Glycopin, GMDP, Licopid, -Drug Synthesis Database

【结构式】

【药物名称】Glycopin, GMDP, Licopid

【化学名称】N-[2(R)-[2-Acetamido-4-O-(2-acetamido-2-deoxy-beta-D-glucopryanosyl)-2-deoxy-D-glucopyranos-3-O-yl]propionyl]-L-alanyl-D-isoglutamine
　　　　　　N-[4-O-(2-Acetamido-2-deoxy-beta-D-glucopyranosyl)-N-acetylmuramyl]-L-alanyl-D-isoglutamine

【CA登记号】70280-03-4

【分子式】C₂₇H₄₅N₅O₁₆

【分子量】695.6836

【开发单位】Peptech (Originator)

【药理作用】Antipsoriatics, DERMATOLOGIC DRUGS, IMMUNOMODULATING AGENTS, Immunostimulants

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6 合成路线7 合成路线8 合成路线9 合成路线10 合成路线11

合成路线1

Acylation of 3,4,6-tri-O-benzyl-D-glucosamine (I) by means of pentachlorophenyl dichloroacetate (II) yielded the dichloroacetamide (III). Acylation of glucosamine (III) with acid chloride (IV) in pyridine/CH2Cl2 provided the 1-O-p-nitrobenzoyl derivative (V), which was treated with hydrogen bromide in CH2Cl2 to furnish glycosyl bromide (VI). Coupling of bromide (VI) with the glucosamine cyclic carbamate (VII) was performed in the presence of mercury(II) cyanide to afford the disaccharide (VIII). Alkaline hydrolysis of the dichloroacetamide and cyclic carbamate functions of (VIII) gave diamine (IX), which was subsequently acetylated to diamide (X) by means of acetic anhydride in pyridine.

参考文献中间体

【1】 Kusumoto, S.; et al.; Chemical synthesis and biological activities of two disaccharide dipeptides corresponding to the repeating units of bacterial peptidoglycan. Bull Chem Soc Jpn 1986, 59, 5, 1411.
【2】 Kusumoto, S.; et al.; Synthesis of N-acetyl-beta-D-glucosaminyl-(1-4)-N-acetylmuramyl-L-alanyl-D-isoglutamine. Tetrahedron Lett 1978, 45, 4407.

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)	56323	(3R,4R,5S,6R)-3-amino-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-ol		C₂₇H₃₁NO₅	详情	详情
(II)	56324	Pentachlorophenyl dichloroacetate	19745-69-8	C₈HCl₇O₂	详情	详情
(III)	56325	N-{(3R,4R,5S,6R)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]-2-hydroxytetrahydro-2H-pyran-3-yl}-2,2-dichloroacetamide		C₂₉H₃₁Cl₂NO₆	详情	详情
(IV)	18941	p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride	122-04-3	C₇H₄ClNO₃	详情	详情
(V)	56326	(3R,4R,5S,6R)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]-3-[(2,2-dichloroacetyl)amino]tetrahydro-2H-pyran-2-yl 4-nitrobenzoate		C₃₆H₃₄Cl₂N₂O₉	详情	详情
(VI)	56327	N-{(3R,4R,5S,6R)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl}-2,2-dichloroacetamide		C₂₉H₃₀BrCl₂NO₅	详情	详情
(VII)	56328	(4R,5R)-4-(diethoxymethyl)-5-[(R)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl](hydroxy)methyl]-1,3-oxazolidin-2-one		C₄₃H₅₄Cl₂N₂O₁₂	详情	详情
(VIII)	56329	N-[(2S,3R,4R,5S,6R)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]-2-({(R)-[(4R,5R)-4-(diethoxymethyl)-2-oxo-1,3-oxazolidin-5-yl][(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}oxy)tetrahydro-2H-pyran-3-yl]-2,2-dichloroacetamide		C₄₃H₅₄Cl₂N₂O₁₂	详情	详情
(IX)	56330	(1S,2R,3R)-3-amino-1-({(2S,3R,4R,5S,6R)-3-amino-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4,4-diethoxy-2-butanol		C₄₀H₅₆N₂O₁₀	详情	详情
(X)	56331	N-{(1R,2R,3S)-3-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-1-(diethoxymethyl)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxypropyl}acetamide		C₄₄H₆₀N₂O₁₂	详情	详情

