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【结 构 式】 
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【分子编号】27980 【品名】Diisopropyl (diisopropoxyphosphoryl)methylphosphonate; Tetraisopropyl methylenediphosphonate 【CA登记号】1660-95-3 |
【 分 子 式 】C13H30O6P2 【 分 子 量 】344.325124 【元素组成】C 45.35% H 8.78% O 27.88% P 17.99% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of di(4-chlorophenyl)disulfide (I) with tetraisopropyl methylenediphosphonate (II) by means of NaH in hot DMF gives tetraisopropyl (4-chlorophenyl)thiomethylenediphosphonate (III), which is finally hydrolyzed with refluxing aqueous 6N HCl.
| 【1】 Shirasaki, M. (Sanofi-Synthelabo); Polarizing elements. DE 3378140; EP 0100718 . |
| 【2】 Serradell, M.N.; Castaner, J.; SR-41319. Drugs Fut 1985, 10, 6, 482. |
| 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) | 29707 | bis(4-chlorophenyl) disulfide; 1-chloro-4-[(4-chlorophenyl)disulfanyl]benzene | 1142-19-4 | C12H8Cl2S2 | 详情 | 详情 |
| (II) | 27980 | Diisopropyl (diisopropoxyphosphoryl)methylphosphonate; Tetraisopropyl methylenediphosphonate | 1660-95-3 | C13H30O6P2 | 详情 | 详情 |
| (III) | 10200 | Diisopropyl [(4-chlorophenyl)sulfanyl](diisopropoxyphosphoryl)methylphosphonate | C19H33ClO6P2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The reaction of dibromomethane (I) with triisopropylphosphite (II) at 145 C gives tetraisopropyl methylenediphosphonate (III), which is treated first with sodium and then with chlorine to give the compound (IV). This compound is finally hydrolyzed with refluxing concentrated HCl, or treated with refluxing tetrachloroethane.
| 【1】 Nicholson, D.A.; Prentice, J.B.; Quimby, O.T.; Tetrasodium carbonyldiphosphonate. Synthesis reactions and spectral properties. J Org Chem 1967, 32, 12, 4111-14. |
| 【2】 Roy, C.H.; Substituted methylene diphosphonic acids and their salts. NL 6514133 . |
| 【3】 Roy, C.H. (The Procter & Gamble Co.); Substituted methylene diphosphonic acids and their salts. BE 0672205; DE 1793768; FR 1457272; GB 1026366; US 3404178; US 3422021 . |
| 【4】 Castaner, J.; Hopkins, S.J.; Blancafort, P.; Serradell, M.N.; Clodronate disodium. Drugs Fut 1982, 7, 9, 615. |
| 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) | 32163 | Dibromomethane | 74-95-3 | CH2Br2 | 详情 | 详情 |
| (II) | 32162 | Triisopropyl phosphite | 116-17-6 | C9H21O3P | 详情 | 详情 |
| (III) | 27980 | Diisopropyl (diisopropoxyphosphoryl)methylphosphonate; Tetraisopropyl methylenediphosphonate | 1660-95-3 | C13H30O6P2 | 详情 | 详情 |
| (IV) | 32164 | diisopropyl dichloro(diisopropoxyphosphoryl)methylphosphonate | C13H28Cl2O6P2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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
| 【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 . |
合成路线4
该中间体在本合成路线中的序号：(I)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
| 【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5
该中间体在本合成路线中的序号：(I)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)
| 【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6
该中间体在本合成路线中的序号：(I)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
| 【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 |
合成路线7
该中间体在本合成路线中的序号：(III)Benzylic bromination of 3-chloro-4-methylbenzonitrile (I) by means of N-bromosuccinimide and azobis(isobutyronitrile) provided bromide (II). Subsequent displacement of the bromine atom of (II) by potassium phthalimide (III) afforded the N-substituted phthalimide (IV), which was then deprotected with ethanolic hydrazine to furnish the primary amine (V).
| 【1】 Antane, M.M.; Herbst, D.R.; McFarlane, G.R.; Gundersen, E.G.; Hirth, B.H.; Quagliato, D.A.; Graceffa, R.F.; Butera, J.A.; Gilbert, A.M. (American Home Products Corp.); Substd. N-arylmethylamino derivs. of cyclobutene-3, 4-diones. US 5763474; US 5780505; WO 9802413 . |
| 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) | 32959 | 3-chloro-4-methylbenzonitrile | C8H6ClN | 详情 | 详情 | |
| (II) | 32960 | 4-(bromomethyl)-3-chlorobenzonitrile | C8H5BrClN | 详情 | 详情 | |
| (III) | 27980 | Diisopropyl (diisopropoxyphosphoryl)methylphosphonate; Tetraisopropyl methylenediphosphonate | 1660-95-3 | C13H30O6P2 | 详情 | 详情 |
| (IV) | 32961 | 3-chloro-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile | C16H9ClN2O2 | 详情 | 详情 | |
| (V) | 32962 | 4-(aminomethyl)-3-chlorobenzonitrile | C8H7ClN2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Tetraisopropyl methylenediphosphonate (I) was alkylated with 3-(acetylthio)propyl iodide (II) in the presence of NaH to give (III). Then, hydrolysis of both thioester and phosphonate esters of (III) with refluxing HCl provided the intermediate thiol (IV).
| 【1】 Gil, L.; et al.; Prostaglandin E2-bisphosphonate conjugates: Potential agents for treatment of osteoporosis. Bioorg Med Chem 1999, 7, 5, 901. |
| 【2】 Gil, L.; Young, R.N.; Ruel, R.; Han, Y. (Merck Frosst Canada Inc.); Prostaglandin conjugates for treating or preventing bone disease. US 6121253; WO 0031084 . |
| 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) | 27981 | S-(3-iodopropyl) ethanethioate | C5H9IOS | 详情 | 详情 | |
| (III) | 27982 | S-[4,4-bis(diisopropoxyphosphoryl)butyl] ethanethioate | C18H38O7P2S | 详情 | 详情 | |
| (IV) | 27983 | 1-phosphono-4-sulfanylbutylphosphonic acid | C4H12O6P2S | 详情 | 详情 |