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【结 构 式】 
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【药物名称】Pradefovir Mesilate, MB-06866，MB-6866，Hepavir B，Remofovir mesylate 【化学名称】9-[2-[(2R,4S)-4-(3-Chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-ylmethoxy]ethyl]adenine mesylate 【CA登记号】625095-61-6, 371778-91-5 (racemic free base), 625095-60-5 (free base) 【 分 子 式 】C18H23ClN5O7PS 【 分 子 量 】519.8972 |
【开发单位】Metabasis Therapeutics, Inc. (US); licensed to Valeant Pharmaceuticals International and just recently to Schering-Plough Corp. 【药理作用】Treatment of hepatitis B |
合成路线1
The optically pure diol intermediate (VIII) can be obtained by several procedures. Aldol condensation of 3-chlorobenzaldehyde (XII) with the lithium enolate of ethyl acetate gives the hydroxy ester (XIII), which is reduced to racemic 1-(3-chlorophenyl)-1,3-propanediol (XIV) by means of LiAlH4 in Et2O. Ketalization of diol (XIV) with (-)-menthone (XV) employing trimethylsilyl triflate and hexamethyldisilazane produces the spiro ketal (XVI) as a diastereomeric mixture, from which the target (S)-diol (VIII) is obtained by fractional crystallization, followed by acidic ketal hydrolysis (1-3). In a different strategy utilizing an enantioselective reduction, 3’-chloroacetophenone (XVII) is condensed with diethyl carbonate by means of t-BuOK in THF to yield the keto ester (XVIII), which is selectively reduced to the (S)-hydroxy ester (XIX) by catalytic hydrogenation over a chiral ruthenium catalyst. After saponification of ester (XIX), the chiral hydroxy acid obtained (XX) is reduced to (VIII) with borane in THF. Similarly, the (S)-hydroxy acid (XX) can be produced by condensation of 3-chlorobenzoyl chloride (XXI) with the lithium enolate of trimethylsilyl acetate, followed by acidic desilylation to yield the keto acid (XXII), which is then reduced to (XX) utilizing (–)-B-chlorodiisopinocamphenylborane (DIP-Cl) in cold CH2Cl2 (1-5). In a further method, 3-chlorocinnamic acid (XXIII) is esterified with H2SO4/EtOH, followed by reduction with DIBAL to provide the cinnamyl alcohol (XXIV), which undergoes Sharpless asymmetric epoxidation to (XXV) with t-butyl hydroperoxide in the presence of (+)-diethyl tartrate. Reductive cleavage of the chiral epoxide obtained (XXV) by means of Red-Al then furnishes the target 1(S)-(3-chlorophenyl)-1,3-propanediol (VIII) (1, 2). Scheme 2.
| 【1】 Kopcho, J.J., Matelich, M.C., Reddy, K.R., Ugarkar, B.G. (Metabasis Therapeutics, Inc.). Process for preparation of cyclic prodrugs of PMEA and PMPA. JP 2005525422, US 2003225277, WO 2003095665. |
| 【2】 Erion, M.D., Kopcho, J.J., Matelich, M.C., Reddy, K.R. (Metabasis Therapeutics, Inc.). Novel phosphonic acid based prodrugs of PMEA and its analogues. EP 1532157, US 2003229225, WO 2004037161. |
| 【3】 Reddy, K.R., Matelich, M.C., Ugarkar, B.G. et al. HepDirect prodrugs of adefovir: Design, synthesis and optimization. 227th ACS Natl Meet (March 28-April 1, Anaheim) 2004, Abst MEDI- 27. |
| 【4】 Martin, K. (Metabasis Therapeutics, Inc.). Lewis acid mediated synthesis of cyclic esters. CA 2565966, EP 1753762, US 2005282782, WO 2005123729. |
| 【5】 Erion, M.D., Reddy, K.R., Boyer, S.H. et al. Design, synthesis, and characterization of a series of cytochrome P450 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phospho(on)ate-based drugs to the liver. J Am Chem Soc 2004, 126(16): 5154-63. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 13660 | 3-Chlorobenzaldehyde | 587-04-2 | C7H5ClO | 详情 | 详情 |
| (XIII) | 65236 | C11H13ClO3 | 详情 | 详情 | ||
| (XIV) | 65237 | 1(RS)-(3-chlorophenyl)-1,3-propanediol | C9H11ClO2 | 详情 | 详情 | |
| (XV) | 10208 | L-Menthone; (2S,5R)-2-Isopropyl-5-methylcyclohexanone | 14073-97-3 | C10H18O | 详情 | 详情 |
| (XVI) | 65238 | C19H27ClO2 | 详情 | 详情 | ||
