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Name Biapenem;CL-186815;L-627;LJC-10627;Omegacin
Chemical Name (1R,5S,6S)-2-[(6,7-Dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolio-6-yl)thio]-6-[(R)-1-hydroxyethyl]-1-methylcarbapenem-3-carboxylate
CAS 120410-24-4
Related CAS
Formula C15H18N4O4S
Structure
Formula Weight 350.39911
Stage 上市-2002
Company Wyeth Pharmaceuticals (Originator)
Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY, Treatment of Septic Shock, Carbapenems
Syn. Route 3
Route 1
reaction of 3-(benzyloxy)propionic acid (i) with 4(r)-isopropyl-1,3-thiazolidine-2-thione (ii) in the presence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and dmap gives 3-[3-(benzyloxy)propanoyl]-4(r)-isopropyl-1,3-thiazolidine-2-thione (iii), which by treatment with tin(ii) trifluoromethanesulfonate and excess acetaldehyde affords 3-[(2s,3r)-2-(benzyloxymethyl)-3-hydroxybutanoyl]-4(r)-isopropyl-1,3-thiazolidine-2-thione (iv). protection of the hydroxy group of (iv) with tert-butyldimethylsilyl chloride in the presence of imidazole yields 3-[(2s,3r)-2-(benzyloxymethyl)-3-(tert-butyldimethylsilyloxy)butanoyl]-4(r)-isopropyl-1,3-thiazolidine-2-thione (v), which is treated with p-anisidine to afford (2s,3r)-2-(benzyloxymethyl)-3-(tert-butyldimethylsilyloxy)-n-(4-methoxyphenyl)butylamide (vi). deprotection of (vi) by hydrogenation with pd/c in methanol-acetic acid gives (2s,3r)-3-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)-n-(4-methoxyphenyl)butylamide (vii), which is mesylated with methanesulfonyl chloride in the presence of triethylamine to yield (2s,3r)-3-(tert-butyldimethylsilyloxy)-2-[(methanesulfonyloxy)methyl]-n-(4-methoxyphenyl)butylamide (viii). cyclization of (viii) with sodium hydride in ch2cl2-dmf affords 3(s)-[1(r)-(tert-butyldimethylsilyloxy)ethyl]-1-(4-methoxyphenyl) azetidin-2-one (ix), the nitrogen atom of which is deprotected with cerium ammonium nitrate (can) in a mixture of acetonitrile-water to yield 3(s)-[1(r)-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (x). compound (x) is stereoselectively converted to (3s,4r)-3-[1(r)-(tert-butyldimethylsilyloxy)ethyl]-4-acetoxyazetidin-2-one (xi) on treatment with peracetic acid and ruthenium(iii) chloride. compound (xi) and 4(s)-ethyl-3-propionyl-1,3-thiazolidine-2-thione (xii) give, on treatment with tin(ii) trifluoromethanesulfonate, (3s,4r)-3-[1(r)-(tert-butyldimethysilyloxy)methyl]-4-[1(r)-[4(s)-ethyl-2-thioxo-1,3-thiazolidin-3-ylcarbonyl]ethyl]azetidin-2-one (xiii) as the major diastereoisomer. reaction of (xiii) with imidazole in acetonitrile gives (3s,4r)-3-[1(r)-(tert-butyldimethylsilyloxy)ethyl]-4-[1(r)-(imidazol-1-ylcarbonyl)ethyl]azetidin-2-one (xiv), which is treated with mg(o2ch2co2pnb)2 in acetonitrile to yield (3s,4r)-3-[1(r)-(tert-butyldimethylsilyloxy)ethyl]-4-[1(r)-methyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one (xv). compound (xv) is deprotected with hydrochloric acid in methanol to give (3s,4r)-3-[1(r)-hydroxyethyl]-4-[1(r)-methyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]azetidin-2-one (xvi), which on diazotization with dodecylbenzenesulfonyl azide in acetonitrile yields (3s,4r)-4-[3-diazo-1(r)-methyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-3-[1(r)-hydroxyethyl]azetidin-2-one (xvii). treatment of compound (xvii) with rhodium(ii) octanoate in ethylacetate gives p-nitrobenzyl (1r,5r,6s)-6-[1(r)-hydroxyethyl]-1-methyl-2-oxocarbapenam-3-carboxylate (xviii), which is reacted with diphenylchlorophosphate and diisopropylethylamine to afford p-nitrobenzyl (1r,5r,6s)-2-[(diphenylphosphono)oxy]-6-[1(r)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (xix).
