1-(2-bromoethoxy)-4-fluorobenzene; 2-bromoethyl 4-fluorophenyl ether -Drug Synthesis Database

【结构式】

【分子编号】20830

【品名】1-(2-bromoethoxy)-4-fluorobenzene; 2-bromoethyl 4-fluorophenyl ether

【CA登记号】332-48-9

【分子式】C₈H₈BrFO

【分子量】219.0533232

【元素组成】C 43.87% H 3.68% Br 36.48% F 8.67% O 7.3%

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：(III)

The condensation of 4-fluorophenol (I) with 1,2-dibromoethane (II) in basic medium gives 2-(4-fluorophenyl)ethyl bromide (III), which by reaction with N-benzoyl-2-hydroxyglycine (IV) in methanesulfonic acid yields N-benzoyl-2-[2-(2-bromoethoxy)-5-fluorophenyl]glycine (V). The cyclization of (V) with acetic anhydride and triethylamine at 50 C affords 6-fluoro-2'-phenylspiro[2,3-dihydro-4H-1-benzopyran-4,4'-oxazolidine]-5'-one (VI), which is hydrolyzed with refluxing formic acid-HCl giving the amino acid (VII). The esterification of (VII) with SOCl2 and methanol in the usual way yields the methyl ester (VIII), which is submitted to optical resolution by selective hydrolysis with alpha-chymotrypsine affording methyl 4(S)-amino-6-fluoro-2,3-dihydro-4H-1-benzopyrano-4-carboxylate (IX). Finally, this compound is converted into sorbinil by cyclization with sodium cyanate in acetic acid at room temperature.

参考文献中间体

合成目标

【1】 Dirlam, N.L.; Moore, B.S.; Urban, F.J.; Novel synthesis of the aldose reductase inhibitor sorbinil via amidoalkylation, intramolecular oxazolidin-5-one alkylation, and chymotrypsin resolution. J Org Chem 1987, 52, 16, 3587-91.

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)	19369	2-iodopropane	75-30-9	C₃H₇I	详情	详情
(II)	10252	1,2-Dibromoethane; Ethylene dibromide	106-93-4	C₂H₄Br₂	详情	详情
(III)	20830	1-(2-bromoethoxy)-4-fluorobenzene; 2-bromoethyl 4-fluorophenyl ether	332-48-9	C₈H₈BrFO	详情	详情
(IV)	20606	2-(benzoylamino)-2-hydroxyacetic acid	16555-77-4	C₉H₉NO₄	详情	详情
(V)	20832	2-(benzoylamino)-2-[2-(2-bromoethoxy)-5-fluorophenyl]acetic acid		C₁₇H₁₅BrFNO₄	详情	详情
(VI)	20833	6-Fluoro-2'-phenyl-3,4,4',5'-tetrahydro-2H-spiro[1-benzopyran-4,4'-oxazol]-5'-one		C₁₇H₁₂FNO₃	详情	详情
(VII)	20834	4-amino-6-fluoro-4-chromanecarboxylic acid		C₁₀H₁₀FNO₃	详情	详情
(VIII)	20835	methyl 4-amino-6-fluoro-4-chromanecarboxylate		C₁₁H₁₂FNO₃	详情	详情
(IX)	20836	[(4S)-4-amino-6-fluoro-3,4-dihydro-2H-chromen-4-yl]methyl formate		C₁₁H₁₂FNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Alkylation of 1-benzylpiperazine (VI) with 2-(4-fluorophenoxy)ethyl bromide (VII) produced the dialkylated piperazine (VIII). The benzyl protecting group of (VIII) was then removed hydrogenolysis in the presence of Pearlman's catalyst to furnish (IX). The title compound was then obtained by condensation of piperazine (IX) with mesylate (V) or, alternatively, by reductive alkylation of (IX) with aldehyde (X) in the presence of sodium triacetoxyborohydride.

参考文献中间体

合成目标

【1】 Yamamoto, N.; et al.; Discovery of a potent neuron-selective calcium channel blocker: Structure-activity relationships and neuroprotective effects of novel piperazine derivatives. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 51.
【2】 Niidome, T.; Norimine, Y.; Teramoto, T.; Kawano, K.; Kimura, T.; Iimura, Y.; Yamamoto, N.; Suzuki, Y.; Ito, K.; Hatakeyama, S.; Nagato, S.; Komatsu, M. (Eisai Co., Ltd.); N,N-Substd. cyclic amine derivs.. EP 1099692; JP 2000169462; WO 0005210 .

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)	49823	4-cyano-5-methyl-4-phenylhexyl methanesulfonate		C₁₅H₂₁NO₃S	详情	详情
(VI)	28542	N-Benzylpiperazine; 1-Benzylpiperazine	2759-28-6	C₁₁H₁₆N₂	详情	详情
(VII)	20830	1-(2-bromoethoxy)-4-fluorobenzene; 2-bromoethyl 4-fluorophenyl ether	332-48-9	C₈H₈BrFO	详情	详情
(VIII)	49824	1-benzyl-4-[2-(4-fluorophenoxy)ethyl]piperazine; 2-(4-benzyl-1-piperazinyl)ethyl 4-fluorophenyl ether		C₁₉H₂₃FN₂O	详情	详情
(IX)	49825	4-fluorophenyl 2-(1-piperazinyl)ethyl ether; 1-[2-(4-fluorophenoxy)ethyl]piperazine		C₁₂H₁₇FN₂O	详情	详情
(X)	49826	2-isopropyl-5-oxo-2-phenylpentanenitrile		C₁₄H₁₇NO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

In a further procedure, 1-benzylpiperazine (VI) was alkylated with mesylate (V) to yield adduct (XI). Catalytic hydrogenolysis of the benzyl group of (XI) afforded piperazine (XII), which was finally alkylated with 2-(4-fluorophenoxy)ethyl bromide (VII) in the presence of triethylamine.

参考文献中间体

合成目标

【1】 Yamamoto, N.; et al.; Discovery of a potent neuron-selective calcium channel blocker: Structure-activity relationships and neuroprotective effects of novel piperazine derivatives. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 51.

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)	49823	4-cyano-5-methyl-4-phenylhexyl methanesulfonate		C₁₅H₂₁NO₃S	详情	详情
(VI)	28542	N-Benzylpiperazine; 1-Benzylpiperazine	2759-28-6	C₁₁H₁₆N₂	详情	详情
(VII)	20830	1-(2-bromoethoxy)-4-fluorobenzene; 2-bromoethyl 4-fluorophenyl ether	332-48-9	C₈H₈BrFO	详情	详情
(XI)	49827	5-(4-benzyl-1-piperazinyl)-2-isopropyl-2-phenylpentanenitrile		C₂₅H₃₃N₃	详情	详情
(XII)	49828	2-isopropyl-2-phenyl-5-(1-piperazinyl)pentanenitrile		C₁₈H₂₇N₃	详情	详情

Extended Information