LJP-920, -Drug Synthesis Database

【结构式】

【药物名称】LJP-920

【化学名称】30-[3-O-(alpha-D-Galactopyranosyl)-beta-D-galactopyranosyloxy]-14(S)-[11-[3-O-(alpha-D-galactopyranosyl)-beta-D-galactopyranosyloxy]-6,9-dioxa-3-thiaundecanamido]-2-[28-[3-O-(alpha-D-galactopyranosyl)-beta-D-galactopyranosyloxy]-12(S)-[11-[3-O-(alpha-D-galactopyranosyl)-beta-D-galactopyranosyloxy]-6,9-dioxa-3-thiaundecanamido]-4,11,18-trioxo-23,26-dioxa-20-thia-3,10,17-triazaoctacosyl]-6,13,20-trioxo-25,28-dioxa-22-thia-2,5,12,19-tetraazatriacontanoic acid 3,6-dioxaooctane-1,8-diyl diester

【CA登记号】274681-16-2

【分子式】C₂₂₄H₄₀₀N₁₈O₁₂₆S₈

【分子量】5618.2426

【开发单位】La Jolla Pharmaceutical (Originator)

【药理作用】IMMUNOMODULATING AGENTS, Immunosuppressants, Treatment of Transplant Rejection

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

Condensation of galactose pentaacetate (I) with 2-[2-(2-chloroethoxy)ethoxy]ethanol (II) in the presence of boron trifluoride etherate afforded the galactopyranoside (III). Subsequent hydrolysis of the acetate esters of (III) to give (IV) was carried out employing K2CO3 in MeOH. The galactose 3-hydroxyl group of (IV) was selectively protected as the p-methoxybenzyl ether (VI) by treatment with p-methoxybenzyl chloride (V) in the presence of dibutyltin oxide. After acetylation of the remaining free hydroxyl groups of (VII) to give (VIII), oxidative cleavage of its p-methoxybenzyl ether by means of cerium ammonium nitrate afforded the 2,4,6-triacetylated pyranoside (VIII). This was condensed with the galactose thioglycoside (IX) in the presence of methyl triflate to furnish the protected disaccharide (X). The benzyl protecting groups of (X) were then removed by hydrogenolysis yielding (XI).

参考文献中间体

【1】 Yu, L.; Jack, R.M.; Jones, D. (La Jolla Pharmaceutical Co.); Conjugates comprising galactose alpha 1,3 galactosyl epitopes and methods of using same. EP 1137652; WO 0034296 .
【2】 Jones, D.S.; Engle, S.B.; Yu, L.; Jack, R.M. (La Jolla Pharmaceutical Co.); Methods and formulations for reducing circulating antibodies. WO 0033887 .

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)	52047	[(2R,3S,4S,5R,6R)-3,4,5,6-tetrakis(acetoxy)tetrahydro-2H-pyran-2-yl]methyl acetate		C₁₆H₂₂O₁₁	详情	详情
(II)	14748	2-[2-(2-Chloroethoxy)ethoxy]-1-ethanol; 2-(2-(2-Chloroethoxy)ethoxy)ethanol	5197-62-6	C₆H₁₃ClO₃	详情	详情
(III)	52048	(2R,3S,4S,5R,6S)-3,5-bis(acetoxy)-2-[(acetoxy)methyl]-6-[2-[2-(2-chloroethoxy)ethoxy]ethoxy]tetrahydro-2H-pyran-4-yl acetate		C₂₀H₃₁ClO₁₂	详情	详情
(IV)	52049	(2S,3R,4S,5R,6R)-2-[2-[2-(2-chloroethoxy)ethoxy]ethoxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol		C₁₂H₂₃ClO₈	详情	详情
(V)	11910	4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether	824-94-2	C₈H₉ClO	详情	详情
(VI)	52050	(2S,3R,4S,5R,6R)-2-[2-[2-(2-chloroethoxy)ethoxy]ethoxy]-6-(hydroxymethyl)-4-[(4-methoxybenzyl)oxy]tetrahydro-2H-pyran-3,5-diol		C₂₀H₃₁ClO₉	详情	详情
(VII)	52051	(2R,3R,4S,5R,6S)-5-(acetoxy)-2-[(acetoxy)methyl]-6-[2-[2-(2-chloroethoxy)ethoxy]ethoxy]-4-[(4-methoxybenzyl)oxy]tetrahydro-2H-pyran-3-yl acetate		C₂₆H₃₇ClO₁₂	详情	详情
(VIII)	52052	(2R,3R,4S,5R,6S)-5-(acetoxy)-2-[(acetoxy)methyl]-6-[2-[2-(2-chloroethoxy)ethoxy]ethoxy]-4-hydroxytetrahydro-2H-pyran-3-yl acetate		C₁₈H₂₉ClO₁₁	详情	详情
(IX)	52053	benzyl (2R,3R,4S,5R,6R)-3,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-(methylsulfanyl)tetrahydro-2H-pyran-4-yl ether; (2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-[(benzyloxy)methyl]-6-(methylsulfanyl)tetrahydro-2H-pyran		C₃₅H₃₈O₅S	详情	详情
(X)	52054	(2R,3S,4S,5R,6S)-5-(acetoxy)-2-[(acetoxy)methyl]-6-[2-[2-(2-chloroethoxy)ethoxy]ethoxy]-4-([(2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]oxy)tetrahydro-2H-pyran-3-yl acetate		C₅₂H₆₃ClO₁₆	详情	详情
(XI)	52055	(2R,3S,4S,5R,6S)-5-(acetoxy)-2-[(acetoxy)methyl]-6-[2-[2-(2-chloroethoxy)ethoxy]ethoxy]-4-[[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]tetrahydro-2H-pyran-3-yl acetate		C₂₄H₃₉ClO₁₆	详情	详情

合成路线2

Basic hydrolysis of the acetate ester groups of (XI) provided the fully deprotected disaccharide glycoside (XII). The chloro group of (XII) was then displaced with potassium thioacetate to furnish the intermediate thioester (XIII).