合成路线2

Alkylation of the sodium alkoxide of (X) with (S)-2-chloropropionic acid (XI), followed by esterification with diazomethane provided the methyl ester adduct (XII). Alkaline hydrolysis of ester (XII) with KOH yielded carboxylic acid (XIII), which was coupled with the dipeptide amide (XIV) to give the protected disaccharide dipeptide (XV). Subsequent acidic hydrolysis of the ketal functions of (XV) proceeded with concomitant cyclization to the pyranose form (XVI). The O-benzyl protecting groups of (XVI) were finally removed by catalytic hydrogenolysis in the presence of palladium black.

参考文献中间体

【1】 Kusumoto, S.; et al.; Synthesis of N-acetyl-beta-D-glucosaminyl-(1-4)-N-acetylmuramyl-L-alanyl-D-isoglutamine. Tetrahedron Lett 1978, 45, 4407.
【2】 Kusumoto, S.; et al.; Chemical synthesis and biological activities of two disaccharide dipeptides corresponding to the repeating units of bacterial peptidoglycan. Bull Chem Soc Jpn 1986, 59, 5, 1411.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	56331	N-{(1R,2R,3S)-3-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-1-(diethoxymethyl)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxypropyl}acetamide		C₄₄H₆₀N₂O₁₂	详情	详情
(XI)	56332	(S)-(-)-2-Chloropropionic acid; (S)-2-Chloropropionic acid	29617-66-1	C₃H₅ClO₂	详情	详情
(XII)	56333	methyl (2R)-2-[((1R,2R)-2-(acetylamino)-1-{(S)-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3,3-diethoxypropyl)oxy]propanoate		C₄₈H₆₆N₂O₁₄	详情	详情
(XIII)	56334	(2R)-2-[((1R,2R)-2-(acetylamino)-1-{(S)-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3,3-diethoxypropyl)oxy]propanoic acid		C₄₇H₆₄N₂O₁₄	详情	详情
(XIV)	27130	benzyl (4R)-5-amino-4-[[(2S)-2-aminopropanoyl]amino]-5-oxopentanoate		C₁₅H₂₁N₃O₄	详情	详情
(XV)	56335	benzyl (5R,6R,8R,11S,14R)-5-(acetylamino)-6-{(S)-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-14-(aminocarbonyl)-4-ethoxy-8,11-dimethyl-9,12-dioxo-3,7-dioxa-10,13-diazaheptadecan-17-oate		C₆₂H₈₃N₅O₁₇	详情	详情
(XVI)	56336	benzyl (4R)-4-({(2S)-2-[((2R)-2-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-5-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-2-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy}propanoyl)amino]propanoyl}amino)-5-amino-5-oxopentanoate		C₅₅H₆₉N₅O₁₆	详情	详情

合成路线3

In an alternative route, 2-N-acetyl-4,6-O-isopropylidene-D-glucosamine benzyl pyranoside (XVII) was alkylated with 1-bromo-2-butene (XVIII) in the presence of barium oxide and barium hydroxide to produce the 3-O-crotyl ether (XIX). After acidic hydrolysis of the isopropylidene ketal (XIX), the resultant diol (XX) was selectively mono-acylated at the primary hydroxyl with benzoyl chloride (XXI) to afford the 6-benzoate ester (XXII). Protection of the 3-hydroxyl group of (XXII) by means of dihydropyran (DHP) and p-toluenesulfonic acid gave rise to the tetrahydropyranyl ether (XXIII). After methanolysis of the benzoate ester of (XXIII) in the presence of NaOMe, the resultant primary alcohol (XXIV) was protected as the benzyl ether (XXV). Subsequent hydrolysis of the tetrahydropyranyl group of (XXV) in aqueous HOAc furnished the protected glucosamine intermediate (XXVI).

