3,4-Dichlorophenol -Drug Synthesis Database

【结构式】

【分子编号】34044

【品名】3,4-Dichlorophenol

【CA登记号】95-77-2

【分子式】C₆H₄Cl₂O

【分子量】163.00256

【元素组成】C 44.21% H 2.47% Cl 43.5% O 9.82%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XI)

A stereoselective synthesis of sertraline has been described: The silylation of 1,2-dihydronaphthalen-1(R)-ol (I) with tert-butyldiphenylsilyl chloride (TBDPS-Cl) gives the corresponding silyl ether (II), which is brominated with Br2 and triethylamine (TEA) in dichloromethane yielding the 4-bromo-compound (III). The condensation of (III) with 3,4-dichlorophenyltrimethyltin (IV), by means of a palladium catalyst affords the silylated phenylnaphthalenol (V), which is deprotected with TBAF and acetic acid to provide 4-(3,4-dichlorophenyl)-1,2-dihydronaphthalen-1(R)-ol (VI). The regioselective hydrogenation with H2 over chiral iridium or rhodium catalysts gives the (1R-trans)-tetrahydronaphthol (VII), which is treated with diphenylphosphoryl azide (DPPA) and DBU in THF yielding the (1S-cis)-azide (VIII). The reduction of (VIII) with H2 over Pd/C in ethanol affords the corresponding amine (IX), which is treated with ethyl chloroformate to give the expected carbamate (X). Finally, this compound is reduced with LiAlH(OMe)3 in THF. 2,4-Dichlorophenyltrimethyltin (IV) is prepared by reaction of 3,4-dichlorophenol (XI) with triflic anhydride in pyridine/CH2Cl2 to give triflate (XII), which is converted to (IV) by reaction with hexamethylditin and Pd(PPh3)4 in THF. The silylated naphthalenol (V) can also be obtained by condensation of (III) with the phenylboronic acid (XIII) in the presence of a palladium catalyst.

参考文献中间体

合成目标

【1】 Rovis, T.; Lautens, M.; Selective functionalization of 1,2-dihydronaphthalenols leads to a concise, stereoselective synthesis of sertraline. Tetrahedron 1999, 55, 29, 8967.

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)	34037	1,2-dihydronaphthalen-1(R)-ol; (1R)-1,2-dihydro-1-naphthalenol		C₁₀H₁₀O	详情	详情
(II)	34038	tert-butyl(diphenyl)silyl (1R)-1,2-dihydro-1-naphthalenyl ether; tert-butyl[(1R)-1,2-dihydro-1-naphthalenyloxy]diphenylsilane		C₂₆H₂₈OSi	详情	详情
(III)	34039	(1R)-4-bromo-1,2-dihydro-1-naphthalenyl tert-butyl(diphenyl)silyl ether; [[(1R)-4-bromo-1,2-dihydro-1-naphthalenyl]oxy](tert-butyl)diphenylsilane		C₂₆H₂₇BrOSi	详情	详情
(IV)	34042	(3,4-dichlorophenyl)(trimethyl)stannane; 3,4-dichlorophenyltrimethyltin		C₉H₁₂Cl₂Sn	详情	详情
(V)	34041	tert-butyl(diphenyl)silyl (1R)-4-(3,4-dichlorophenyl)-1,2-dihydro-1-naphthalenyl ether; tert-butyl[[(1R)-4-(3,4-dichlorophenyl)-1,2-dihydro-1-naphthalenyl]oxy]diphenylsilane		C₃₂H₃₀Cl₂OSi	详情	详情
(VI)	34045	(1R)-4-(3,4-dichlorophenyl)-1,2-dihydro-1-naphthalenol; 4-(3,4-dichlorophenyl)-1,2-dihydronaphthalen -1(R)-o		C₁₆H₁₂Cl₂O	详情	详情
(VII)	34046	(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenol		C₁₆H₁₄Cl₂O	详情	详情
(VIII)	34047	(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl azide; (1S,4S)-1-azido-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalene		C₁₆H₁₃Cl₂N₃	详情	详情
(IX)	34048	(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenylamine		C₁₆H₁₅Cl₂N	详情	详情
(X)	34049	methyl (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenylcarbamate		C₁₈H₁₇Cl₂NO₂	详情	详情
(XI)	34044	3,4-Dichlorophenol	95-77-2	C₆H₄Cl₂O	详情	详情
(XII)	34043	3,4-dichlorophenyl trifluoromethanesulfonate		C₇H₃Cl₂F₃O₃S	详情	详情
(XIII)	34040	3,4-Dichlorophenylboronic acid	151169-75-4	C₆H₅BCl₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of 3,4-dichlorophenol (I) with 1,3-dibromopropane (II) by means of NaOH and tetrabutylammonium hydrogensulfate gives the corresponding phenol ether (III), which is condensed with N-acetylhydroxylamine (IV) by means of NaOH or KOH in an alcoholic solvent to yield the O-substituted acetylhydroxylamine (V). The hydrolysis of (V) with HCl in methanol affords the free O-substituted hydroxylamine (VI), which is finally condensed with N1-cyano-N3-isopropylguanidine (VII) in hot ethyl acetate. The intermediate N1-cyano-N3-isopropylguanidine (VII) has been obtained by reaction of sodium dicyanamide (VIII) with isopropylamine (IX) and HCl in a hot alcoholic solvent.

参考文献中间体

合成目标

【1】 Jensen, N.P.; et al.; Phenoxypropoxybiguanides, prodrugs of DHFR-inhibiting diaminotriazine antimalarials. J Med Chem 2001, 44, 23, 3925.

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)	34044	3,4-Dichlorophenol	95-77-2	C₆H₄Cl₂O	详情	详情
(II)	12581	1,3-Dibromopropane	109-64-8	C₃H₆Br₂	详情	详情
(III)	52210	3-bromopropyl 3,4-dichlorophenyl ether; 4-(3-bromopropoxy)-1,2-dichlorobenzene		C₉H₉BrCl₂O	详情	详情
(IV)	23102	N-hydroxyacetamide	546-88-3	C₂H₅NO₂	详情	详情
(V)	52211	N-[3-(3,4-dichlorophenoxy)propoxy]acetamide		C₁₁H₁₃Cl₂NO₃	详情	详情
(VI)	52212	4-[3-(aminooxy)propoxy]-1,2-dichlorobenzene; O-[3-(3,4-dichlorophenoxy)propyl]hydroxylamine		C₉H₁₁Cl₂NO₂	详情	详情
(VII)	52213	N-cyano-N'-isopropylguanidine		C₅H₁₀N₄	详情	详情
(VIII)	52214			C₂N₃Na	详情	详情
(IX)	23933	2-Propanamine; Isopropylamine	75-31-0	C₃H₉N	详情	详情

Extended Information