(2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl 4-methylbenzenesulfonate -Drug Synthesis Database

【结构式】

【分子编号】40857

【品名】(2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl 4-methylbenzenesulfonate

【CA登记号】

【分子式】C₁₈H₁₉FO₅S

【分子量】366.4102632

【元素组成】C 59% H 5.23% F 5.19% O 21.83% S 8.75%

与该中间体有关的原料药合成路线共 6 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1

该中间体在本合成路线中的序号：(XIII)

The chiral amine intermediate (XV) has been obtained as follows: The alkylation of 4-fluorophenol (I) with allyl bromide (II) and K2CO3 gives the allyl ether (III), which by thermal rearrangement at 210 C yields 2-allyl-4-fluorophenol (IV). The silylation of (IV) with TBDMS-Cl and imidazole affords the silyl ether (V), which is submitted to hydroboration with BH3 and H2O2 to provide the propanol (VI). The oxidation of (VI) with Dess Martin periodinane (DMP) gives the aldehyde (VII), which is condensed with the phosphorane (VIII) to yield the pentenoic ester (IX). The reduction of (IX) with DIBAL affords the unsaturated alcohol, which is desilylated with TBAF in THF furnishing the diol (XI). The treatment of (XI) under the Sharpless asymmetric epoxidation conditions ((-)-DET and titanium tetraisopropoxide) gives, after cyclization with NaOH, 1(R)-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2(S)-yl)-1,2-ethanediol (XII), which is selectively tosylated with TsCl and pyridine yielding the monotosylate (XIII). The reaction of (XIII) with sodium azide in DMF affords the azide (XIV), which is reduced to the corresponding amine (XV) with H2 over Pd/C in ethanol.

参考文献中间体

合成目标

【1】 Chandrasekhar, S.; Reddy, M.V.; Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol. Tetrahedron 2000, 56, 34, 6339.

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)	19639	4-fluorophenol	371-41-5	C₆H₅FO	详情	详情
(II)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(III)	40848	1-(allyloxy)-4-fluorobenzene; allyl 4-fluorophenyl ether		C₉H₉FO	详情	详情
(IV)	40849	2-allyl-4-fluorophenol		C₉H₉FO	详情	详情
(V)	40850	(2-allyl-4-fluorophenoxy)(tert-butyl)dimethylsilane; 2-allyl-4-fluorophenyl tert-butyl(dimethyl)silyl ether		C₁₅H₂₃FOSi	详情	详情
(VI)	40851	3-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-1-propanol		C₁₅H₂₅FO₂Si	详情	详情
(VII)	40852	3-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)propanal		C₁₅H₂₃FO₂Si	详情	详情
(VIII)	14182	ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane	1099-45-2	C₂₂H₂₁O₂P	详情	详情
(IX)	40853	ethyl (E)-5-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-2-pentenoate		C₁₉H₂₉FO₃Si	详情	详情
(X)	40854	(E)-5-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-2-penten-1-ol		C₁₇H₂₇FO₂Si	详情	详情
(XI)	40855	4-fluoro-2-[(E)-5-hydroxy-3-pentenyl]phenol		C₁₁H₁₃FO₂	详情	详情
(XII)	40856	(1R)-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1,2-ethanediol		C₁₁H₁₃FO₃	详情	详情
(XIII)	40857	(2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl 4-methylbenzenesulfonate		C₁₈H₁₉FO₅S	详情	详情
(XIV)	40858	(1R)-2-azido-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1-ethanol		C₁₁H₁₂FN₃O₂	详情	详情
(XV)	40859	(1R)-2-amino-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1-ethanol		C₁₁H₁₄FNO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

