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药物详细合成路线

Name Ezetimibe;SCH-58235;Ezetrol;Zetia
Chemical Name 1-(4-Fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl]-4(S)-(4-hydroxyphenyl)azetidin-2-one
CAS 163222-33-1
Related CAS 163380-16-3 ([3R-[3alpha(R*), 4beta]]-isomer)
Formula C24H21F2NO3
Structure
Formula Weight 409.43667
Stage 上市-2002
Company Essex (Originator), Schering-Plough (Originator), Merck & Co. (Licensee)
Activity/Mechanism ENDOCRINE DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Therapy of Inborn Errors of Metabolism, Treatment of Diabetic Complications, Cholesterol Absorption Inhibitors
Syn. Route 9
Route 1
treatment of acid chloride (i) with tributylamine generated the corresponding ketene, which was cyclocondensed to imine (ii) to produce the racemic trans b-lactam (iii). resolution of (iii) into enantiomers was then achieved by preparative hplc on a chiralcel od column. subsequent saponification of the desired enantiomer with methanolic lioh afforded acid (iv), which was converted to acid chloride (v) upon treatment with oxalyl chloride. further pd-mediated coupling of (v) with the arylzinc reagent (vi) provided ketone (vii). then, carbonyl reduction with bh3-me2s, followed by chromatographic separation of the isomers furnished alcohol (viii), which was finally deprotected by hydrogenolysis over pd/c to afford the target phenol.
List of intermediates No.
(4r,5s,6s)-6-[(1r)-1-hydroxyethyl]-4-methyl-3-[[(2r,3r)-2-([[(2s)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butanoyl]amino]methyl)tetrahydro-3-furanyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (i)
s-[(2r,3r)-2-(aminomethyl)tetrahydro-3-furanyl] ethanethioate (ii)
(2r,3r)-2-(aminomethyl)tetrahydro-3-furanylhydrosulfide; (2r,3r)-2-(aminomethyl)tetrahydro-3-furanthiol (iii)
4-nitrobenzyl (1s)-2-methyl-1-[([[(2r,3r)-3-sulfanyltetrahydro-2-furanyl]methyl]amino)carbonyl]propylcarbamate (iv)
4-nitrobenzyl (4r,5s,6s)-6-[(1r)-1-hydroxyethyl]-4-methyl-3-[[(2r,3r)-2-([[(2s)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butanoyl]amino]methyl)tetrahydro-3-furanyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (v)
(4s)-4-ethyl-3,11,14-trioxo-3,4,6,11,12,14-hexahydro-1h-pyrano[3,4:6,7]indolizino[1,2-b]quinolin-4-yl acetate (vi)
(4s)-4-ethyl-3,14-dioxo-11-[[(trifluoromethyl)sulfonyl]oxy]-3,4,12,14-tetrahydro-1h-pyrano[3,4:6,7]indolizino[1,2-b]quinolin-4-yl acetate (vii)
(4s)-4-ethyl-11-(methylsulfanyl)-3,14-dioxo-3,4,12,14-tetrahydro-1h-pyrano[3,4:6,7]indolizino[1,2-b]quinolin-4-yl acetate (viii)
Reference 1:
    afonso, a.; davis, h.r. jr.; huynh, t.; yumibe, n.; clader, j.w.; burnett, d.a.; rosenblum, s.b.; discovery of 1-(4-fluorophenyl)-(3r)-[3-(4-fluorophenyl)-(3s)-hydroxypropyl]-(4s)-(4-hydroxyphenyl)-2-azetidinone (sch 58235): a designed, potent, orally active inhibitor of cholesterol absorption. j med chem 1998, 41, 6, 973.

