene; 4-Fluorophenyl isocyanate	1195-45-5	C₇H₄FNO	详情	详情
(XII)	25981	2-(4-[2-[[(4-fluoroanilino)carbonyl](heptyl)amino]ethyl]phenoxy)-2-methylpropionic acid		C₂₆H₃₅FN₂O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

The condensation of ethyl 2-[4-[2-(heptylamino)ethyl]phenoxy]-2-methylpropionate (XIII) with 4-fluorophenyl isocyanate (XI) gives the corresponding ureido compound (XIV), which is then hydrolyzed with NaOH in refluxing ethanol.

参考文献中间体

合成目标

【1】 Brown, P.J.; et al.; Generation of secondary alkyl amines on solid support by borane reduction. Application to the parallel synthesis of PPAR ligands. Synthesis 1997, 7, 778.
【2】 Willson, T.M. (Glaxo Group Ltd.); Use of agonists of the peroxisome proliferator activated receptor alpha for treating obesity. WO 9736579 .

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)	17977	1-Fluoro-4-isocyanatobenzene; 4-Fluorophenyl isocyanate	1195-45-5	C₇H₄FNO	详情	详情
(XIII)	25982	ethyl 2-[4-[2-(heptylamino)ethyl]phenoxy]-2-methylpropanoate		C₂₁H₃₅NO₃	详情	详情
(XIV)	25983	ethyl 2-(4-[2-[[(4-fluoroanilino)carbonyl](heptyl)amino]ethyl]phenoxy)-2-methylpropanoate		C₂₈H₃₉FN₂O₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

In an alternative procedure, sodium 4-acetylbenzenesulfonate (IV) was refluxed with POCl3 and subsequently treated with dibenzylamine to afford sulfonamide (V). Bromination of (V) in chloroform yielded the bromo ketone (VI), which was hydrolyzed to phenacyl alcohol (VII) by treatment with ethanolic betaine, followed by aqueous NaHCO3. Addition of 4-fluorophenyl isocyanate (VIII) to (VII) and then cyclization in refluxing HOAc yielded the oxazolone (IX). Final debenzylation was achieved with concentrated H2SO4 to give the target sulfonamide.

参考文献中间体

合成目标

【1】 Godessart, N.; Crespo, M.I.; Puig, C.; et al.; Synthesis and biological evaluation of 3,4-diaryloxazolones: A new class of orally active cyclooxygenase-2 inhibitors. J Med Chem 2000, 43, 2, 214.

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)	44956	sodium 4-acetylbenzenesulfonate	61827-67-6	C₈H₇NaO₄S	详情	详情
(V)	44957	4-acetyl-N,N-dibenzylbenzenesulfonamide		C₂₂H₂₁NO₃S	详情	详情
(VI)	44958	N,N-dibenzyl-4-(2-bromoacetyl)benzenesulfonamide		C₂₂H₂₀BrNO₃S	详情	详情
(VII)	44959	N,N-dibenzyl-4-glycoloylbenzenesulfonamide		C₂₂H₂₁NO₄S	详情	详情
(VIII)	17977	1-Fluoro-4-isocyanatobenzene; 4-Fluorophenyl isocyanate	1195-45-5	C₇H₄FNO	详情	详情
(IX)	44960	N,N-dibenzyl-4-[3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1,3-oxazol-4-yl]benzenesulfonamide		C₂₉H₂₃FN₂O₄S	详情	详情

Extended Information