参考文献中间体

【1】 Kiso, M.; et al.; A general, convenient synthesis of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan by the oxazoline method. Carbohydr Res 1980, 83, 1, C8.
【2】 Kiso, M.; et al.; Synthesis and immunoadjuvant activities of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan and of some carbohydrate analogs. Carbohydr Res 1982, 104, 2, 253.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	56337	N-[(4aR,6S,7R,8R,8aS)-6-(benzyloxy)-8-hydroxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]acetamide		C₁₈H₂₅NO₆	详情	详情
(XVIII)	35252	(E)-1-bromo-2-butene	29576-14-5	C₄H₇Br	详情	详情
(XIX)	56338	N-{(4aR,6S,7R,8R,8aS)-6-(benzyloxy)-8-[(E)-2-butenyloxy]-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl}acetamide		C₂₂H₃₁NO₆	详情	详情
(XX)	56339	N-[(2S,3R,4R,5S,6R)-2-(benzyloxy)-4-[(E)-2-butenyloxy]-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]acetamide		C₁₉H₂₇NO₆	详情	详情
(XXI)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(XXII)	56340	{(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-4-[(E)-2-butenyloxy]-3-hydroxytetrahydro-2H-pyran-2-yl}methyl benzoate		C₂₆H₃₁NO₇	详情	详情
(XXIII)	56341	[(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-4-[(E)-2-butenyloxy]-3-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-yl]methyl benzoate		C₃₁H₃₉NO₈	详情	详情
(XXIV)	56342	N-[(2S,3R,4R,5S,6R)-2-(benzyloxy)-4-[(E)-2-butenyloxy]-6-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-3-yl]acetamide		C₂₄H₃₅NO₇	详情	详情
(XXV)	56343	N-[(2S,3R,4R,5S,6R)-2-(benzyloxy)-6-[(benzyloxy)methyl]-4-[(E)-2-butenyloxy]-5-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-3-yl]acetamide		C₃₁H₄₁NO₇	详情	详情
(XXVI)	56344	N-{(2S,3R,4R,5S,6R)-2-(benzyloxy)-6-[(benzyloxy)methyl]-4-[(E)-2-butenyloxy]-5-hydroxytetrahydro-2H-pyran-3-yl}acetamide		C₂₆H₃₃NO₆	详情	详情

合成路线4

Glycosylation of the protected glucosamine (XXVI) with the glucopyranooxazoline (XXVII) was effected in the presence of p-toluenesulfonic acid in dichloroethane to give the protected chitobioside derivative (XXVIII). Methanolysis of the acetate esters of (XXVIII), followed by protection of the resultant triol (XXIX) with acetone dimethylacetal, gave rise to the 4',6'-isopropylidene derivative (XXX). The 3'-hydroxyl group of (XXX) was then protected as the benzyl ether (XXXI) with benzyl bromide in the presence of Ba(OH)2 and BaO. Removal of the 2-butenyl group of (XXXI) to furnish (XXXII) was performed by means of potassium tert-butoxide in hot DMSO. Subsequent alkylation of (XXXII) with (S)-2-chloropropionic acid (XI) led to acid (XXXIII).