Route 2
1) the cyclization of 4(s)-hydroxytetrahydrofuran-2-one (i) with the benzylideneimine derivative (ii) by means of lda gives the trans-azetidinone (iii), which is separated from its cis-isomer by crystallization. the oxidation of (iii) with naio4 in acetonitrile yields the carbaldehyde (iv), which is condensed with the silylated enol ether (v), prepared from 4-fluoroacetophenone (vi), li and tmscl, to afford compound (vii). the dehydration of (vii) by means of tsoh gives the enone (viii), which is hydrogenated and debenzylated with h2 over pd/c in ethanol, providing the saturated ketone (ix). finally, this compound is enantioselectively reduced with borane and the chiral catalyst (r)-1-methyl-3,3-diphenylperhydropyrrolo[1,2-c][1,3,2]oxaazaborole (cbs).2) alternatively, the reduction of enone (viii) with h2 over rhcl(pph3)3 in dichloromethane gives the benzylated saturated ketone (x), which is enantioselectively reduced with borane and cbs, yielding the benzylated alcohol (xi). finally, this compound is debenzylated with h2 over pd/c in ethanol.
List of intermediates No.
(4s)-4-ethyl-3,14-dioxo-11-[[(trifluoromethyl)sulfonyl]oxy]-3,4,12,14-tetrahydro-1h-pyrano[3,4:6,7]indolizino[1,2-b]quinolin-4-yl acetate (trans-x)
(4s)-4-ethyl-11-(methylsulfanyl)-3,14-dioxo-3,4,12,14-tetrahydro-1h-pyrano[3,4:6,7]indolizino[1,2-b]quinolin-4-yl acetate (xi)
methyl (e)-2-hexadecenoate (i)
methyl (3r)-3-[benzyl[(1r)-1-phenylethyl]amino]hexadecanoate (trans-iii)
methyl (3r)-3-aminohexadecanoate (trans-iv)
(2s)-2-[[(benzyloxy)carbonyl]amino]-5-[(tert-butoxycarbonyl)amino]pentanoic acid (vi)
methyl (3r)-3-([(2s)-2-[[(benzyloxy)carbonyl]amino]-5-[(tert-butoxycarbonyl)amino]pentanoyl]amino)hexadecanoate (v)
tert-butyl (4s)-5-([(1r)-1-[2-(1h-1,2,3-benzotriazol-1-yloxy)-2-oxoethyl]tetradecyl]amino)-4-[[(benzyloxy)carbonyl]amino]-5-oxopentylcarbamate (trans-viii)
(3r)-3-[(2r,6s,9s,12r,15r,19r,22s,25r,31s,33as,34s,39s,42r,44as)-22-(3-aminopropyl)-2,34-dihydroxy-9-(4-hydroxybenzyl)-15,25,39,42-tetrakis[(1r)-1-hydroxyethyl]-6-isopropyl-12-methyl-5,8,11,14,17,21,24,27,30,33,38,41,44-tridecaoxo-19-tridecylnonatriacontahydro-1h,5h,21h-dipyrrolo[2,1-o:2,1-x][1,4,7,10,13,16,19,22,25,28,31,34,37]oxadodecaazacyclotetracontin-31-yl]-3-hydroxypropanamide (trans-vii)
(2r,3r)-2-[(2-[[(2s,3r)-5-amino-2-([[(2s,3s)-1-((2s,3r)-2-[[(2r,3r)-2-([[(2s,4r)-1-((2s)-2-[[(2s)-2-[((2r)-2-[[(2r,3r)-2-amino-3-hydroxybutanoyl]amino]propanoyl)amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoyl)-4-hydroxypyrrolidinyl]carbonyl]amino)-3-hydroxybutanoyl]amino]-3-hydroxybutanoyl)-3-hydroxypyrrolidinyl]carbonyl]amino)-3-hydroxy-5-oxopentanoyl]amino]acetyl)amino]-3-hydroxybutyric acid (trans-ix)
(ii)
Reference 1:
    wu, g.-z.; chen, x.; wong, y.-s.; schumacher, d.p.; steinman, m.; 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones. us 5886171 .
Reference 2:
    casta?er, r.m.; sorbera, l.a.; casta?er, j.; ezetimibe. drugs fut 2000, 25, 7, 679.
Reference 3:
    wu, g.z.; chen, x.; ding, z.; wong, y.s.; a novel one-step diastereo- and enantioselective formation of trans-azetidinones and its application to the total synthesis of cholesterol absorption inhibitors. j org chem 1999, 64, 10, 3714.
Reference 4:
    steinman, m.; schumacher, d.p.; chen, x.; wu, g.-z.; wong, y.-s. (schering corp.); 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones. wo 9745406 .

