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Name Furopenem;Faropenem sodium;Fropenem sodium;BLA-857;RU-67655;Wy-49605;YM-044;SY-5555;ALP-201;SUN-5555;Farom
Chemical Name (5R,6S)-6-[1(R)-Hydroxyethyl]-2-[2(R)-tetrahydrofuryl]penem-3-carboxylic acid monosodium salt
      [5R-[3(R*),5alpha,6alpha(R*)]]-6-(1-Hydroxyethyl)-7-oxo-3-(tetrahydro-2-furanyl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt
CAS 122547-49-3
Related CAS 106560-14-9 (free acid)
Formula C12H14NNaO5S
Structure
Formula Weight 307.30288
Stage 上市-1997
Company Daiichi Suntory Pharma (Originator), Bayer (Licensee), Yamanouchi (Comarketer)
Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY, Penems
Syn. Route 2
Route 1
this compound is prepared by several related ways:1) the reaction of silylated azetidinone (i) with tetrahydrofuran-2-thiocarboxylic acid (ii) by means of naoh in thf - water gives the azetidinone thioester (iii), which is condensed with allyl glyoxylate in refluxing benzene yielding the hydroxyester (iv). the reaction of (iv) with socl2 affords the chloroester (v), which by reaction with triphenylphosphine by means of lutidine in hot thf is converted into the phosphoranylidene derivative (vi). the elimination of the silyl protecting group of (vi) with tetrabutylammonium fluoride gives the azetidinone (vii), which is cyclized in refluxing toluene yielding the (5r,6s)-6-[1(r)-hydroxyethyl]-2-[2(r)-tetrahydrofuryl]penem-3-carboxyli c acid allyl ester (viii). finally, this compound is hydrolyzed with triphenylphosphine, sodium 2-ethylhexanoate and pd-tetrakis(triphenylphosphine).2) the condensation of the silver salt of protected azetidinone (ix) with tetrahydrofuran-2(r)-carbonyl chloride (x) also yields the phosphoranylidene salt (vi).3) phosphoranylidene ester (vi) can also be cyclized first in refluxing benzene yielding the silylated penem ester (xi), which is deprotected with tetrabutylammonium fluoride to (viii).4) the hydrolysis of allyl ester (viii) to the final product can also be performed with paladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)-5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethylacetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene, or ethylene glycol dimethyl ether.5) the preceding hydrolysis can also be performed with triphenylphosphine and paladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone.
List of intermediates No.
triphenyl(3,4,5-trimethoxybenzyl)phosphonium (i)
4-(1,4-dioxaspiro[4.5]dec-8-ylidenemethyl)-2,6-dimethoxyphenyl methyl ether; 8-(3,4,5-trimethoxybenzylidene)-1,4-dioxaspiro[4.5]decane (ii)
4-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)-2,6-dimethoxyphenyl methyl ether; 8-(3,4,5-trimethoxybenzyl)-1,4-dioxaspiro[4.5]decane (iii)
4-(3,4,5-trimethoxybenzyl)cyclohexanone (iv)
(2s)-2-[(tert-butoxycarbonyl)amino]-4-phenylbutyric acid (v)
tert-butyl (1s)-1-[[methoxy(methyl)amino]carbonyl]-3-phenylpropylcarbamate (vi)
tert-butyl (1s)-1-formyl-3-phenylpropylcarbamate (vii)
methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane (viii)
chlorophosphoric acid ethyl ester (ix)
diethyl (phenylsulfonyl)methylphosphonate (x)
tert-butyl (1s,2e)-1-phenethyl-3-(phenylsulfonyl)-2-propenylcarbamate (xi)
(1s,3s,4r)-4-(hydroxymethyl)spiro[2.2]pentane-1-carboxylic acid
Reference 1:
    ishiguro, m.; iwata, h.; nakatsuka, t. (suntory ltd.); penem cpds. au 8654460; ep 0199446; jp 1994128267; us 4997829 .
Reference 2:
    ishiguro, m.; iwata, h.; nakatsuka, t.; nakajima, m.; yamada, y.; doi, j.; fujimaru, m. (suntory ltd.); processes for removing allyl groups. ep 0410727 .
Reference 3:
    ishiguro, m.; yamada, y.; kimura, y.; imai, k. (nippon soda co., ltd.; suntory ltd.); methods for removing allyl groups. jp 1992041489 .
Reference 4:
    castaner, j.; mealy, n.; prous, j.; sun-5555. drugs fut 1993, 18, 6, 525.