参考文献中间体

【1】 Kiso, M.; et al.; A general, convenient synthesis of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan by the oxazoline method. Carbohydr Res 1980, 83, 1, C8.
【2】 Kiso, M.; et al.; Synthesis and immunoadjuvant activities of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan and of some carbohydrate analogs. Carbohydr Res 1982, 104, 2, 253.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	56332	(S)-(-)-2-Chloropropionic acid; (S)-2-Chloropropionic acid	29617-66-1	C₃H₅ClO₂	详情	详情
(XXVI)	56344	N-{(2S,3R,4R,5S,6R)-2-(benzyloxy)-6-[(benzyloxy)methyl]-4-[(E)-2-butenyloxy]-5-hydroxytetrahydro-2H-pyran-3-yl}acetamide		C₂₆H₃₃NO₆	详情	详情
(XXVII)	21969	(3aR,5R,6R,7R,7aR)-6-(acetoxy)-5-[(acetoxy)methyl]-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]oxazol-7-yl acetate		C₁₄H₁₉NO₈	详情	详情
(XXVIII)	56345	(2R,3R,4R,5R,6R)-3-(acetylamino)-2-({(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]-4-[(E)-2-butenyloxy]tetrahydro-2H-pyran-3-yl}oxy)-5-(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-4-yl acetate		C₄₀H₅₂N₂O₁₄	详情	详情
(XXIX)	56346	N-[(2S,3R,4R,5S,6R)-2-({(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]-4-[(E)-2-butenyloxy]tetrahydro-2H-pyran-3-yl}oxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]acetamide		C₃₄H₄₆N₂O₁₁	详情	详情
(XXX)	56347	N-[(4aR,6R,7R,8R,8aS)-6-({(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]-4-[(E)-2-butenyloxy]tetrahydro-2H-pyran-3-yl}oxy)-8-hydroxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]acetamide		C₃₇H₅₀N₂O₁₁	详情	详情
(XXXI)	56348	N-[(4aR,6R,7R,8R,8aS)-6-({(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]-4-[(E)-2-butenyloxy]tetrahydro-2H-pyran-3-yl}oxy)-8-(benzyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]acetamide		C₄₄H₅₆N₂O₁₁	详情	详情
(XXXII)	56349	N-[(4aR,6R,7R,8R,8aS)-6-({(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]-4-hydroxytetrahydro-2H-pyran-3-yl}oxy)-8-(benzyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]acetamide		C₄₀H₅₀N₂O₁₁	详情	详情
(XXXIII)	56350	(2R)-2-({(2R,3S,4R,5R,6S)-3-{[(4aR,6R,7R,8R,8aS)-7-(acetylamino)-8-(benzyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy}-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoic acid		C₄₃H₅₄N₂O₁₃	详情	详情

合成路线5

Coupling of acid (XXXIII) with the dipeptide amide (XIV) was conducted with DCC and NHS as the activating agents to give the lactoyl-dipeptide derivative (XXXIV). Hydrolytic removal of the isopropylidene ketal provided diol (XXXV). The benzyl groups of (XXXV) were finally removed by hydrogenolysis in the presence of Pd/C to afford the title compound.

参考文献中间体

【1】 Kiso, M.; et al.; Synthesis and immunoadjuvant activities of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan and of some carbohydrate analogs. Carbohydr Res 1982, 104, 2, 253.
【2】 Kiso, M.; et al.; A general, convenient synthesis of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan by the oxazoline method. Carbohydr Res 1980, 83, 1, C8.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	27130	benzyl (4R)-5-amino-4-[[(2S)-2-aminopropanoyl]amino]-5-oxopentanoate	C₁₅H₂₁N₃O₄	详情	详情
(XXXIII)	56350	(2R)-2-({(2R,3S,4R,5R,6S)-3-{[(4aR,6R,7R,8R,8aS)-7-(acetylamino)-8-(benzyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy}-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoic acid	C₄₃H₅₄N₂O₁₃	详情	详情
(XXXIV)	56351	benzyl (4R)-4-[((2S)-2-{[(2R)-2-({(2R,3S,4R,5R,6S)-3-{[(4aR,6R,7R,8R,8aS)-7-(acetylamino)-8-(benzyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy}-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoyl]amino}propanoyl)amino]-5-amino-5-oxopentanoate	C₅₈H₇₃N₅O₁₆	详情	详情
(XXXV)	56352	benzyl (4R)-4-[((2S)-2-{[(2R)-2-({(2S,3R,4R,5S,6R)-3-(acetylamino)-5-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-4-(benzyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2-(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoyl]amino}propanoyl)amino]-5-amino-5-oxopentanoate	C₅₅H₆₉N₅O₁₆	详情	详情

合成路线6

A more direct procedure was based on the activation of the unprotected disaccharide acid (XXXVI) as the pentafluorophenyl ester (XXXVII) by treatment with bis(pentafluorophenyl) carbonate. Active ester (XXXVII) was subsequently coupled with L-alanyl-D-isoglutamine (XXXVIII) to afford the corresponding amide.