Route 3
3) the reaction of 4-hydroxybenzaldehyde (xii) with benzyl bromide and k2co3 in acetone gives 4-(benzyloxy)benzaldehyde (xiii), which is condensed with 4-fluoroaniline (xiv) in isopropanol, yielding the imine (ii). cyclization of (ii) with methyl 4-(chloroformyl)butyrate (xv) by means of tributylamine in toluene affords the trans-azetidinone (xvi), which is hydrolyzed with lioh in thf/water to provide the propionic acid derivative (xvii). the reaction of (xvii) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (xviii), which is condensed with 4-fluorophenylmagnesium bromide (xix) by means of zncl2 and pd(pph3)4 in thf to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral hplc to the trans-(3r,4s)-enantiomer (xx). the enantioselective reduction of (xx) with bh3 and the chiral oxaborole catalyst cbs gives the benzylated alcohol (xi), which is finally debenzylated as before with h2 over pd/c in ethanol.
List of intermediates No.
n,n-dihexyl-4-(phenoxyimino)-4-phenylbutanamide (xii)
2-[(e)-(dimethylamino)methylidene]-1-(3-methoxyphenyl)-1,3-butanedione (xix)
(4r,5s,6s)-6-[(1r)-1-hydroxyethyl]-4-methyl-3-[[(2r,3r)-2-([[(2s)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butanoyl]amino]methyl)tetrahydro-3-furanyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (xv)
(2r,3r)-2-(aminomethyl)tetrahydro-3-furanylhydrosulfide; (2r,3r)-2-(aminomethyl)tetrahydro-3-furanthiol (trans-xvi)
4-nitrobenzyl (1s)-2-methyl-1-[([[(2r,3r)-3-sulfanyltetrahydro-2-furanyl]methyl]amino)carbonyl]propylcarbamate (trans-xvii)
4-nitrobenzyl (4r,5s,6s)-6-[(1r)-1-hydroxyethyl]-4-methyl-3-[[(2r,3r)-2-([[(2s)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butanoyl]amino]methyl)tetrahydro-3-furanyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (trans-xviii)
(4s)-4-ethyl-3,14-dioxo-11-[[(trifluoromethyl)sulfonyl]oxy]-3,4,12,14-tetrahydro-1h-pyrano[3,4:6,7]indolizino[1,2-b]quinolin-4-yl acetate (xx)
(4s)-4-ethyl-11-(methylsulfanyl)-3,14-dioxo-3,4,12,14-tetrahydro-1h-pyrano[3,4:6,7]indolizino[1,2-b]quinolin-4-yl acetate (xi)
(3s,4r)-4-(4-chlorophenyl)-1-methyl-3-piperidinecarboxylic acid (xiii)
(ii)
1-(2-nitrophenyl)hydrazine (xiv)
Reference 1:
    vaccaro, w.d.; sher, r.; davis, h.r. jr.; 2-azetidinone cholesterol absorption inhibitors: increased potency by substitution of the c-4 phenyl ring. bioorg med chem 1998, 6, 9, 1429.
Reference 2:
    rosenblum, s.b.; dugar, s.; burnett, d.a.; clader, j.w.; mckittrick, b.a. (schering corp.); hydroxy-substd. azetidinone cpds. useful as hypocholesterolemic agents. ep 0720599; jp 1996509989; us 5631365; wo 9508532 .
Reference 3:
    casta?er, r.m.; sorbera, l.a.; casta?er, j.; ezetimibe. drugs fut 2000, 25, 7, 679.