参考文献中间体

合成目标

【1】余婧，张稳稳，李映红，等.2008.奈必洛尔的不对称合成.有机化学，28（3）：511～514

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)	19639	4-fluorophenol	371-41-5	C₆H₅FO	详情	详情
(II)	40848	1-(allyloxy)-4-fluorobenzene; allyl 4-fluorophenyl ether		C₉H₉FO	详情	详情
(III)	40849	2-allyl-4-fluorophenol		C₉H₉FO	详情	详情
(IV)	40850	(2-allyl-4-fluorophenoxy)(tert-butyl)dimethylsilane; 2-allyl-4-fluorophenyl tert-butyl(dimethyl)silyl ether		C₁₅H₂₃FOSi	详情	详情
(V)	40851	3-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-1-propanol		C₁₅H₂₅FO₂Si	详情	详情
(VI)	40852	3-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)propanal		C₁₅H₂₃FO₂Si	详情	详情
(VII)	40853	ethyl (E)-5-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-2-pentenoate		C₁₉H₂₉FO₃Si	详情	详情
(VIII)	40854	(E)-5-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-2-penten-1-ol		C₁₇H₂₇FO₂Si	详情	详情
(IX)	40855	4-fluoro-2-[(E)-5-hydroxy-3-pentenyl]phenol		C₁₁H₁₃FO₂	详情	详情
(X)	40856	(1R)-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1,2-ethanediol		C₁₁H₁₃FO₃	详情	详情
(XI)	40857	(2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl 4-methylbenzenesulfonate		C₁₈H₁₉FO₅S	详情	详情
(XII)	40858	(1R)-2-azido-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1-ethanol		C₁₁H₁₂FN₃O₂	详情	详情
(XIII)	40859	(1R)-2-amino-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1-ethanol		C₁₁H₁₄FNO₂	详情	详情
(XIV)	67297	(1S)-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1,2-ethanediol		C₁₁H₁₃FO₃	详情	详情
(XV)	67298	(S)-2-((S)-6-fluorochroman-2-yl)-2-hydroxyethyl benzoate		C₁₈H₁₇FO₄	详情	详情
(XVI)	67299	(S)-2-((S)-6-fluorochroman-2-yl)-2-(tosyloxy)ethyl benzoate		C₂₅H₂₃FO₆S	详情	详情
(XVII)	67300	(R)-6-fluoro-2-((R)-oxiran-2-yl)chroman		C₁₁H₁₁FO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

参考文献中间体

合成目标

【1】 Volpicelli R, Maragni P, Cotarca L, et al.2008.Process for preparation nebivolol. WO 2008064827.

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)	36759	(4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde	15186-48-8	C₆H₁₀O₃	详情	详情
(II)	67309	1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol		C₈H₁₄O₃	详情	详情
(III)	67310	(4S)-4-(1-(2-bromo-4-fluorophenoxy)allyl)-2,2-dimethyl-1,3-dioxolane		C₁₄H₁₆BrFO₃	详情	详情
(IV)	67311	9-(3-(2-bromo-4-fluorophenoxy)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl)-9-borabicyclo[3.3.1]nonane		C₂₂H₃₁BBrFO₃	详情	详情
(V)	67312	2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-6-fluorochroman		C₁₄H₁₇FO₃	详情	详情
(VI)	67313	(S)-1-((R)-6-fluorochroman-2-yl)ethane-1,2-diol		C₁₁H₁₃FO₃	详情	详情
(VII)	67314	(S)-1-((S)-6-fluorochroman-2-yl)ethane-1,2-diol		C₁₁H₁₃FO₃	详情	详情
(VIII)	67315	(S)-2-((R)-6-fluorochroman-2-yl)-2-hydroxyethyl 4-methylbenzenesulfonate		C₁₈H₁₉FO₅S	详情	详情
(IX)	67316			C₁₁H₁₁FO₂	详情	详情
(X)	67317	2-(benzylamino)-1-(6-fluorochroman-2-yl)ethanol		C₁₈H₂₀FNO₂	详情	详情
(XI)	40857	(2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl 4-methylbenzenesulfonate		C₁₈H₁₉FO₅S	详情	详情
(XII)	67300	(R)-6-fluoro-2-((R)-oxiran-2-yl)chroman		C₁₁H₁₁FO₂	详情	详情
(XIII)	67318	(S)-1-((R)-6-fluorochroman-2-yl)-2-(((S)-2-((S)-6-fluorochroman-2-yl)-2-hydroxyethyl)(phenyl)amino)ethanol		C₂₈H₂₉F₂NO₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

参考文献中间体

合成目标

【1】王乃兴，于安广，王桂霞，等。2007.（R,R,R,S）2,2'-[亚氨基二（亚甲基）]双-（6-氟-3,4-二氢-2H-1-苯骈吡喃-2-甲醇）奈比洛尔盐酸盐的合成方法。发明专利申请公开说明书，1978442.