参考文献中间体

【1】 Andronova, T.M.; et al.; Bacterial cell wall glycopeptides as adjuvants. Colloq INSERM 1989, 174, 561.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXXVI)	56354	2,3,4,5,6-pentafluorophenyl (2R)-2-{[(3R,4R,5S,6R)-3-(acetylamino)-5-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy}propanoate	C₂₅H₃₁F₅N₂O₁₃	详情	详情
(XXXVII)	56355	(4R)-5-amino-4-{[(2S)-2-aminopropanoyl]amino}-5-oxopentanoic acid	C₈H₁₅N₃O₄	详情	详情
(XXXVIII)	56356	(2R,3S,4R,5R,6S)-3-(acetyloxy)-2-[(acetyloxy)methyl]-6-chloro-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)tetrahydro-2H-pyran-4-yl acetate	C₂₀H₂₀ClNO₉	详情	详情

合成路线7

The title disaccharide-dipeptide was obtained by enzymatic degradation of the peptidoglycan of Actinomadura R39. The peptidoglycan was hydrolyzed successively by the 3 following enzymes: lysozyme, DD-carboxypeptidase and gamma-D-glutamyl-meso-diaminopimelate endopeptidase I.

参考文献中间体

【1】 Guinand, M.; et al.; Enzymatic preparation of an immunostimulant, the disaccharide-dipeptide, N-acetyl-beta-D-glucosaminyl-(1--4)-N-acetylmuramyl-L-alanyl-D-isoglutamine, from a bacterial peptidoglycan. Eur J Biochem 1984, 143, 2, 359.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成

合成路线8

Condensation of the glucopyranosyl chloride (XXXIX) with the protected glucosamine (XL) in the presence of silver triflate-s-collidine complex gave disaccharide (XLI). Subsequent dephthaloylation and ester hydrolysis of (XLI) by means of n-butylamine in boiling MeOH furnished (XLII). Chemoselective acylation of the amino group of (XLII) with Ac2O in MeOH provided acetamide (XLIII). The free hydroxyl groups of (XLIII) were then protected as the corresponding benzyl ethers (XLIV) employing benzyl bromide in the presence of barium oxide and barium hydroxyde. The O-allyl group of (XLIV) was then isomerized in the presence of DABCO and rhodium catalyst to the 1-propenyl analogue (XLV), which was further hydrolyzed to alcohol (XLVI) by treatment with HgCl2.

参考文献中间体

【1】 Durette, P.L.; et al.; Synthesis of O-(2-acetamido-2-deoxy-beta-D-glucosyl)-(1--4)-N-acetylmuramoyl-L-alanyl-D-isoglutamine, the repeating disaccharide-dipeptide unit of the bacterial cell-wall peptidoglycan. Carbohydr Res 1979, 77, C1.
【2】 Durette, P.L.; Shen, T.-Y. (Merck & Co., Inc.); Immunologically active peptidyl disaccharides, methods of preparation and vaccine. EP 0018901 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXXIX)	56356	(2R,3S,4R,5R,6S)-3-(acetyloxy)-2-[(acetyloxy)methyl]-6-chloro-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)tetrahydro-2H-pyran-4-yl acetate	C₂₀H₂₀ClNO₉	详情	详情
(XL)	56357	N-{(2S,3R,4R,5S,6R)-4-(allyloxy)-2-(benzyloxy)-6-[(benzyloxy)methyl]-5-hydroxytetrahydro-2H-pyran-3-yl}acetamide	C₂₅H₃₁NO₆	详情	详情
(XLI)	56358	(2R,3R,4R,5R,6R)-2-({(2R,3S,4R,5R,6S)-5-(acetylamino)-4-(allyloxy)-6-(benzyloxy)-2-[(benzyloxy)methyl]tetrahydro-2H-pyran-3-yl}oxy)-5-(acetyloxy)-6-[(acetyloxy)methyl]-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)tetrahydro-2H-pyran-4-yl acetate	C₄₅H₅₀N₂O₁₅	详情	详情
(XLII)	56359	N-{(2S,3R,4R,5S,6R)-4-(allyloxy)-5-{[(2S,3R,4R,5S,6R)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2-(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-3-yl}acetamide	C₃₁H₄₂N₂O₁₀	详情	详情
(XLIII)	56360	N-[(2S,3R,4R,5S,6R)-2-({(2R,3S,4R,5R,6S)-5-(acetylamino)-4-(allyloxy)-6-(benzyloxy)-2-[(benzyloxy)methyl]tetrahydro-2H-pyran-3-yl}oxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]acetamide	C₃₃H₄₄N₂O₁₁	详情	详情
(XLIV)	56361	N-{(2S,3R,4R,5S,6R)-2-({(2R,3S,4R,5R,6S)-5-(acetylamino)-4-(allyloxy)-6-(benzyloxy)-2-[(benzyloxy)methyl]tetrahydro-2H-pyran-3-yl}oxy)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-3-yl}acetamide	C₅₄H₆₂N₂O₁₁	详情	详情
(XLV)	56362	N-{(2S,3R,4R,5S,6R)-2-({(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]-4-[(E)-1-propenyloxy]tetrahydro-2H-pyran-3-yl}oxy)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-3-yl}acetamide	C₅₄H₆₂N₂O₁₁	详情	详情
(XLVI)	56363	N-{(2S,3R,4R,5S,6R)-2-({(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]-4-hydroxytetrahydro-2H-pyran-3-yl}oxy)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-3-yl}acetamide	C₅₁H₅₈N₂O₁₁	详情	详情