Route 4
4) the reaction of methyl 4-(chloroformyl)butyrate (xv) with the chiral oxazolidinone (xxi) by means of dmap and tea in dichloromethane gives the acylated oxazolidinone (xxii), which is cyclized with the benzylideneimine (ii) by means of ticl4, titanium isopropoxide and tbaf in dichloromethane, yielding trans-(3r,4s)-azetidinone (xxiii). this chiral compound (xxiii) is worked up to give ezetimibe by the same reaction sequence used for its racemic analogue (xvi) but without optical resolution.5) racemic trans-azetidinone (xvi) can be submitted to chiral chromatography (chiracel od column), microbial or enzymatic subtractive resolution to provide the trans-(3r,4s)-azetidinone (xxiii) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3r,4s)-azetidinone-propionic acid (xxiv), the compound also obtained by hydrolysis of (xxiii) with lioh. this (3r,4s)-free acid (xxiv) is treated with oxalyl chloride giving the (3r,4s)-acyl chloride (xxv), which by condensation with 4-fluorophenylmagnesium bromide (xix) yields the (3r,4s)-azetidinone (xx). reduction of (xx) with borane-dimethylsulfide complex in thf affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a chiracel od column providing the benzylated (3s)-alcohol (xi).
List of intermediates No.
2-(4-iodophenyl)acetic acid (xxi)
2-[(e)-(dimethylamino)methylidene]-1-(3-methoxyphenyl)-1,3-butanedione (xix)
(4r,5s,6s)-6-[(1r)-1-hydroxyethyl]-4-methyl-3-[[(2r,3r)-2-([[(2s)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butanoyl]amino]methyl)tetrahydro-3-furanyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (xv)
(2r,3r)-2-(aminomethyl)tetrahydro-3-furanylhydrosulfide; (2r,3r)-2-(aminomethyl)tetrahydro-3-furanthiol (trans-xvi)
4-nitrobenzyl (1s)-2-methyl-1-[([[(2r,3r)-3-sulfanyltetrahydro-2-furanyl]methyl]amino)carbonyl]propylcarbamate (xx)
4-nitrobenzyl (4r,5s,6s)-6-[(1r)-1-hydroxyethyl]-4-methyl-3-[[(2r,3r)-2-([[(2s)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butanoyl]amino]methyl)tetrahydro-3-furanyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (xxiv)
(4s)-4-ethyl-3,14-dioxo-11-[[(trifluoromethyl)sulfonyl]oxy]-3,4,12,14-tetrahydro-1h-pyrano[3,4:6,7]indolizino[1,2-b]quinolin-4-yl acetate (xxv)
(4s)-4-ethyl-11-(methylsulfanyl)-3,14-dioxo-3,4,12,14-tetrahydro-1h-pyrano[3,4:6,7]indolizino[1,2-b]quinolin-4-yl acetate (xx)
(xi)
(1s,2r,13r,21r)-22-(cyclopropylmethyl)-9-nitro-14-oxa-11,22-diazaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaene-2,16-diol (ii)
Reference 1:
    afonso, a.; davis, h.r. jr.; huynh, t.; yumibe, n.; clader, j.w.; burnett, d.a.; rosenblum, s.b.; discovery of 1-(4-fluorophenyl)-(3r)-[3-(4-fluorophenyl)-(3s)-hydroxypropyl]-(4s)-(4-hydroxyphenyl)-2-azetidinone (sch 58235): a designed, potent, orally active inhibitor of cholesterol absorption. j med chem 1998, 41, 6, 973.
Reference 2:
    casta?er, r.m.; sorbera, l.a.; casta?er, j.; ezetimibe. drugs fut 2000, 25, 7, 679.
Reference 3:
    homann, m.j.; morgan, w.b. (schering corp.); resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(r)-[(s)-hydroxy-3-(4-fluorophenyl)-propyl]-4(s)-(4-hydroxyphenyl)-2-azetidinone. us 5919672 .

Route 5
6) the reaction of 5-(4-fluorophenyl)-4-pentenoic acid (xxvi) with oxalyl chloride gives the acyl chloride (xxvii), which is condensed with the chiral oxazolidinone (xxi) by means of dmap and diea in dichloromethane, yielding the acyloxazolidinone (xxviii). condensation of (xxviii) with the benzylideneimine (ii) by means of ticl4 affords adduct (xxix), which is cyclized to the chiral azetidinone (xxx). the oxidation of the double bond of (xxx) with benzoquinone and hclo4 catalyzed by pd(oac)2 in acetonitrile/water provides the previously reported trans-(3r,4s)-azetidinone (xx), which is worked up to give azetimibe as described before.
List of intermediates No.
2-(4-iodophenyl)acetic acid (xxi)
(4s)-4-ethyl-3,14-dioxo-11-[[(trifluoromethyl)sulfonyl]oxy]-3,4,12,14-tetrahydro-1h-pyrano[3,4:6,7]indolizino[1,2-b]quinolin-4-yl acetate (xx)
(ii)
(1s,2r,13r,21r)-9-amino-22-(cyclopropylmethyl)-14-oxa-11,22-diazaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaene-2,16-diol (xxvi)
3,4-dimethylbenzoic acid; o-xylene-4-carboxylic acid (xxvii)
3,4-bis(dibromomethyl)benzoic acid (xxviii)
3,4-bis(2-oxoethyl)benzoic acid (xxix)
3,4-di(1,3-dioxolan-2-yl)benzoic acid (xxx)
Reference 1:
    casta?er, r.m.; sorbera, l.a.; casta?er, j.; ezetimibe. drugs fut 2000, 25, 7, 679.
Reference 2:
    shankar, b.b. (schering corp.); process for preparing 1-(4-fluorophenyl)-3(r)-(3(s)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(s)-(4-hydroxyphenyl)-2-azetidinone. us 5856473; wo 9716424 .

