Faropenem daloxate, BAY-56-6854, SUN-A0026, SUN-208, -Drug Synthesis Database

【结构式】

【药物名称】Faropenem daloxate, BAY-56-6854, SUN-A0026, SUN-208

【化学名称】(5R,6S)-6-[1(R)-Hydroxyethyl]-2-[2(R)-tetrahydrofuryl]-2-penem-3-carboxylic acid 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl ester

【CA登记号】141702-36-5

【分子式】C₁₇H₁₉NO₈S

【分子量】397.40688

【开发单位】Daiichi Suntory Pharma (Originator), Bayer (Licensee), Replidyne (Licensee)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, Penems

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

Treatment of the silylated azetidinone (I) with tritylmercaptan affords the tritylsulfanylazetidinone (II), which by reaction with AgNO3 is converted into the silver salt (III). Compound (III) is coupled with tetrahydrofuran-2(R)-carbonyl chloride (IV) obtained by treatment of carboxylic acid (V) with thionyl chloride to provide the azetidinone thioester (VI). Alternatively, compound (VI) can be obtained by condensation of tetrahydrofuran-2(R)-thiocarboxylic S-acid (VII) obtained by treatment of carboxylic acid (V) with hydrogen sulfide with silylated azetidinones (I) or (VIII) by means of NaOH in THF/water. Condensation of azetidinone thioester (VI) with allyl glyoxylate (IX) in refluxing benzene gives the hydroxy ester (X), which is treated with SOCl2 to yield the chloro ester (XI). Reaction of compound (XI) with triphenylphosphine and lutidine in hot THF provides the phosphoranylidene derivative (XII), which is converted into (5R,6S)-6-[1(R)-hydroxyethyl]-2-[2(R)-tetrahydrofuryl]penem-3-carboxylic acid allyl ester, faropenem allyl ester (XIII) by removal of the silyl protecting group with tetrabutylammonium fluoride, followed by cyclization in refluxing toluene. Compound (XII) can also be obtained by condensation of the silver salt of protected azetidinone (XIV) with tetrahydrofuran-2(R)-carbonyl chloride (V).

参考文献中间体

【1】 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.
【2】 Rabasseda, X.; Sorbera, L.A.; del Fresno, M.; Castaner, J.; Faropenem daloxate. Drugs Fut 2002, 27, 3, 223.
【3】 Ishiguro, M.; Iwata, H.; Nakatsuka, T. (Suntory Ltd.); Penem cpds. AU 8654460; EP 0199446; JP 1994128267; US 4997829 .

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)	11687	(2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate		C₁₃H₂₅NO₄Si	详情	详情
(II)	52161	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(tritylsulfanyl)-2-azetidinone		C₃₀H₃₇NO₂SSi	详情	详情
(III)	52162			C₁₁H₂₂AgNO₂SSi	详情	详情
(IV)	11696	(2R)Tetrahydro-2-furancarbonyl chloride		C₅H₇ClO₂	详情	详情
(V)	52163	(2R)-Tetrahydro-2-furancarboxylic acid; (2R)-2-Tetrahydrofuroic acid	87392-05-0	C₅H₈O₃	详情	详情
(VI)	11689	S-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl] (2R)tetrahydro-2-furancarbothioate		C₁₆H₂₉NO₄SSi	详情	详情
(VII)	11688	(2R)Tetrahydro-2-furancarbothioic S-acid		C₅H₈O₂S	详情	详情
(VIII)	52164	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(phenylsulfonyl)-2-azetidinone		C₁₇H₂₇NO₄SSi	详情	详情
(IX)	30139	allyl 2-oxoacetate		C₅H₆O₃	详情	详情
(X)	11690	allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetanyl)-2-hydroxyacetate		C₂₁H₃₅NO₇SSi	详情	详情
(XI)	11691	allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetanyl)-2-chloroacetate		C₂₁H₃₄ClNO₆SSi	详情	详情
(XII)	52165	allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetidinyl)-2-(triphenylphosphoranylidene)acetate		C₃₉H₄₈NO₆PSSi	详情	详情
(XIII)	11694	allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₁₅H₁₉NO₅S	详情	详情
(XIV)	52166			C₃₄H₄₁AgNO₄PSSi	详情	详情