Route 2
treatment of the silylated azetidinone (i) with tritylmercaptan affords the tritylsulfanyl-azetidinone (ii), which is converted into the silver salt (iii) by reaction with agno3. compound (iii) is coupled with tetrahydrofuran-2(r)-carbonyl chloride (iv) -- obtained by treatment of carboxylic acid (v) with thionyl chloride -- providing the azetidinone thioester (vi). coupling of azetidinone (vi) with allyl oxalyl chloride (vii) in ch2cl2 by means of et3n, followed by intramolecular wittig cyclization by means of triethyl phosphite in refluxing xylene, affords penem (viii).alternatively, compound (viii) can also be obtained as follows: substitution of phenyl sulfonyl group of azetidinone (x) by tritylmercaptan by means of naoh in acetone/water provides tritylsulfanyl-azetidinone (xi), which is condensed with allyl oxalyl chloride (vii) by means of diea in ch2cl2 to give the oxalyl amide (xii). compound (xii) is then treated with agno3 and pyridine in acetonitrile, providing the silver mercaptide (xiii), which is acylated with tetrahydrofuran-2(r)-carbonyl chloride (iv) in acetonitrile to afford the penem precursor (xiv). penem (viii) is obtained by intramolecular wittig cyclization of (xiv) with p(oet)3 in refluxing xylene.finally, faropenem sodium can be obtained by removal of the tbdms protecting group of (viii) by means of either et3n tris(hydrogen fluoride) in ethyl acetate or tetrabutylammonium fluoride (tbaf) and hoac in thf to give compound (ix). this is followed by allyl ester group removal of (ix), which can be performed under several different conditions: i) triphenylphosphine, sodium 2-ethylhexanoate and palladium tetrakis(triphenylphosphine); ii) palladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)-5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethyl acetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene or ethylene glycol dimethyl ether; iii) triphenylphosphine and palladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone; or iv) palladium acetate in the presence of p(obu)3 and sodium propionate in thf.
List of intermediates No.
triphenyl(3,4,5-trimethoxybenzyl)phosphonium (i)
4-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)-2,6-dimethoxyphenyl methyl ether; 8-(3,4,5-trimethoxybenzyl)-1,4-dioxaspiro[4.5]decane (vi)
methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane (ix)
diethyl (phenylsulfonyl)methylphosphonate (iv)
tert-butyl (1s,2e)-1-phenethyl-3-(phenylsulfonyl)-2-propenylcarbamate (viii)
1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-3-(dimethylamino)-1-propanone (vii)
Reference 1:
    nakatsuka, t.; tanaka, r.; noguchi, t.; ishiguro, m.; iwata, h.; nishino, t.; nishihara, t.; maeda, y.; studies on penem antibiotics. i. synthesis and in vitro activity of novel 2-chiral substituted penems. j antibiot 1988, 41, 11, 1685.
Reference 2:
    oyama, y.; imajo, s.; tanaka, r.; matsuki, s.; ishiguro, m.; structure-activity relationships of penem antibiotics: crystallographic structures and implications for their antimicrobial activities. bioorg med chem 1997, 5, 7, 1389.
Reference 3:
    jin, j.; han, h.-n.; liu, j.; synthesis of the key intermediate of faropenem: (3s,4r)-3-[(r)-1-tert-butyldimethylsilyloxyethyl]-4-[(r)-tetrahydrofuranoylthio]-2-azetidinone. j shenyang pharm univ 2001, 18, 1, 20.
Reference 4:
    ishiguro, m.; iwata, h.; nakatsuka, t. (suntory ltd.); penem cpds. au 8654460; ep 0199446; jp 1994128267; us 4997829 .
Reference 5:
    ishiguro, m.; iwata, h.; nakatsuka, t.; nakajima, m.; yamada, y.; doi, j.; fujimaru, m. (suntory ltd.); processes for removing allyl groups. ep 0410727 .
Reference 6:
    ishiguro, m.; yamada, y.; kimura, y.; imai, k. (nippon soda co., ltd.; suntory ltd.); methods for removing allyl groups. jp 1992041489 .
Reference 7:
    matsunaga, k.; shimanuki, k. (nippon soda co., ltd.; suntory ltd.); removal method of allyl group. jp 1994321952 .
Reference 8:
    ishiguro, m.; kanebo, a.; kaku, t.; nakatsuka, t. (nippon soda co., ltd.; suntory ltd.); method of desilylating silylether cpds.. ep 0612749 .
Reference 9:
    fukami, h.; shima, k.; nakatsuka, t.; iwata, h.; yoshida, t.; mizukawa, y.; shibata, m.; sekiuchi, k.; iwanami, t. (suntory ltd.); preparation method of penem derivs.. jp 1994192270 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名法罗培南钠;英文名Furopenem;Faropenem sodium;Fropenem sodium;BLA-857;RU-67655;Wy-49605;YM-044;SY-5555;ALP-201;SUN-5555;Farom;CAS[122547-49-3]

 
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