参考文献中间体

【1】 Yu, L.; Jack, R.M.; Jones, D. (La Jolla Pharmaceutical Co.); Conjugates comprising galactose alpha 1,3 galactosyl epitopes and methods of using same. EP 1137652; WO 0034296 .
【2】 Jones, D.S.; Engle, S.B.; Yu, L.; Jack, R.M. (La Jolla Pharmaceutical Co.); Methods and formulations for reducing circulating antibodies. WO 0033887 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	52055	(2R,3S,4S,5R,6S)-5-(acetoxy)-2-[(acetoxy)methyl]-6-[2-[2-(2-chloroethoxy)ethoxy]ethoxy]-4-[[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]tetrahydro-2H-pyran-3-yl acetate	C₂₄H₃₉ClO₁₆	详情	详情
(XII)	52056	(2R,3R,4S,5R,6R)-2-[[(2S,3R,4S,5S,6R)-2-[2-[2-(2-chloroethoxy)ethoxy]ethoxy]-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol	C₁₈H₃₃ClO₁₃	详情	详情
(XIII)	52057	S-[2-(2-[2-[((2S,3R,4S,5S,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]tetrahydro-2H-pyran-2-yl)oxy]ethoxy]ethoxy)ethyl] ethanethioate	C₂₀H₃₆O₁₄S	详情	详情

合成路线3

Coupling of the tetraamino compound (XIV) with bis(carbobenzoxy)lysine hydroxysuccinimidyl ester (XV) yielded the corresponding tetraamide (XVI). The carbobenzoxy groups of (XVI) were removed by catalytic hydrogenation over Pd/C, and the deprotected polyamino compound was then acylated with chloroacetic anhydride to afford the octa(chloroacetamide) (XVII).

参考文献中间体

【1】 Yu, L.; Jack, R.M.; Jones, D. (La Jolla Pharmaceutical Co.); Conjugates comprising galactose alpha 1,3 galactosyl epitopes and methods of using same. EP 1137652; WO 0034296 .
【2】 Jones, D.S.; Engle, S.B.; Yu, L.; Jack, R.M. (La Jolla Pharmaceutical Co.); Methods and formulations for reducing circulating antibodies. WO 0033887 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	52058	20-amino-11-[2-[(6-aminohexanoyl)amino]ethyl]-10,15-dioxo-3,6,9-trioxa-11,14-diazaicos-1-yl bis[2-[(6-aminohexanoyl)amino]ethyl]carbamate	C₄₀H₈₀N₁₀O₁₀	详情	详情
(XV)	52059	benzyl (1S)-5-[[(benzyloxy)carbonyl]amino]-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]pentylcarbamate	C₂₆H₂₉N₃O₈	详情	详情
(XVI)	52060	benzyl (1S,38S)-38-[[(benzyloxy)carbonyl]amino]-1-(4-[[(benzyloxy)carbonyl]amino]butyl)-13,26-bis((12S)-12-[[(benzyloxy)carbonyl]amino]-4,11,18-trioxo-20-phenyl-19-oxa-3,10,17-triazaicos-1-yl)-2,9,14,25,30,37,44-heptaoxo-46-phenyl-15,18,21,24,45-pentaoxa-3,10,13,26,29,36,43-heptaazahexatetracont-1-ylcarbamate	C₁₂₈H₁₇₆N₁₈O₃₀	详情	详情
(XVII)	52061	(23S)-11-(2-[[6-([(2S)-2,6-bis[(2-chloroacetyl)amino]hexanoyl]amino)hexanoyl]amino]ethyl)-30-chloro-23-[(2-chloroacetyl)amino]-10,15,22,29-tetraoxo-3,6,9-trioxa-11,14,21,28-tetraazatriacont-1-yl bis(2-[[6-([(2S)-2,6-bis[(2-chloroacetyl)amino]hexanoyl]amino)hexanoyl]amino]ethyl)carbamate	C₈₀H₁₃₆Cl₈N₁₈O₂₂	详情	详情

合成路线4

Finally, the corresponding thiol, liberated in situ from thioacetate ester (XIII), was condensed with the octa chloro derivative (XVII) to furnish the title compound.

参考文献中间体

【1】 Yu, L.; Jack, R.M.; Jones, D. (La Jolla Pharmaceutical Co.); Conjugates comprising galactose alpha 1,3 galactosyl epitopes and methods of using same. EP 1137652; WO 0034296 .
【2】 Jones, D.S.; Engle, S.B.; Yu, L.; Jack, R.M. (La Jolla Pharmaceutical Co.); Methods and formulations for reducing circulating antibodies. WO 0033887 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	52057	S-[2-(2-[2-[((2S,3R,4S,5S,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-[[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]tetrahydro-2H-pyran-2-yl)oxy]ethoxy]ethoxy)ethyl] ethanethioate		C₂₀H₃₆O₁₄S	详情	详情
(XVII)	52061	(23S)-11-(2-[[6-([(2S)-2,6-bis[(2-chloroacetyl)amino]hexanoyl]amino)hexanoyl]amino]ethyl)-30-chloro-23-[(2-chloroacetyl)amino]-10,15,22,29-tetraoxo-3,6,9-trioxa-11,14,21,28-tetraazatriacont-1-yl bis(2-[[6-([(2S)-2,6-bis[(2-chloroacetyl)amino]hexanoyl]amino)hexanoyl]amino]ethyl)carbamate		C₈₀H₁₃₆Cl₈N₁₈O₂₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)