合成路线2

Alternatively, faropenem allyl ester (XIII) can also be prepared by cyclization of compound (XII) in refluxing benzene to yield silylated penem allyl ester (XV), which is then deprotected with either tetrabutylammonium fluoride in AcOH or triethylamine tris(hydrogen fluoride) in methyl isobutyl ketone or toluene. Penem (XV) can also be synthesized by several related ways: a) By coupling of azetidinone (VI) with allyl oxalyl chloride (XVI) in CH2Cl2 by means of Et3N, followed by intramolecular Wittig cyclization by means of triethyl phosphite in refluxing xylene. b) Substitution of phenyl sulfonyl group of azetidinone (VIII) by tritylmercaptan by means of NaOH in acetone/water provides tritylsulfanyl-azetidinone (II), which is condensed with allyl oxalyl chloride (XVI) by means of DIEA in CH2Cl2 to give the oxalyl amide (XVII). Compound (XVII) is then treated with AgNO3 and pyridine in acetonitrile to provide the silver mercaptide (XVIII), which is acylated with tetrahydrofuran-2(R)-carbonyl chloride (IV) in acetonitrile to afford the penem precursor (XIX). Finally, compound (XV) is obtained by intramolecular Wittig cyclization of (XX) with P(OEt)3 in refluxing xylene.

参考文献中间体

【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.
【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.
【3】 Rabasseda, X.; Sorbera, L.A.; del Fresno, M.; Castaner, J.; Faropenem daloxate. Drugs Fut 2002, 27, 3, 223.
【4】 Ishiguro, M.; Iwata, H.; Nakatsuka, T. (Suntory Ltd.); Penem cpds. AU 8654460; EP 0199446; JP 1994128267; US 4997829 .
【5】 Ishiguro, M.; Iwata, H.; Nakatsuka, T.; Nakajima, M.; Yamada, Y.; Doi, J.; Fujimaru, M. (Suntory Ltd.); Processes for removing allyl groups. EP 0410727 .
【6】 Ishiguro, M.; Kanebo, A.; Kaku, T.; Nakatsuka, T. (Nippon Soda Co., Ltd.; Suntory Ltd.); Method of desilylating silylether cpds.. EP 0612749 .

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)	52161	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(tritylsulfanyl)-2-azetidinone		C₃₀H₃₇NO₂SSi	详情	详情
(V)	52163	(2R)-Tetrahydro-2-furancarboxylic acid; (2R)-2-Tetrahydrofuroic acid	87392-05-0	C₅H₈O₃	详情	详情
(VI)	11689	S-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl] (2R)tetrahydro-2-furancarbothioate		C₁₆H₂₉NO₄SSi	详情	详情
(VIII)	52164	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-(phenylsulfonyl)-2-azetidinone		C₁₇H₂₇NO₄SSi	详情	详情
(XII)	52165	allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetidinyl)-2-(triphenylphosphoranylidene)acetate		C₃₉H₄₈NO₆PSSi	详情	详情
(XIII)	11694	allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₁₅H₁₉NO₅S	详情	详情
(XV)	11697	allyl (5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-7-oxo-3-[(2R)tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₁H₃₃NO₅SSi	详情	详情
(XVI)	15585	allyl 2-chloro-2-oxoacetate		C₅H₅ClO₃	详情	详情
(XVII)	52169	allyl 2-[(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-(tritylsulfanyl)azetidinyl]-2-oxoacetate		C₃₅H₄₁NO₅SSi	详情	详情
(XVIII)	52168			C₁₆H₂₆AgNO₅SSi	详情	详情
(XIX)	52167	allyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetidinyl)-2-oxoacetate		C₂₁H₃₃NO₇SSi	详情	详情

合成路线3

Hydrolysis of faropenem allyl ester (XIII) to faropenem sodium (XX) 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; and iv) palladium acetate in the presence of P(OBu)3 and sodium propionate in THF. Finally, faropenem daloxate can be directly obtained from faropenem sodium (XX) by esterification with 4-(iodomethyl)-5-methyl-1,3-dioxol-2-one (XXI) in DMF.