| (XVII) | 15268 | m-chloroacetophenone; 1-(3-chlorophenyl)-1-ethanone | 99-02-5 | C8H7ClO | 详情 | 详情 |
| (XVIII) | 65239 | ethyl 3-(3-chlorophenyl)-3-oxopropanoate | C11H11ClO3 | 详情 | 详情 | |
| (XIX) | 65240 | C11H13ClO3 | 详情 | 详情 | ||
| (XX) | 65241 | C9H9ClO3 | 详情 | 详情 | ||
| (XXI) | 16687 | 3-chlorobenzoyl chloride | 618-46-2 | C7H4Cl2O | 详情 | 详情 |
| (XXII) | 65242 | C9H7ClO3 | 详情 | 详情 | ||
| (XXIII) | 65243 | 3-Chlorocinnamic acid | 14473-90-6 | C9H7ClO2 | 详情 | 详情 |
| (XXIV) | 65244 | C9H9ClO | 详情 | 详情 | ||
| (XXV) | 65245 | C9H9ClO2 | 详情 | 详情 |
合成路线2
Treatment of adenosine (I) with ethylene carbonate (II) in the presence of NaOH in refluxing DMF gives 9-(2-hydroxyethyl)adenosine (III). Diethyl phosphite (IV) is then condensed with formaldehyde, followed by reaction with p-toluenesulfonyl chloride and Et3N to afford diethyl (tosyloxymethyl)phosphonate (V). Subsequent condensation of tosylate (V) with (III) in the presence of t-BuONa gives the phosphonyloxymethoxyethyl adenosine (PMEA) diethyl ester (VI), which is hydrolyzed to the corresponding phosphonic acid adefovir (VII) by means of in situ-generated iodotrimethylsilane. The condensation of phosphonic acid (VII) with 1(S)-(3-chlorophenyl)-1,3-propanediol (VIII) utilizing DCC/pyridine leads to the cyclic phosphonate (IX) as a roughly equimolecular mixture of diastereoisomers, which can be chromatographically separated to furnish the title cis-isomer pradefovir. In an improved procedure, activation of adefovir (VII) with oxalyl chloride and N,N-diethylformamide generates the formamidine-protected phosphonyl dichloridate (X), which upon condensation with diol (VIII) at low temperature gives the cyclic phosphonate (XI) as a mixture in which the desired cis-diastereoisomer predominates. After hydrolysis of the formamidine (XI) with ethanolic AcOH, recrystallization as the corresponding mesylate salt provides the title adefovir prodrug in high diastereomeric excess (1-5). Scheme 1.
| 【1】 Kopcho, J.J., Matelich, M.C., Reddy, K.R., Ugarkar, B.G. (Metabasis Therapeutics, Inc.). Process for preparation of cyclic prodrugs of PMEA and PMPA. JP 2005525422, US 2003225277, WO 2003095665. |
| 【2】 Erion, M.D., Kopcho, J.J., Matelich, M.C., Reddy, K.R. (Metabasis Therapeutics, Inc.). Novel phosphonic acid based prodrugs of PMEA and its analogues. EP 1532157, US 2003229225, WO 2004037161. |
| 【3】 Reddy, K.R., Matelich, M.C., Ugarkar, B.G. et al. HepDirect prodrugs of adefovir: Design, synthesis and optimization. 227th ACS Natl Meet (March 28-April 1, Anaheim) 2004, Abst MEDI- 27. |
| 【4】 Martin, K. (Metabasis Therapeutics, Inc.). Lewis acid mediated synthesis of cyclic esters. CA 2565966, EP 1753762, US 2005282782, WO 2005123729. |
| 【5】 Erion, M.D., Reddy, K.R., Boyer, S.H. et al. Design, synthesis, and characterization of a series of cytochrome P450 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phospho(on)ate-based drugs to the liver. J Am Chem Soc 2004, 126(16): 5154-63. |
| 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) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (II) | 32802 | 1,3-dioxolan-2-one | 96-49-1 | C3H4O3 | 详情 | 详情 |
| (III) | 39672 | 2-(6-amino-9H-purin-9-yl)-1-ethanol | C7H9N5O | 详情 | 详情 | |
| (IV) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (V) | 12702 | (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate | 31618-90-3 | C12H19O6PS | 详情 | 详情 |
| (VI) | 39673 | diethyl [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonate | C12H20N5O4P | 详情 | 详情 | |
| (VII) | 16165 | [2-(6-amino-9H-purin-9-yl)ethoxy]methylphosphonic acid | C8H12N5O4P | 详情 | 详情 | |
| (VIII) | 65232 | 1(S)-(3-chlorophenyl)-1,3-propanediol | C9H11ClO2 | 详情 | 详情 | |
| (IX) | 65233 | C17H19ClN5O4P | 详情 | 详情 | ||
| (X) | 65234 | C13H19Cl2N6O2P | 详情 | 详情 | ||
| (XI) | 65235 | C22H28ClN6O4P | 详情 | 详情 |