3-(cyclopropyloxy)-4-(difluoromethoxy)benzaldehyde -Drug Synthesis Database

【结构式】

【分子编号】59749

【品名】3-(cyclopropyloxy)-4-(difluoromethoxy)benzaldehyde

【CA登记号】

【分子式】C₁₁H₁₀F₂O₃

【分子量】228.1954064

【元素组成】C 57.9% H 4.42% F 16.65% O 21.03%

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：(IX)

The preparation of the precursor aldehyde (IX) is illustrated in Scheme 1. Alkylation of 3-hydroxy-4-(difluoromethoxy)benzaldehyde (I) with 1-bromo-2-chloroethane (II) affords the chloroethyl ether (III). After reduction of the aldehyde function of (III) with NaBH4, the resulting alcohol (IV) is protected as the corresponding silyl ether (V) with triisopropylsilyl triflate and 2,6-lutidine. Dehydrohalogenation of the chloroethyl ether moiety of (V) with NaOH under phase-transfer conditions, followed by resilylation with triisopropylsilyl triflate, leads to the vinyl ether (VI). This is converted into the cyclopropyl derivative (VII) following the Simmons-Smith procedure in the presence of chloroiodomethane and diethylzinc. Desilylation of (VII) with tertbutylammonium fluoride yields the benzylic alcohol (VIII), which is again oxidized to aldehyde (IX) employing MnO2 in CH2Cl2.

参考文献中间体

合成目标

【1】 Girard, M.; Frenette, R.; Hamel, P.; Guay, D.; Ducharme, Y.; Blouin, M.; Friesen, R.; Cote, B.; Martins, E.; Laliberte, S. (Merck Frosst Canada Inc.); Tri-aryl-substd.-ethane PDE4 inhibitors. EP 1272488; US 6399636; WO 0170738 .

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)	59742	4-(difluoromethoxy)-3-hydroxybenzaldehyde		C₈H₆F₂O₃	详情	详情
(II)	24271	1-bromo-2-chloroethane	107-04-0	C₂H₄BrCl	详情	详情
(III)	59743	3-(2-chloroethoxy)-4-(difluoromethoxy)benzaldehyde		C₁₀H₉ClF₂O₃	详情	详情
(IV)	59744	[3-(2-chloroethoxy)-4-(difluoromethoxy)phenyl]methanol		C₁₀H₁₁ClF₂O₃	详情	详情
(V)	59745	3-(2-chloroethoxy)-4-(difluoromethoxy)benzyl triisopropylsilyl ether; {[3-(2-chloroethoxy)-4-(difluoromethoxy)benzyl]oxy}(triisopropyl)silane		C₁₉H₃₁ClF₂O₃Si	详情	详情
(VI)	59746	{[4-(difluoromethoxy)-3-(vinyloxy)benzyl]oxy}(triisopropyl)silane; 2-(difluoromethoxy)-5-{[(triisopropylsilyl)oxy]methyl}phenyl vinyl ether		C₁₉H₃₀F₂O₃Si	详情	详情
(VII)	59747	cyclopropyl 2-(difluoromethoxy)-5-{[(triisopropylsilyl)oxy]methyl}phenyl ether; {[3-(cyclopropyloxy)-4-(difluoromethoxy)benzyl]oxy}(triisopropyl)silane		C₂₀H₃₂F₂O₃Si	详情	详情
(VIII)	59748	[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]methanol		C₁₁H₁₂F₂O₃	详情	详情
(IX)	59749	3-(cyclopropyloxy)-4-(difluoromethoxy)benzaldehyde		C₁₁H₁₀F₂O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Lithiation of thiazole (X) with butyllithium, and then addition to hexafluoroacetone (XI) in cold Et2O gives the carbinol adduct (XII), which is subsequently protected with 2-(trimethylsilyl)ethoxymethyl chloride (XIII), yielding the SEM ether (XIV). A further metalation of (XIV) with butyllithium, followed by addition to aldehyde (IX) provides alcohol (XV). Bromination of (XV), with simultaneous SEM group cleavage to afford (XVI), is accomplished by treatment with thionyl bromide and pyridine. Alkylation of the potassium enolate of ethyl 3-pyridylacetate N-oxide (XVII) with bromide (XVI) gives ester (XVIII). Finally, decarboethoxylation of (XVIII) by means of LiOH, followed by resolution of the racemic mixture using chiral HPLC furnishes the title enantiomer.

参考文献中间体

合成目标

【1】 Girard, M.; Frenette, R.; Hamel, P.; Guay, D.; Ducharme, Y.; Blouin, M.; Friesen, R.; Cote, B.; Martins, E.; Laliberte, S. (Merck Frosst Canada Inc.); Tri-aryl-substd.-ethane PDE4 inhibitors. EP 1272488; US 6399636; WO 0170738 .

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)	59749	3-(cyclopropyloxy)-4-(difluoromethoxy)benzaldehyde		C₁₁H₁₀F₂O₃	详情	详情
(X)	23000	1,3-thiazole	288-47-1	C₃H₃NS	详情	详情
(XI)	44260	1,1,1,3,3,3-hexafluoroacetone	684-16-2	C₃F₆O	详情	详情
(XII)	59750	1,1,1,3,3,3-hexafluoro-2-(1,3-thiazol-2-yl)-2-propanol		C₆H₃F₆NOS	详情	详情
(XIII)	27243	[2-(chloromethoxy)ethyl](trimethyl)silane	76513-69-4	C₆H₁₅ClOSi	详情	详情
(XIV)	59751	2-(2,2,2-trifluoro-1-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)-1,3-thiazole; [2,2,2-trifluoro-1-(1,3-thiazol-2-yl)-1-(trifluoromethyl)ethoxy]methyl 2-(trimethylsilyl)ethyl ether		C₁₂H₁₇F₆NO₂SSi	详情	详情
(XV)	59752	[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl][2-(2,2,2-trifluoro-1-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)-1,3-thiazol-5-yl]methanol		C₂₃H₂₇F₈NO₅SSi	详情	详情
(XVI)	59753	2-(5-{bromo[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]methyl}-1,3-thiazol-2-yl)-1,1,1,3,3,3-hexafluoro-2-propanol		C₁₇H₁₂BrF₈NO₃S	详情	详情
(XVII)	59754	3-(2-ethoxy-2-oxoethyl)-1-pyridiniumolate		C₉H₁₁NO₃	详情	详情
(XVIII)	59755	3-(2-[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]-1-(ethoxycarbonyl)-2-{2-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,3-thiazol-5-yl}ethyl)-1-pyridiniumolate		C₂₆H₂₂F₈N₂O₆S	详情	详情

Extended Information