3,4-Dichlorophenylboronic acid -Drug Synthesis Database

【结构式】

【分子编号】34040

【品名】3,4-Dichlorophenylboronic acid

【CA登记号】151169-75-4

【分子式】C₆H₅BCl₂O₂

【分子量】190.8209

【元素组成】C 37.77% H 2.64% B 5.67% Cl 37.16% O 16.77%

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：(XIII)

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：(X)

Acetonedicarboxylic acid (I) was converted to the monomethyl ester (III) via the cyclic anhydride (II). Dialdehyde (V), prepared in situ by acid hydrolysis of 2,5-dimethoxydihydrofuran (IV), was subjected to a double Mannich condensation with keto ester (III) and methylamine to produce a mixture of tropane derivatives. Column chromatography of the obtained crude product provided a mixture of 7-hydroxy- (VI) and 6-hydroxy- (VII) tropanes, which were separated from the minor 6- and 7-methoxy analogues. Treatment of alcohols (VI) and (VII) with dimethoxymethane and p-toluenesulfonic acid generated the corresponding mixture of mixed acetals, from which the desired 7-methoxymethyl isomer (VIII) was isolated by column chromatography. Conversion of (VIII) to the enol triflate (IX) was achieved with N-phenyltrifluoromethanesulfonimide and sodium bis(trimethylsilyl)amide at low temperature. The aryl tropene (XI) was then obtained by Suzuki coupling of triflate (IX) with 3,4-dichlorophenylboronic acid (X), followed by trimethylsilyl bromide-promoted deprotection of the methoxymethyl group. Resolution of the racemic tropenol (XI) was effected by esterification with (1S)-(-)-camphanic chloride followed by separation of the resulting diastereomeric mixture. The desired isomer (XII) was then hydrolyzed with LiOH to provide the enantiopure (1S)-alcohol (XIII). Then, reduction to the saturated tropane derivative by means of samarium iodide at low temperature produced a diastereomeric mixture of 3-aryltropanes from which the title 3alpha-isomer was isolated by flash chromatography.

参考文献中间体

合成目标

【1】 Meltzer, P.C.; et al.; Synthesis of 6- and 7-hydroxy-8-azabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters. J Med Chem 2001, 4, 16, 2619.

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)	15530	1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid	542-05-2	C₅H₆O₅	详情	详情
(II)	49965	2H-pyran-2,4,6(3H,5H)-trione		C₅H₄O₄	详情	详情
(III)	49966	5-methoxy-3,5-dioxopentanoic acid		C₆H₈O₅	详情	详情
(IV)	49967	2,5-dimethoxy-2,5-dihydrofuran	332-77-4	C₆H₁₀O₃	详情	详情
(V)	49968	(Z)-2-butenedial		C₄H₄O₂	详情	详情
(VI)	49969	methyl (1S,2R,5S,7R)-7-hydroxy-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate		C₁₀H₁₅NO₄	详情	详情
(VII)	49970	methyl (1R,2R,5R,6S)-6-hydroxy-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate		C₁₀H₁₅NO₄	详情	详情
(VIII)	49971	methyl (1S,2R,5S,7R)-7-(methoxymethoxy)-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate		C₁₂H₁₉NO₅	详情	详情
(IX)	49972	methyl (1S,5S,7R)-7-(methoxymethoxy)-8-methyl-3-[[(trifluoromethyl)sulfonyl]oxy]-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate		C₁₃H₁₈F₃NO₇S	详情	详情
(X)	34040	3,4-Dichlorophenylboronic acid	151169-75-4	C₆H₅BCl₂O₂	详情	详情
(XI)	49973	(rac)-methyl (1S,5R,7R)-3-(3,4-dichlorophenyl)-7-hydroxy-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate		C₁₆H₁₇Cl₂NO₃	详情	详情
(XII)	49974	methyl (1S,5R,7R)-3-(3,4-dichlorophenyl)-8-methyl-7-([[(4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-1-yl]carbonyl]oxy)-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate		C₂₆H₂₉Cl₂NO₆	详情	详情
(XIII)	49975	methyl (1S,5R,7R)-3-(3,4-dichlorophenyl)-7-hydroxy-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate		C₁₆H₁₇Cl₂NO₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

Treatment of methyl 3-hydroxy-8-oxabicyclo[3.2.1]oct-2-ene-2-carboxylate (I) with N-phenyl trifluoromethanesulfonimide leads to the vinyl triflate (II). Suzuki coupling of triflate (II) with 3,4-dichlorophenylboronic acid (III) furnishes the oxabicyclooctene adduct (IV), which is further reduced to the oxabicyclooctane (V) with SmI2. Ester reduction in (V) with LiAlH4 provides alcohol (VI). This is finally esterified with 4-pentenoyl chloride (VII) to furnish the title compound.

参考文献中间体

合成目标

【1】 Meltzer, P.C.; Liu, S.; Blanchette, H.; Blundell, P.; Madras, B.; Design and synthesis of an irreversible dopamine-sparing cocaine antagonist. Bioorg Med Chem 2002, 10, 11, 3583.

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)	61643	methyl (1R,5S)-3-hydroxy-8-oxabicyclo[3.2.1]oct-2-ene-2-carboxylate		C₉H₁₂O₄	详情	详情
(II)	61644	methyl (1R,5S)-3-{[(trifluoromethyl)sulfonyl]oxy}-8-oxabicyclo[3.2.1]oct-2-ene-2-carboxylate		C₁₀H₁₁F₃O₆S	详情	详情
(III)	34040	3,4-Dichlorophenylboronic acid	151169-75-4	C₆H₅BCl₂O₂	详情	详情
(IV)	61645	methyl (1R,5S)-3-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]oct-2-ene-2-carboxylate		C₁₅H₁₄Cl₂O₃	详情	详情
(V)	61646	methyl (1R,2S,3R,5S)-3-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]octane-2-carboxylate		C₁₅H₁₆Cl₂O₃	详情	详情
(VI)	61647	[(1R,2R,3R,5S)-3-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]oct-2-yl]methanol		C₁₄H₁₆Cl₂O₂	详情	详情
(VII)	61648	4-PENTENOYL CHLORIDE		C₅H₇ClO	详情	详情

Extended Information