List of intermediates No.
triphenyl(3,4,5-trimethoxybenzyl)phosphonium (xi)
tert-butyl 4-[(4r,7s,10s,13r,16s,19r)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-(4-hydroxybenzyl)-7-[(1r)-1-hydroxyethyl]-4-([[(1r,2r)-2-hydroxy-1-(hydroxymethyl)propyl]amino]carbonyl)-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5, (i)
2-[4-[2-[((1r)-2-[[(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-16-(4-hydroxybenzyl)-7-[(1r)-1-hydroxyethyl]-4-([[(1r,2r)-2-hydroxy-1-(hydroxymethyl)propyl]amino]carbonyl)-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazac (ii)
n-[(1s,15s,18s,24s,27r,29s,34s,37r)-29-benzyl-21-[(z)ethylidene]-5,6,27-trihydroxy-34-isopropyl-31,37-dimethyl-10,16,19,22,30,32,35,38-octaoxo-36-oxa-9,11,17,20,23,28,31,33-octaazatetracyclo[16.13.6.1(24,28).0(3,8)]octatriaconta-3,5,7-trien-15-yl]-2 (iii)
2-tridecyn-1-ol (iv)
4-bromobenzyl 2-tridecynyl ether (v)
ethyl 3-iodopropanoate (vi)
(3-ethoxy-3-oxopropyl)(iodo)zinc (vii)
ethyl 3-[4-[(2-tridecynyloxy)methyl]phenyl]propanoate (viii)
2-hydroxy-4-(4-methoxyphenyl)-3-oxo-2(e)-butenoic acid ethyl ester lithium salt (ix)
ethyl 1,5-bis(4-methoxyphenyl)-1h-pyrazole-3-carboxylate (x)
[1,5-bis(4-methoxyphenyl)-1h-pyrazol-3-yl][4-chloro-3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]methanone (xii)
5-[[1,5-bis(4-methoxyphenyl)-1h-pyrazol-3-yl]carbonyl]-2-chlorobenzoic acid (xiii)
5-[[1,5-bis(4-methoxyphenyl)-1h-pyrazol-3-yl]carbonyl]-2-chlorobenzamide (xiv)
(3s,4s)-1-benzyl-4-(trifluoromethyl)-3-pyrrolidinecarboxamide (xix)
diethyl 2-(3,4,5-trimethoxybenzylidene)malonate (xvi)
iodomethyl acetate (xv)
2-bromo-5-methoxybenzoyl chloride (xviii)
benzyl (2r,3s)-3-hydroxy-2-[3-(phenylsulfanyl)propyl]-1-piperidinecarboxylate (xvii)
Reference 1:
    kumagai, t.; matsunaga, h.; machida, y.; nagase, y.; hikida, m.; nagao, y. (lederle (japan), ltd.); (1r,5s,6s)-2-(substd. thio)-6-[(r)-1-hydroxy-ethyl]-1-methyl-carbapenem-3-carboxylic-acid derivatives. au 8814428; ep 0289801; jp 1989025779; us 4925836 .
Reference 2:
    abe, t.; matsunaga, h.; kumagai, t.; nagase, y. (lederle (japan), ltd.); method of preparation of carbapenem cpds. jp 1990088578 .
Reference 3:
    rabasseda, x.; prous, j.; castaner, j.; biapenem. drugs fut 1994, 19, 7, 631.
Reference 4:
    hayashi, t.; shimada, o.; inoue, y.; nagao, y.; matsunaga, h.; nagase, y.; kumagai, t.; abe, t.; beta-lactams. 3. asymmetric total synthesis of new non-natural 1beta-methylcarbapenems exhibiting strong antimicrobial activities and stability against human renal dehydropeptidase-. j org chem 1992, 57, 15, 4243-9.

Route 2
compound (xix) reacts with 4-mercapto-n,n-bis(p-nitrobenzyloxycarbonyl)pyrazolidine (xx) in the presence of diisopropylethylamine to give p-nitrobenzyl (1r,5r,6s)-2-[[n,n-bis(p-nitrobenzyloxycarbonyl)pyrazolidin-4-yl]thio]-6-[1(r)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (xxiii).compound (xxiii) is reduced with h2 over pd/c to give (1r,5r,6s)-2-[[n,n-bis(p-nitrobenzyloxycarbonyl)pyrazolidin-4-yl]thio]-6-[1(r)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (xxiv), which is finally reacted with ethylformimidate hydrochloride (xxv).compound (xx) is obtained from epichlorohydrin (xxi) by treatment with hydrazine monohydrate followed by reaction with p-nitrobenzyloxycarbonyl chloride to give 4-hydroxy-n,n-bis(p-nitrobenzyloxycarbonyl)pyrazolidine (xxii), which is subsequently treated with methanesulfonyl chloride and triethylamine in dichloromethane, potassium acetate in acetone and sodium methoxide in methanol-thf. compound (xx) can also be obtained from hydrazine hydrate using a longer alternative procedure.
List of intermediates No.