合成路线9

Alkylation of (XLVI) with (S)-2-chloropropionic acid (XI) provided the lactic acid derivative (XLVII). This was subsequently coupled with the dipeptide amide (XIV), via activation as the mixed anhydride with isobutyl chloroformate, to give the protected disaccharide dipeptide (XLVIII). Finally, hydrogenolysis of the O-benzyl protecting groups of (XLVIII) in the presence of palladium black led to the title compound.

参考文献中间体

【1】 Durette, P.L.; et al.; Synthesis of O-(2-acetamido-2-deoxy-beta-D-glucosyl)-(1--4)-N-acetylmuramoyl-L-alanyl-D-isoglutamine, the repeating disaccharide-dipeptide unit of the bacterial cell-wall peptidoglycan. Carbohydr Res 1979, 77, C1.
【2】 Durette, P.L.; Shen, T.-Y. (Merck & Co., Inc.); Immunologically active peptidyl disaccharides, methods of preparation and vaccine. EP 0018901 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	56332	(S)-(-)-2-Chloropropionic acid; (S)-2-Chloropropionic acid	29617-66-1	C₃H₅ClO₂	详情	详情
(XIV)	27130	benzyl (4R)-5-amino-4-[[(2S)-2-aminopropanoyl]amino]-5-oxopentanoate		C₁₅H₂₁N₃O₄	详情	详情
(XLVI)	56363	N-{(2S,3R,4R,5S,6R)-2-({(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]-4-hydroxytetrahydro-2H-pyran-3-yl}oxy)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-3-yl}acetamide		C₅₁H₅₈N₂O₁₁	详情	详情
(XLVII)	56364	(2R)-2-({(2S,3R,4R,5S,6R)-3-(acetylamino)-5-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-2-(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoic acid		C₅₄H₆₂N₂O₁₃	详情	详情
(XLVIII)	56365	benzyl (4R)-4-[((2S)-2-{[(2R)-2-({(2S,3R,4R,5S,6R)-3-(acetylamino)-5-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-2-(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoyl]amino}propanoyl)amino]-5-amino-5-oxopentanoate		C₆₉H₈₁N₅O₁₆	详情	详情

合成路线10

The disaccharide derivative (XXXVI) was isolated from the enzymatic hydrolysis of the cell walls obtained from cultures of Micrococcus lysodeikticus. Condensation of (XXXVI) with L-alanyl-D-isoglutamine benzyl ester (XIV), by means of N-ethyl-5-phenylisoxazolium-3'-sulfonate (NEPIS, Woodward's reagent K) as the coupling reagent, furnished amide (XLIX). The benzyl ester group of (XLIX) was finally cleaved by hydrogenolysis over Pd/C.