Route 6
the 3h-labeling of sch-58235 has been performed by hydrogen/tritium exchange catalyzed by crabtrees catalyst [ir(cod)(cy3p)pyf6] in dichloromethane.
List of intermediates No.
(3s,4as,8as)-n-(tert-butyl)-2-[(2r,3r)-3-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)-2-hydroxy-4-(phenylsulfanyl)butyl]decahydro-3-isoquinolinecarboxamide (i)
Reference 1:
    hesk, d.; et al.; synthesis of 3h, 14c and 13c6 labelled sch 58235. j label compd radiopharm 2002, 45, 2, 145.

Route 7
the enantioselective reduction of the oxazolidinone (i) with bh3/sme2 and a chiral borinated catalyst gives the (s)-alcohol (ii), which is condensed with the labeled imine (iii) (prepared by reaction of 4-fluoroaniline (iv) and 13c-labeled 4-hydroxybenzaldehyde (v)) by means of ticl4 in dichloromethane to yield the silylated adduct (vi) (previously the reactants are silylated with tms-cl and diea). finally, adduct (vi) is resilylated with bis(trimethylsilyl)acetamide and cyclized and desilylated by treatment with tbaf in dichloromethane to afford the target 13c-labeled sch-58235.
List of intermediates No.
n,n-dihexyl-4-(phenoxyimino)-4-phenylbutanamide (v)
4-[4-(4-[[(2s,4r)-2-(2,4-dichlorophenyl)-2-(1h-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl)-1-piperazinyl]aniline (vi)
1-(2-nitrophenyl)hydrazine (iv)
Reference 1:
    hesk, d.; et al.; synthesis of 3h, 14c and 13c6 labelled sch 58235. j label compd radiopharm 2002, 45, 2, 145.

Route 8
the enantioselective reduction of the oxazolidinone (i) with bh3/sme2 and a chiral borinated catalyst gives the (s)-alcohol (ii), which is condensed with the labeled imine (iii) (prepared by reaction of 4-fluoroaniline (iv) and 14c-labeled 4-hydroxybenzaldehyde (v)) by means of ticl4 in dichloromethane to yield the silylated adduct (vi) (previously the reactants are silylated with tms-cl and diea). finally, adduct (vi) is resilylated with bis(trimethylsilyl)acetamide and cyclized and desilylated by treatment with tbaf in dichloromethane to afford the target 14c-labeled sch-58235.
List of intermediates No.
n,n-dihexyl-4-(phenoxyimino)-4-phenylbutanamide (v)
1-(2-nitrophenyl)hydrazine (iv)
Reference 1:
    hesk, d.; et al.; synthesis of 3h, 14c and 13c6 labelled sch 58235. j label compd radiopharm 2002, 45, 2, 145.

Route 9
the activation of 5-(4-fluorophenyl)-5-oxopentanoic acid (i) with pivaloyl chloride (ii) gives the mixed anhydride (iii), which is condensed with the chiral oxazolidinone (iv) by means of dmap to yield the acylated oxazolidine (v) (1). the asymmetric reduction of (v) by means of bh3/me2s catalyzed by the chiral boron catalyst (vi) affords the chiral alcohol (vii) (1-3), which is condensed with the imine (viii) by means of tms-cl, diea and ticl4 to provide the adduct (ix). the cyclization of (ix) by means of bis(trimethylsilyl)acetamide and tbaf gives the protected azetidinone (x), which is finally desilylated by means of sulfuric acid in isopropanol
List of intermediates No.
2-(4-iodophenyl)acetic acid (iv)
3-sulfanyl-1-propanol (ii)
4-nitrobenzyl (4r)-4-[(2r,3s)-3-((1r)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-oxopentanoate (vi)
Reference 1:
    fu, x.y.; et al.; process for preparing ezetimibe intermediate by an acid enhanced chemo- and enantioselective cbs catalyzed ketone reduction. tetrahedron lett 2003, 44, 4, 801.
Reference 2:
    thiruvengadam, t.k.; tann, c.-h.; fu, x.; mcallister, t.l. (schering corp.); enantioselective synthesis of azetidinone intermediate cpds.. us 2002193607; wo 0279174 .

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依泽替米贝;英文名Ezetimibe;SCH-58235;Ezetrol;Zetia;CAS[163222-33-1]

 
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