参考文献中间体

【1】 Rabasseda, X.; Sorbera, L.A.; del Fresno, M.; Castaner, J.; Faropenem daloxate. Drugs Fut 2002, 27, 3, 223.
【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.
【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.
【4】 Ishiguro, M.; Iwata, H.; Nakatsuka, T. (Suntory Ltd.); Penem cpds. AU 8654460; EP 0199446; JP 1994128267; US 4997829 .
【5】 Ishiguro, M.; Yamada, Y.; Kimura, Y.; Imai, K. (Nippon Soda Co., Ltd.; Suntory Ltd.); Methods for removing allyl groups. JP 1992041489 .
【6】 Iwata, H.; Nakatsuka, T.; Tanaka, R.; Ishiguro, M. (Suntory Ltd.); Antibacterial penem esters derivs.. EP 0544907; EP 0757050; JP 1994500769; JP 2000302786; US 5885981; WO 9203442 .
【7】 Ishiguro, M.; Iwata, H.; Nakatsuka, T.; Nakajima, M.; Yamada, Y.; Doi, J.; Fujimaru, M. (Suntory Ltd.); Processes for removing allyl groups. EP 0410727 .
【8】 Matsunaga, K.; Shimanuki, K. (Nippon Soda Co., Ltd.; Suntory Ltd.); Removal method of allyl group. JP 1994321952 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	11694	allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₁₅H₁₉NO₅S	详情	详情
(XX)	52170	sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₁₂H₁₄NNaO₅S	详情	详情
(XXI)	52171	4-(iodomethyl)-5-methyl-1,3-dioxol-2-one	C₅H₅IO₃	详情	详情

合成路线4

Treatment of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (XXII) with potassium formate (XXIII) by means of KI and NaHCO3 in DMF affords the formyloxymethyl derivative (XXIV), which is converted into the hydroxymethyl derivative (XXV) by refluxing in MeOH. Coupling of compound (XXV) with oxalyl chloride (XXVI) in dichloromethane furnishes compound (XXVII), which is then condensed with protected azetidinone (VI) by means of Et3N in dichloromethane to yield compound (XXVIII). Intramolecular Wittig cyclization of compound (XXVIII) by means of triethyl phosphite in refluxing xylene provides the silylated faropenem daloxate (XXIX), which is finally deprotected by means of either Et3N tris(hydrogen fluoride) in ethyl acetate or tetrabutylammonium fluoride (TBAF) and AcOH in THF.

参考文献中间体

【1】 Rabasseda, X.; Sorbera, L.A.; del Fresno, M.; Castaner, J.; Faropenem daloxate. Drugs Fut 2002, 27, 3, 223.
【2】 Ishiguro, M.; Kanebo, A.; Kaku, T.; Nakatsuka, T. (Nippon Soda Co., Ltd.; Suntory Ltd.); Method of desilylating silylether cpds.. EP 0612749 .
【3】 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 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	11689	S-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl] (2R)tetrahydro-2-furancarbothioate		C₁₆H₂₉NO₄SSi	详情	详情
(XXII)	16911	4-(chloromethyl)-5-methyl-1,3-dioxol-2-one		C₅H₅ClO₃	详情	详情
(XXIII)	52172	Potassium formate; Formic acid potassium salt	590-29-4	CHKO₂	详情	详情
(XXIV)	50467	(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl formate		C₆H₆O₅	详情	详情
(XXV)	50468	4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one		C₅H₆O₄	详情	详情
(XXVI)	29841	Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride	79-37-8	C₂Cl₂O₂	详情	详情
(XXVII)	52173	2-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy]-2-oxoacetyl chloride		C₇H₅ClO₆	详情	详情
(XXVIII)	52174	(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-((3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-oxo-4-[[(2R)tetrahydro-2-furanylcarbonyl]sulfanyl]azetidinyl)-2-oxoacetate		C₂₃H₃₃NO₁₀SSi	详情	详情
(XXIX)	52175	(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (5R,6S)-6-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-7-oxo-3-[(2R)tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₃H₃₃NO₈SSi	详情	详情

Extended Information