参考文献中间体

【1】 Vosika, G.J.; Cornelius, D.A.; Bennek, J.A.; Swenson, K.E.; Gilbert, C.W. (DOR BioPharma, Inc.); Compsn. for macrophage activation. US 5416070; WO 9116347 .
【2】 Vosika, G.J.; Ma, F. (DOR BioPharma, Inc.); Preparation of glucosaminyl muramic acid derivs.. WO 9712894 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	27130	benzyl (4R)-5-amino-4-[[(2S)-2-aminopropanoyl]amino]-5-oxopentanoate	C₁₅H₂₁N₃O₄	详情	详情
(XXXVI)	56354	2,3,4,5,6-pentafluorophenyl (2R)-2-{[(3R,4R,5S,6R)-3-(acetylamino)-5-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy}propanoate	C₂₅H₃₁F₅N₂O₁₃	详情	详情
(XLIX)	56366	benzyl (4R)-4-({(2S)-2-[((2R)-2-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-5-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy}propanoyl)amino]propanoyl}amino)-5-amino-5-oxopentanoate	C₃₄H₅₁N₅O₁₆	详情	详情

合成路线11

The precursor N-acetylglucosaminyl-N-acetylmuramic acid (XXXVI) was obtained by an alternative route. The protected glucosamine acid (L) was esterified with benzyl alcohol in the presence of EDC and DMAP to yield the benzyl ester (LI). The 4,6-O-benzylidene group of (LI) was then subjected to reductive cleavage with NaBH3CN, producing the 6-O-benzyl-4-hydroxy derivative (LII). Coupling of (LII) with the thioglucoside (LIII) was accomplished in the presence of nitrosyl tetrafluoroborate, to afford (LIV). Depththaloylation and hydrolysis of (LIV) with methanolic butylamine provided (LV). Then, amino group acetylation with Ac2O in MeOH gave amide (LVI). The O-benzyl protecting groups of (LVI) were then removed by catalytic hydrogenation, leading to precursor (XXXVI).

参考文献中间体

【1】 Vosika, G.J.; Cornelius, D.A.; Bennek, J.A.; Swenson, K.E.; Gilbert, C.W. (DOR BioPharma, Inc.); Compsn. for macrophage activation. US 5416070; WO 9116347 .
【2】 Vosika, G.J.; Ma, F. (DOR BioPharma, Inc.); Preparation of glucosaminyl muramic acid derivs.. WO 9712894 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXXVI)	56354	2,3,4,5,6-pentafluorophenyl (2R)-2-{[(3R,4R,5S,6R)-3-(acetylamino)-5-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy}propanoate	C₂₅H₃₁F₅N₂O₁₃	详情	详情
(L)	56367	(2R)-2-{[(4aR,6S,7R,8R,8aS)-7-(acetylamino)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy}propanoic acid	C₂₅H₂₉NO₈	详情	详情
(LI)	56368	benzyl (2R)-2-{[(4aR,6S,7R,8R,8aS)-7-(acetylamino)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy}propanoate	C₃₂H₃₅NO₈	详情	详情
(LII)	56369	benzyl (2R)-2-({(2S,3R,4R,5S,6R)-3-(acetylamino)-2-(benzyloxy)-6-[(benzyloxy)methyl]-5-hydroxytetrahydro-2H-pyran-4-yl}oxy)propanoate	C₃₂H₃₇NO₈	详情	详情
(LIII)	56370	(2R,3S,4R,5R,6R)-3-(acetyloxy)-2-[(acetyloxy)methyl]-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-(methylsulfanyl)tetrahydro-2H-pyran-4-yl acetate	C₂₁H₂₃NO₉S	详情	详情
(LIV)	56371	benzyl (2R)-2-[((2S,3R,4R,5S,6R)-3-(acetylamino)-2-(benzyloxy)-6-[(benzyloxy)methyl]-5-{[(2R,3R,4R,5R,6R)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)tetrahydro-2H-pyran-2-yl]oxy}tetrahydro-2H-pyran-4-yl)oxy]propanoate	C₅₂H₅₆N₂O₁₇	详情	详情
(LV)	56372	benzyl (2R)-2-({(2S,3R,4R,5S,6R)-3-(acetylamino)-5-{[(2S,3R,4R,5S,6R)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2-(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoate	C₃₈H₄₈N₂O₁₂	详情	详情
(LVI)	56373	benzyl (2R)-2-({(2S,3R,4R,5S,6R)-3-(acetylamino)-5-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2-(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoate	C₄₀H₅₀N₂O₁₃	详情	详情

Extended Information