Apomine, SR-45023A, SR-9223i, SK&F-99085, -Drug Synthesis Database

【结构式】

【药物名称】Apomine, SR-45023A, SR-9223i, SK&F-99085

【化学名称】2-(3,5-Di-tert-butyl-4-hydroxyphenyl)ethylidene-1,1-diphosphonic acid tetraisopropyl ester

【CA登记号】126411-13-0

【分子式】C₂₈H₅₂O₇P₂

【分子量】562.67004

【开发单位】Ilex Oncology (Originator)

【药理作用】Bone Diseases, Treatment of, Breast Cancer Therapy, Leukemia Therapy, Lung Cancer Therapy, Melanoma Therapy, METABOLIC DRUGS, Oncolytic Drugs, Ovarian Cancer Therapy, Prostate Cancer Therapy, Treatment of Osteoporosis, Apoptosis Inducers, Bisphosphonates, Farnesoid X Receptor (FXR) Agonists

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

The title compound was prepared by several related methods. The sodium salt generated from tetraisopropyl methylenediphosphonate (I) and NaH was alkylated with 3,5-di-t-butyl-4-hydroxybenzyl chloride (II) in refluxing THF to afford the target arylethyl diphosphonate

参考文献中间体

【1】 Nguyen, L.; Niesor, E.; Phan, H.; Maechler, P.; Bentzen, C. (Ilex Oncology Research-Europe SA); Phenol substd. gem-diphosphonate derivs., process for their preparation and pharmaceutical compsns. containing them. CH 675422; EP 0339237; JP 1990022285; US 5043330; US 5128331 .
【2】 Grinter, T.J.; Harris, M.A.; Hayler, J.D.; Negus, A. (Ilex Oncology Research-Europe SA); A process for the preparation of diphosphonate derivs.. WO 9731004 .

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)	27980	Diisopropyl (diisopropoxyphosphoryl)methylphosphonate; Tetraisopropyl methylenediphosphonate	1660-95-3	C₁₃H₃₀O₆P₂	详情	详情
(II)	62335	2,6-di(tert-butyl)-4-(chloromethyl)phenol		C₁₅H₂₃ClO	详情	详情

合成路线2

Alternatively, tetraisopropyl methylenediphosphonate (I) was alkylated with the benzyl alcohol (III) or with the dimethyl benzylamine (IV) in the presence of strong bases such as NaH or NaO-t-Bu

参考文献中间体

【1】 Grinter, T.J.; Harris, M.A.; Hayler, J.D.; Negus, A. (Ilex Oncology Research-Europe SA); A process for the preparation of diphosphonate derivs.. WO 9731004 .

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)	27980	Diisopropyl (diisopropoxyphosphoryl)methylphosphonate; Tetraisopropyl methylenediphosphonate	1660-95-3	C₁₃H₃₀O₆P₂	详情	详情
(III)	37706	2,6-di(tert-butyl)-4-(hydroxymethyl)phenol	88-26-6	C₁₅H₂₄O₂	详情	详情
(IV)	62336	2,6-di(tert-butyl)-4-[(dimethylamino)methyl]phenol		C₁₇H₂₉NO	详情	详情

合成路线3

In a related procedure, the dimethyl benzylamine (IV) was quaternized with iodomethane, and the resultant ammonium salt (V) was then condensed with the sodium salt of diphosphonate (I) (1). Other reported alkylating reagents included the bis-benzyl methyl amine (VII), prepared by Mannich reaction of methylamine with 2,6-di-t-butylphenol (VI) and formaldehyde, and the tris-benzyl amine (VIII), prepared by alkylation of ammonia with the benzyl chloride (II)

参考文献中间体

【1】 Grinter, T.J.; Harris, M.A.; Hayler, J.D.; Negus, A. (Ilex Oncology Research-Europe SA); A process for the preparation of diphosphonate derivs.. WO 9731004 .

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)	27980	Diisopropyl (diisopropoxyphosphoryl)methylphosphonate; Tetraisopropyl methylenediphosphonate	1660-95-3	C₁₃H₃₀O₆P₂	详情	详情
(II)	62335	2,6-di(tert-butyl)-4-(chloromethyl)phenol		C₁₅H₂₃ClO	详情	详情
(IV)	62336	2,6-di(tert-butyl)-4-[(dimethylamino)methyl]phenol		C₁₇H₂₉NO	详情	详情
(V)	62338	[3,5-di(tert-butyl)-4-hydroxyphenyl]-N,N,N-trimethylmethanaminium iodide		C₁₈H₃₂INO	详情	详情
(VI)	25925	2,6-di(tert-butyl)phenol	128-39-2	C₁₄H₂₂O	详情	详情
(VII)	62339	2,6-di(tert-butyl)-4-{[[3,5-di(tert-butyl)-4-hydroxybenzyl](methyl)amino]methyl}phenol		C₃₁H₄₉NO₂	详情	详情
(VIII)	62340	4-({bis[3,5-di(tert-butyl)-4-hydroxybenzyl]amino}methyl)-2,6-di(tert-butyl)phenol		C₄₅H₆₉NO₃	详情	详情

合成路线4

In a further method, condensation of benzyl alcohol (III) with methanol in the presence of a catalytic amount of HCl afforded the corresponding methyl ether (IX), which was then reacted with diphosphonate (I) in the presence of NaH to furnish the target arylethyl diphosphonate (1). Optionally, diphosphonate (I) was condensed with the benzyl acetate ester (X), prepared from benzyl chloride (II) and potassium acetate in acetone

参考文献中间体

【1】 Grinter, T.J.; Harris, M.A.; Hayler, J.D.; Negus, A. (Ilex Oncology Research-Europe SA); A process for the preparation of diphosphonate derivs.. WO 9731004 .

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)	27980	Diisopropyl (diisopropoxyphosphoryl)methylphosphonate; Tetraisopropyl methylenediphosphonate	1660-95-3	C₁₃H₃₀O₆P₂	详情	详情
(II)	62335	2,6-di(tert-butyl)-4-(chloromethyl)phenol		C₁₅H₂₃ClO	详情	详情
(III)	37706	2,6-di(tert-butyl)-4-(hydroxymethyl)phenol	88-26-6	C₁₅H₂₄O₂	详情	详情
(IX)	62341	2,6-di(tert-butyl)-4-(methoxymethyl)phenol		C₁₆H₂₆O₂	详情	详情
(X)	62342	3,5-di(tert-butyl)-4-hydroxybenzyl acetate		C₁₇H₂₆O₃	详情	详情

Extended Information