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)	67319	(2R,3S,4R,5S)-hexane-1,2,3,4,5,6-hexaol	50-70-4	C₆H₁₄O₆	详情	详情
(II)	45944	(1S,2S)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,2-ethanediol	1707-77-3	C₁₂H₂₂O₆	详情	详情
(III)	36759	(4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde	15186-48-8	C₆H₁₀O₃	详情	详情
(IV)	19639	4-fluorophenol	371-41-5	C₆H₅FO	详情	详情
(V)	60391	1-(5-fluoro-2-hydroxyphenyl)-1-ethanone	394-32-1	C₈H₇FO₂	详情	详情
(VI)	67320	(S)-2-(R-2,2-dimethyl-1,3-dioxolan-4-yl)-6-fluorochroman-4-one		C₁₄H₁₅FO₄	详情	详情
(VII)	67314	(S)-1-((S)-6-fluorochroman-2-yl)ethane-1,2-diol		C₁₁H₁₃FO₃	详情	详情
(VIII)	40857	(2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl 4-methylbenzenesulfonate		C₁₈H₁₉FO₅S	详情	详情
(IX)	67305	(S)-2-amino-1-((S)-6-fluorochroman-2-yl)ethanol		C₁₁H₁₄FNO₂	详情	详情
(XI)	67321	(R)-2-(R-2,2-dimethyl-1,3-dioxolan-4-yl)-6-fluorochroman-4-one		C₁₄H₁₅FO₄	详情	详情
(XII)	67313	(S)-1-((R)-6-fluorochroman-2-yl)ethane-1,2-diol		C₁₁H₁₃FO₃	详情	详情
(XIII)	67315	(S)-2-((R)-6-fluorochroman-2-yl)-2-hydroxyethyl 4-methylbenzenesulfonate		C₁₈H₁₉FO₅S	详情	详情

合成路线5

该中间体在本合成路线中的序号：(XI)

参考文献中间体

合成目标

【1】陈鹏，吕春雷。2005.DL-奈比洛尔及盐酸盐的制备方法。发明专利申请公开说明书，1683355.
【2】 Chandrasekhar S,Reddy MV.2000.Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol. Tetrahedron, 56: 6339～6344.
【3】 Charles W,Johannes MS, Visser GS, et al. 1998. Zr-catalyzed kinetic resolution of allylic ethers and mo-catalyzed chromene formation in synthesis. Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol. J Am Chem Soc,120: 8340～8347.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX）	40855	4-fluoro-2-[(E)-5-hydroxy-3-pentenyl]phenol		C₁₁H₁₃FO₂	详情	详情
(I)	19639	4-fluorophenol	371-41-5	C₆H₅FO	详情	详情
(II)	40848	1-(allyloxy)-4-fluorobenzene; allyl 4-fluorophenyl ether		C₉H₉FO	详情	详情
(III)	40849	2-allyl-4-fluorophenol		C₉H₉FO	详情	详情
(IV)	40850	(2-allyl-4-fluorophenoxy)(tert-butyl)dimethylsilane; 2-allyl-4-fluorophenyl tert-butyl(dimethyl)silyl ether		C₁₅H₂₃FOSi	详情	详情
(V)	40851	3-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-1-propanol		C₁₅H₂₅FO₂Si	详情	详情
(VI)	40852	3-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)propanal		C₁₅H₂₃FO₂Si	详情	详情
(VII)	40853	ethyl (E)-5-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-2-pentenoate		C₁₉H₂₉FO₃Si	详情	详情
(VIII)	40854	(E)-5-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-2-penten-1-ol		C₁₇H₂₇FO₂Si	详情	详情
(X)	40856	(1R)-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1,2-ethanediol		C₁₁H₁₃FO₃	详情	详情
(XI)	40857	(2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl 4-methylbenzenesulfonate		C₁₈H₁₉FO₅S	详情	详情
(XII)	40858	(1R)-2-azido-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1-ethanol		C₁₁H₁₂FN₃O₂	详情	详情
(XIII)	40859	(1R)-2-amino-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1-ethanol		C₁₁H₁₄FNO₂	详情	详情
(XIV)	67322	(1R,7S)-8-oxabicyclo[5.1.0]octane		C₇H₁₂O	详情	详情
(XV)	67323	tert-butyl(((1S,2R)-2-(4-fluoro-2-((Z)-prop-1-en-1-yl)phenoxy)cyclohept-3-en-1-yl)oxy)dimethylsilane		C₂₂H₃₃FO₂Si	详情	详情
(XVI)	67324	tert-butyl(((S)-1-((R)-6-fluoro-2H-chromen-2-yl)hex-5-en-1-yl)oxy)dimethylsilane		C₂₁H₃₁FO₂Si	详情	详情
(XVII)	67325	tert-butyl(((S)-1-((R)-6-fluoro-2H-chromen-2-yl)allyl)oxy)dimethylsilane		C₁₈H₂₅FO₂Si	详情	详情
(XVIII)	67326	(R)-2-((tert-butyldimethylsilyl)oxy)-2-((S)-6-fluorochroman-2-yl)acetaldehyde		C₁₇H₂₅FO₃Si	详情	详情
(XIX)	67328	(R)-2-(((S)-2-((tert-butyldimethylsilyl)oxy)-2-((S)-6-fluorochroman-2-yl)ethyl)amino)-1-((R)-6-fluorochroman-2-yl)ethanol		C₂₈H₃₉F₂NO₄Si	详情	详情
(XX)	67327	(R)-2-(((S)-2-((tert-butyldimethylsilyl)oxy)-2-((S)-6-fluorochroman-2-yl)ethyl)amino)-1-((R)-6-fluorochroman-2-yl)ethanol hydrochloride		C₂₈H₃₉F₂NO₄Si.HCl	详情	详情

