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【结 构 式】

【药物名称】Everolimus, RAD-001, NVP-RAD-001, SDZ-RAD, Certican

【化学名称】[1R,9S,12S[1'R(1''S,3''R,4''R)],15R,18R,19R,21R,23S,30S,32S,35R]-1,18-Dihydroxy-12-[2-[4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16(E),24(E),26(E),28(E)-tetraene-2,3,10,14,20-pentaone
　　　　　　40-O-(2-Hydroxyethyl)rapamycin
　　　　　　(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1(R)-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentaone

【CA登记号】159351-69-6

【 分 子 式 】C53H83NO14

【 分 子 量 】958.25076

【开发单位】Novartis (Originator), Guidant (Licensee)

【药理作用】Antiarthritic Drugs, CARDIOVASCULAR DRUGS, IMMUNOMODULATING AGENTS, Immunosuppressants, Oncolytic Drugs, Restenosis Treatment of, Rheumatoid Arthritis, Treatment of, Solid Tumors Therapy, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Transplant Rejection, Inhibitors of Signal Transduction Pathways, mTOR Inhibitors, Rapamycins, Rotamase (FKBP12) Inhibitors
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

Alkylation of rapamycin (I) with 2-(tert-butyldimethylsilyloxy)ethyl triflate (II) by means of 2,6-lutidine in hot toluene gives the silylated target compound (III), which is deprotected by means of 1N HCl in methanol.

参考文献 中间体
【1】 Castañer, J.; Sorbera, L.A.; Leeson, P.A.; SDZ-RAD. Drugs Fut 1999, 24, 1, 22.
【2】 Cottens, S.; Sedrani, R. (Novartis AG; Novartis Deutschland GmbH); O-Alkylated rapamycin derivs. and their use, particularly as immunosuppressants. EP 0663916; EP 0867438; JP 1996502266; JP 1999240884; US 5665772; WO 9409010 .
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) 20296 (1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone 53123-88-9 C51H79NO13 详情 详情
(II) 20297 2-[[tert-butyl(dimethyl)silyl]oxy]ethyl trifluoromethanesulfonate C9H19F3O4SSi 详情 详情
(III) 20298 (1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-12-[(1R)-2-[(1S,3R,4R)-4-(2-[[tert-butyl(dimethyl)silyl]oxy]ethoxy)-3-methoxycyclohexyl]-1-methylethyl]-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone C59H97NO14Si 详情 详情

合成路线2

The compound has been obtained biosynthetically by an optimized fermentation process using Streptomyces hygroscopicus mutant RSH 1701 with a complex culture medium were [14C]-labeled (1R,3R,4R)-2,3-dichydroxycyclo-hexanecarboxylic acid (I) and [14C]-labeled (S)-pipecolic acid (II) have been added. This fermentation process yielded [14C]-labeled rapamycin (III), which was finally selectively O-alkylated at the C-40 position with monosilylated ethylene glycol triflate in DMSO/dimethoxyethane.

参考文献 中间体
【1】 Moenius, T.; et al.; C-14 labelling of NVP RAD001 - A new rapamycin derivative. J Label Compd Radiopharm 1999, 42, 1, 29.
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) 32019 (1R,3R,4R)-3,4-dihydroxycyclohexanecarboxylic acid C7H12O4 详情 详情
(I) 45302 (1R,3R,4R)-3,4-dihydroxycyclohexanecarboxylic acid C7H12O4 详情 详情
(II) 17380 (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid 3105-95-1 C6H11NO2 详情 详情
(II) 45303 (2S)-2-piperidinecarboxylic acid C6H11NO2 详情 详情
(III) 20296 (1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone 53123-88-9 C51H79NO13 详情 详情
(III) 45304 (1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16,24,26,28-tetraene-2 C51H79NO13 详情 详情

合成路线3

The reaction of the labeled acylated (+)-bornane-10,2-sultam (IV) with triethyl phosphite gives the phosphonate (V), which is treated with paraformaldehyde, galvinoxyl and K2CO3 yielding the acrylate derivative (VI). The cyclization of (VI) with butadiene (VII) by means of diethylaluminum chloride and galvinoxyl (as radical scavenger) affords the cyclohexene-carboxamide derivative (VIII), which is hydrolyzed with LiOH in THF/water giving the (1R)-3-cyclohexenecarboxylic acid (IX). The oxidation of (IX) with m-chloroperbenzoic acid and triethylamine in CCl4 yielded regioselectively the hydroxylactone (X), which is finally hydrolyzed with HCl to the labeled intermediate (I).

