O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane -Drug Synthesis Database

【结构式】

【分子编号】26091

【品名】O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane

【CA登记号】22737-36-6

【分子式】C₃H₁₁NOSi

【分子量】105.21198

【元素组成】C 34.25% H 10.54% N 13.31% O 15.21% Si 26.69%

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：(X)

2. The reaction of the diacid monoester (IV) with oxalyl chloride in benzene gives the corresponding acyl chloride (V), which is treated with aniline (II) and pyridine in THF, yielding the monoester monoamide (VI). The hydrolysis of the ester group of (VI) with OH in refluxing methanol affords the monoamide carboxylic acid (VII), which is condensed with O-benzylhydroxylamine (VIII) by means of DCC in pyridine to provide the protected hydroxamic acid (IX). Finally, this compound is debenzylated with H2 over Pd/C in methanol to furnish the target hydroxamic acid with yields of 35-65%. 3. A mixture of diacid dichloride (I), aniline (II) and O-benzylhydroxylamine (VIII) in pyridine gives, after chromatographic purification, the protected hydroxamic acid (IX), which is debenzylated as before to provide the target hydroxamic acid with yields of 20-35%. 4. The reaction of acid dichloride (I) with aniline (II) and O-(trimethylsilyl)hydroxylamine (X) by means of TEA in chloroform gives the trimethylsilyl protected compound (XI), which is desilylated with NH4Cl in hot methanol to afford the target hydroxamic acid with yields of 20-33%.

参考文献中间体

合成目标

【1】 Breslow, R.; Rifkind, R.A.; Jursic, B. (Columbia University; Sloan-Kettering Institute); Novel potent inducers of terminal differentiation and methods of use thereof. WO 9307148 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	12294	Aniline; Phenylamine	62-53-3	C₆H₇N	详情	详情
(IV)	53943	Ethyl hydrogen suberate; Monoethyl suberate; Suberic acid monoethyl ester	14113-01-0	C₁₀H₁₈O₄	详情	详情
(V)	53944	ethyl 8-chloro-8-oxooctanoate		C₁₀H₁₇ClO₃	详情	详情
(VI)	53945	ethyl 8-anilino-8-oxooctanoate		C₁₆H₂₃NO₃	详情	详情
(VII)	53946	8-anilino-8-oxooctanoic acid		C₁₄H₁₉NO₃	详情	详情
(VIII)	14640	O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene	622-33-3	C₇H₉NO	详情	详情
(IX)	53947	N~1~-(benzyloxy)-N~8~-phenyloctanediamide		C₂₁H₂₆N₂O₃	详情	详情
(X)	26091	O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane	22737-36-6	C₃H₁₁NOSi	详情	详情
(XI)	53948	N~1~-phenyl-N~8~-[(trimethylsilyl)oxy]octanediamide		C₁₇H₂₈N₂O₃Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：

Horner-Emmons condensation of 5-phenylpentanal (I) with phosphonate (II) in the presence of NaH yielded tert-butyl 7-phenyl-2-heptenoate (III). Subsequent Michael addition of 4-methoxythiophenol (IV) to (III) using a catalytic amount of BuLi provided thioether (V). After acid deprotection of the tert-butyl ester of (V) with TFA, the resulting carboxylic acid (VI) was converted to acid chloride (VII) and then condensed with O-(trimethylsilyl)hydroxylamine to produce hydroxamic acid (VIII). Finally, sulfide oxidation of (VIII) with Oxone furnished the target beta-sulfonylhydroxamic acid. Alternatively tet-butyl ester (III) can be hydrolyzed first to the free acid (IX) with TFA, and then condensed with thiophenol (IV) by means of piperidine to afford the previously described carboxylic acid (VI).

参考文献中间体

合成目标

【1】 Burns, C.J.; Groneberg, R.D.; Morrissette, M.M.; et al.; Dual inhibition of phosphodiesterase 4 and matrix metalloproteinases by an (arylsulfonyl)hydroxamic acid template. J Med Chem 1999, 42, 4, 541.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	26091	O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane	22737-36-6	C₃H₁₁NOSi	详情	详情
(I)	25636	5-phenylpentanal		C₁₁H₁₄O	详情	详情
(II)	25637	tert-butyl 2-(diethoxyphosphoryl)acetate	6273-47-8	C₁₀H₂₁O₅P	详情	详情
(III)	25638	tert-butyl (E)-7-phenyl-2-heptenoate		C₁₇H₂₄O₂	详情	详情
(IV)	25639	4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol	34320-82-6	C₇H₈OS	详情	详情
(V)	25640	tert-butyl 3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanoate		C₂₄H₃₂O₃S	详情	详情
(VI)	25641	3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanoic acid		C₂₀H₂₄O₃S	详情	详情
(VII)	25642	3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanoyl chloride		C₂₀H₂₃ClO₂S	详情	详情
(VIII)	25643	N-hydroxy-3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanamide		C₂₀H₂₅NO₃S	详情	详情
(IX)	25644	(E)-7-phenyl-2-heptenoic acid		C₁₃H₁₆O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

The reaction of 5-phenylpentanal (I) with triethyl 2-phosphonopropionate (II) by means of NaOEt in THF gives ethyl 2-methyl-7-phenyl-2(E)-heptenoate (III), which is hydrolyzed with NaOH in methanol/water to the corresponding free acid (IV). The reaction of (IV) with 4-methoxythiophenol (V) in hot piperidine affords 3-(4-methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (VI), which by reaction first with oxalyl chloride, then with O-trimethylsilylhydroxylamine (VII) in dichloromethane, and finally with HCl is converted into the hydroxamic acid (VIII). Finally, this compound is oxidized with oxone in methanol/water to provide the target compound as mixture of diastereomeric racemates that is separated by reversed phase HPLC.

参考文献中间体

合成目标

【1】 Groneberg, R.D.; Neuenschwander, K.W.; Djuric, S.W.; McGeehan, G.M.; Burns, C.J.; Condon, S.M.; Morrissette, M.M.; Salvino, J.M.; Scotese, A.C.; Ullrich, J.W. (Aventis Pharma SA); Substd. (aryl, heteroaryl, arylmethyl or heteroarylmethyl) hydroxamic acid cpds.. EP 0871439; JP 2000503012; WO 9724117 .

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)	25636	5-phenylpentanal		C₁₁H₁₄O	详情	详情
(II)	18816	ethyl 2-(diethoxyphosphoryl)propanoate	3699-66-9	C₉H₁₉O₅P	详情	详情
(III)	26081	ethyl (E)-2-methyl-7-phenyl-2-heptenoate		C₁₆H₂₂O₂	详情	详情
(IV)	26082	(E)-2-methyl-7-phenyl-2-heptenoic acid		C₁₄H₁₈O₂	详情	详情
(V)	25639	4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol	34320-82-6	C₇H₈OS	详情	详情
(VI)	26083	3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanoic acid		C₂₁H₂₆O₃S	详情	详情
(VII)	26091	O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane	22737-36-6	C₃H₁₁NOSi	详情	详情
(VIII)	26084	N-hydroxy-3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanamide		C₂₁H₂₇NO₃S	详情	详情

Extended Information