合成路线6

该中间体在本合成路线中的序号：(VIII)

参考文献中间体

合成目标

【1】 Trinka P, Reiter J, Beracz G, et al. 2004. New process for the preparation of racemic ([2S [2R * [R[R]]]]) and ([2R [2S [S[S]]]]) -(+-)-α,α'-[imino-bis (methylene)] bis [6-fluoro-chroman-2-methanol] and its pure [2S [2R [R[R]]]]) -, and [2R [2S [S[S*]]]] enantionmers. WO 2004041805.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
（XV）	67337	(S)-2-((S)-1,2-dihydroxyethyl)-6-fluorochroman-4-one		C₁₁H₁₁FO₄	详情	详情
（X）	67339	(R)-1-((S)-6-fluorochroman-2-yl)-2-(phenylamino)ethanol		C₁₇H₁₈FNO₂	详情	详情
(I)	19639	4-fluorophenol	371-41-5	C₆H₅FO	详情	详情
(II)	67331	2-chloro-1-(5-fluoro-2-hydroxyphenyl)ethanone		C₈H₆ClFO₂	详情	详情
(III)	67332	(2-(5-fluoro-2-hydroxyphenyl)-2-oxoethyl)triphenylphosphonium chloride		C₂₆H₂₁ClFO₂P	详情	详情
(IV)	67333	1-(5-fluoro-2-hydroxyphenyl)-2-(triphenylphosphoranylidene)ethanone		C₂₆H₂₀FO₂P	详情	详情
(V)	67334	(R,E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-1-(5-fluoro-2-hydroxyphenyl)prop-2-en-1-one		C₁₄H₁₅FO₄	详情	详情
(VI)	67335	2-(2,2-dimethyl-1,3-dioxolan-4-yl)-6-fluorochroman-4-one		C₁₄H₁₅FO₄	详情	详情
(VII)	67336	(S)-2-((R)-1,2-dihydroxyethyl)-6-fluorochroman-4-one		C₁₁H₁₁FO₄	详情	详情
(VIII)	40857	(2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl 4-methylbenzenesulfonate		C₁₈H₁₉FO₅S	详情	详情
(IX)	67338	(S)-6-fluoro-2-((R)-oxiran-2-yl)chroman		C₁₁H₁₁FO₂	详情	详情
(XI)	40862	(2R)-2-[(2R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl 4-methylbenzenesulfonate		C₁₈H₁₉FO₅S	详情	详情
(XII)	40863	(2R)-6-fluoro-2-[(2R)oxiranyl]-3,4-dihydro-2H-chromene		C₁₁H₁₁FO₂	详情	详情
(XIII)	67318	(S)-1-((R)-6-fluorochroman-2-yl)-2-(((S)-2-((S)-6-fluorochroman-2-yl)-2-hydroxyethyl)(phenyl)amino)ethanol		C₂₈H₂₉F₂NO₄	详情	详情

Extended Information