(6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (xxi)
1,5-bis(4-methoxyphenyl)-1h-pyrazole-3-carbaldehyde (xx)
5-[[1,5-bis(4-methoxyphenyl)-1h-pyrazol-3-yl](hydroxy)methyl]-2-chlorobenzoic acid (xxii)
methyl 5-[[1,5-bis(4-methoxyphenyl)-1h-pyrazol-3-yl](hydroxy)methyl]-2-chlorobenzoate (xxiii)
(1r,3as,5ar,5br,9s,11ar)-3a-(hydroxymethyl)-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-1h-cyclopenta[a]chrysen-9-ol (xxiv)
4,4-dimethyldihydro-2h-pyran-2,6(3h)-dione (xxv)
(3s,4s)-1-benzyl-4-(trifluoromethyl)-3-pyrrolidinecarboxamide (xix)
Reference 1:
    kumagai, t.; matsunaga, h.; machida, y.; nagase, y.; hikida, m.; nagao, y. (lederle (japan), ltd.); (1r,5s,6s)-2-(substd. thio)-6-[(r)-1-hydroxy-ethyl]-1-methyl-carbapenem-3-carboxylic-acid derivatives. au 8814428; ep 0289801; jp 1989025779; us 4925836 .
Reference 2:
    abe, t.; matsunaga, h.; kumagai, t.; nagase, y. (lederle (japan), ltd.); method of preparation of carbapenem cpds. jp 1990088578 .
Reference 3:
    hayashi, t.; shimada, o.; inoue, y.; nagao, y.; matsunaga, h.; nagase, y.; kumagai, t.; abe, t.; beta-lactams. 3. asymmetric total synthesis of new non-natural 1beta-methylcarbapenems exhibiting strong antimicrobial activities and stability against human renal dehydropeptidase-. j org chem 1992, 57, 15, 4243-9.
Reference 4:
    rabasseda, x.; prous, j.; castaner, j.; biapenem. drugs fut 1994, 19, 7, 631.

Route 3
2) the acylation of hydrazine (i) with di-tert-butyl dicarbonate (ii) gives 1,2-di(tert-butyloxycarbonyl)hydrazine (iii), which is cyclized with 1,3-dibromo-2-(tert-butyldimethylsilyloxy)propane (iv) by means of nah in dmf yielding the pyrazolidine (v). the desilylation of (v) with tetrabutylammonium fluoride in thf affords 1,2-di(tert-butoxycarbonyl)-4-hydroxypyrazolidine (vi). acylation of (vi) with methanesulfonyl chloride in dichloromethane gives the corresponding mesylate (vii), which is condensed with 4-methoxybenzyl mercaptane (viii) by means of butyllithium in hexane to yield the benzyl ether (ix). the cyclization of (ix) with methyl formimidate hydrochloride in methanol-water affords 6-(4-methoxybenzylthio)-6,7-dihydro-5h-pyrazolo[1,2-a][1,2,4]triazolium chloride (x), which is deprotected with trifluoroacetic acid giving 6-mercapto-6,7-dihydro-5h-pyrazolo[1,2-a][1,2,4]triazolium chloride (xi). finally, this compound is condensed with (1r,5r,6s)-2-(diphenylphosphonooxy)-6-[1(r)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester (xii) by means of diisopropylethylamine in dmf followed by hydrogenolysis with h2 over pd/c in butanol-etoac-potassium phosphate buffer.
List of intermediates No.
ethyl 3-(1,3-benzodioxol-5-yl)-2-bromopropanoate (ii)
ethyl 3-(1,3-benzodioxol-5-yl)-2-[(2-chloro-1-methyl-2-oxoethyl)sulfanyl]propanoate (iii)
2-[[1-(1,3-benzodioxol-5-ylmethyl)-2-ethoxy-2-oxoethyl]sulfanyl]propionic acid (iv)
ethyl (6r,8s)-8-methyl-9-oxo-5,6,8,9-tetrahydrothiepino[4,5-f][1,3]benzodioxole-6-carboxylate (v)
methyl (2r)-2-hydroxy-2-phenylethanoate (vi)
ethyl (e)-4,4,4-trifluoro-2-butenoate (vii)
n-benzyl-n-(methoxymethyl)-n-[(trimethylsilyl)methyl]amine; n-benzyl-n-(methoxymethyl)(trimethylsilyl)methanamine (viii)
methyl (3s,4s)-1-benzyl-4-(trifluoromethyl)-3-pyrrolidinecarboxylate (ix)
(3s,4s)-1-benzyl-4-(trifluoromethyl)-3-pyrrolidinecarboxylic acid (x)
(3s,4s)-1-benzyl-4-(trifluoromethyl)-3-pyrrolidinecarbonyl chloride (xi)
(3s,4s)-1-benzyl-4-(trifluoromethyl)-3-pyrrolidinecarboxamide (xii)
Reference 1:
    ratcliffe, r.w.; wildonger, k.j.; heteroaryliumthio substituted carbapenem derivatives: synthesis and in vitro activity of 1beta-methyl-2-(dihydropyrrolotriazoliumthio)carbapenems. j antibiot 1993, 46, 12, 1866-82.
Reference 2:
    rabasseda, x.; prous, j.; castaner, j.; biapenem. drugs fut 1994, 19, 7, 631.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名比阿培南;英文名Biapenem;CL-186815;L-627;LJC-10627;Omegacin;CAS[120410-24-4]

 
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