参考文献 中间体
【1】 Moenius, T.; et al.; C-14 labelling of NVP RAD001 - A new rapamycin derivative. J Label Compd Radiopharm 1999, 42, 1, 29.
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) 32019 (1R,3R,4R)-3,4-dihydroxycyclohexanecarboxylic acid C7H12O4 详情 详情
(I) 45302 (1R,3R,4R)-3,4-dihydroxycyclohexanecarboxylic acid C7H12O4 详情 详情
(IV) 32020 (1S,5S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C12H18BrNO3S 详情 详情
(IV) 45305 (1S,5S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C12H18BrNO3S 详情 详情
(V) 32021 diethyl 2-[(1S,5S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]-2-oxoethylphosphonate C16H28NO6PS 详情 详情
(V) 45306 diethyl 2-[(1S,5S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]-2-oxoethylphosphonate C16H28NO6PS 详情 详情
(VI) 32022 (1S,5S)-4-acryloyl-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C13H19NO3S 详情 详情
(VI) 45307 (1S,5S)-4-acryloyl-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C13H19NO3S 详情 详情
(VII) 11579 1,3-Butadiene; Butadiene 106-99-0 C4H6 详情 详情
(VIII) 32023 (1S,5S)-4-[(1R)-3-cyclohexen-1-ylcarbonyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C17H25NO3S 详情 详情
(VIII) 45308 (1S,5S)-4-[(1R)-3-cyclohexen-1-ylcarbonyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C17H25NO3S 详情 详情
(IX) 11581 (1R)-3-Cyclohexene-1-carboxylic acid C7H10O2 详情 详情
(IX) 45309 (1R)-3-cyclohexene-1-carboxylic acid C7H10O2 详情 详情
(X) 11528 (1R,4R,5R)-4-Hydroxy-6-oxabicyclo[3.2.1]octan-7-one C7H10O3 详情 详情
(X) 45310 (1R,4R,5R)-4-hydroxy-6-oxabicyclo[3.2.1]octan-7-one C7H10O3 详情 详情

合成路线4

The reaction of the labeled acylated (-)-bornane-10,2-sultam (XI) with benzophenone imine (XII) gives the glycylsultam derivative (XIII), which is alkylated with 4-iodobutyl chloride (XIV) by means of butyllithium and DMPU in THF yielding intermediate (XV). The selective hydrolysis of (XV) with HCl affords the omega-chloro-L-norleucine derivative (XVI), which is cyclized by means of tetrabutylammonium fluoride and DIEA in hot acetonitrile giving the (2S)-piperidyl derivative (XVII). Finally, this compound is hydrolyzed with LiOH in THF/water to the labeled intermediate (II).

参考文献 中间体
【1】 Moenius, T.; et al.; C-14 labelling of NVP RAD001 - A new rapamycin derivative. J Label Compd Radiopharm 1999, 42, 1, 29.
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) 17380 (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid 3105-95-1 C6H11NO2 详情 详情
(II) 45303 (2S)-2-piperidinecarboxylic acid C6H11NO2 详情 详情
(XI) 32030 (1R,5R)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C12H18BrNO3S 详情 详情
(XI) 45315 (1R,5R)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C12H18BrNO3S 详情 详情
(XII) 32024 diphenylmethanimine 1013-88-3 C13H11N 详情 详情
(XIII) 32025 (1R,5R)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C25H28N2O3S 详情 详情
(XIII) 45311 (1R,5R)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C25H28N2O3S 详情 详情
(XIV) 32026 1-chloro-4-iodobutane 10297-05-9 C4H8ClI 详情 详情
(XV) 32027 (1R,5R)-4-[(2S)-6-chloro-2-[(dibenzylene)amino]hexanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C29H35ClN2O3S 详情 详情
(XV) 45312 (1R,5R)-4-[(2S)-6-chloro-2-[(dibenzylene)amino]hexanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C29H35ClN2O3S 详情 详情
(XVI) 32028 (1R,5R)-4-[(2S)-2-amino-6-chlorohexanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C16H27ClN2O3S 详情 详情
(XVI) 45313 (1R,5R)-4-[(2S)-2-amino-6-chlorohexanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C16H27ClN2O3S 详情 详情
(XVII) 32029 (1R,5R)-10,10-dimethyl-4-[(2S)piperidinylcarbonyl]-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C16H26N2O3S 详情 详情
(XVII) 45314 (1R,5R)-10,10-dimethyl-4-[(2S)piperidinylcarbonyl]-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C16H26N2O3S 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(2)