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Name Diltiazem hydrochloride;CRD-401;MK-793(maleate);SLV-324;Milptin;Teczem(Comb. with enalapril);Tiazac(slow-release);Herbesser;Adizem;Dilzem;Cardizem;Slozem;Cardizem XL;Masdil;Uni-Masdil;Anoheal;Lacerol;Cardizem LA;Tildiem
Chemical Name cis-(+)-3-Acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride
CAS 33286-22-5
Related CAS 42399-41-7 (free base), 144604-00-2 (monomaleate)
Formula C22H27ClN2O4S
Structure
Formula Weight 450.98849
Stage 上市-1974
Company Biovail (Originator), Tanabe Seiyaku (Originator), Elan (Not Determined), Sanofi-Synthélabo (Not Determined), Solvay (Marketer), Aventis Pharma (Licensee), Esteve (Licensee), Forest (Licensee), Lacer (Licensee), SLA Pharma (Licensee), DOV Pharmaceutical (
Activity/Mechanism Angina pectoris, Treatment of, Anorectal Disorders, Treatment of, Antiarrhythmic Drugs, CARDIOVASCULAR DRUGS, GASTROINTESTINAL DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Calcium Channel Blockers
Syn. Route 17
Route 1
electrophilic bromination of ethyl p-methoxycinnamate (i) by means of n-bromosuccinimide in moist acetone gave rise to the racemic erythro bromohydrin (ii), which was esterified with butyric anhydride to produce the racemic bromoester (iii). kinetic resolution of (iii) employing candida cylindracea lipase caused the enantioselective hydrolysis of the (s,s)-enantiomer, yielding the chiral bromohydrin (v). cyclization of (v) in the presence of naome furnished epoxide (vi). the target thiazepinone (viii) was then obtained by condensation between the glycidic ester (vi) and 2-aminobenzenethiol (vii)
List of intermediates No.
(1s,5r,13r,16s,17r)-4-cyano-16-ethyl-10-methoxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one (a)
[(2r,3s,5r)-5-(6-hydroxy-9h-purin-9-yl)-3-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl acetate (vii)
Reference 1:
    mccague, r.; wang, s.; taylor, s.j.c. (celltech group plc); chiral arylpropionates and their use. wo 9413828 .

Route 2
a different method for the preparation of glycidic ester (vi) consists in the asymmetric epoxidation of ethyl 4-methoxycinnamate (i) with oxone(r) in the presence of chiral macrocyclic ketones, such as the binaphthyl ketone (ix)
List of intermediates No.
Reference 1:
    seki, m.; furutani, t.; imashiro, r.; kuroda, t.; yamanaka, t.; harada, n.; arawaka, h.; kusama, m.; hashiyama, t.; a novel synthesis of a key intermediate for diltiazem. tetrahedron lett 2001, 42, 46, 8201.
Reference 2:
    ozaki, y.; arakawa, h.; harada, n.; hashiyama, t.; kuroda, t.; seki, m.; kusama, m. (tanabe seiyaku co., ltd.); process for preparing optically active phenyloxirane cpds.. wo 9856762 .

Route 3
in a further process, the racemic trans glycidic ester (xii), prepared by darzens condensation between anisaldehyde (x) and methyl chloroacetate (xi), was resolved by enantioselective enzymatic hydrolysis, using several different enzymes and reaction conditions to produce the undesired (2s,3r) acid (xiii), while leaving intact the required (2r,3s)-glycidic ester (xiv) (4-7). opening of the chiral epoxide (xiv) with 2-aminobenzenethiol (vii) proceeded with retention of the configuration, producing methyl (2s,3s)-2-hydroxy-3-(2-aminophenylsulfanyl)-3-(4-methoxyphenyl)propionate (xv) (8). alternatively, the (s,s)-amino ester (xv) was obtained by resolution with tartaric acid of the racemic three-adduct resulting from epoxide (xii) and 2-aminobenzenethiol (vii) (9). cyclization of amino ester (xv) in refluxing xylene in the presence of p-toluenesulfonic acid afforded the target lactam (viii) (9). the cyclization of (xv) to lactam (viii) was also accomplished by means of trichloroacetic acid or under basic conditions
List of intermediates No.
(3r,4r)-4-(difluoromethyl)-1-(4-methoxyphenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone (xi)
1-hydrazinecarboxamide (xii)
[(2r,3s,5r)-5-(6-hydroxy-9h-purin-9-yl)-3-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl acetate (vii)
methyl 2-phenoxyacetate (x)
Reference 1:
    bhushan, l.b.; jayachandran, b.e.; bhushan, l.v.; thottappillil, r. (council of scientific and industrial research); process for preparing diltiazem. us 5869697 .

Route 4
a new enantioselective method for the preparation of glycidic ester (xiv) has been disclosed. methyl trichloroacetate (xvi) was converted to the dichloroketene silyl acetal (xvii) by treatment with zinc powder and chlorotrimethylsilane. asymmetric aldol condensation of (xvii) with anisaldehyde (x) in the presence of the chiral oxazaborolidine catalyst (xviii) at -78 c produced methyl (s)-2,2-dichloro-3-hydroxy-3-(4-methoxyphenyl)propionate (xix). reductive mono-dechlorination of (xix) furnished chlorohydrin (xx), which was then cyclized to glycidic ester (xiv) in the presence of naome
List of intermediates No.
methyl 2-phenoxyacetate (x)
Reference 1:
    imashiro, r.; kuroda, t.; asymmetric synthesis of methyl (2r,3s)-3-(4-methoxyphenyl) glycidate, a key intermediate of diltiazem, via mukaiyama aldol reaction. tetrahedron lett 2001, 42, 7, 1313.

Route 5
addition of phenylmagnesium bromide to cyclohexene oxide (xxi) in the presence of cucl gave trans-2-phenylcyclohexanol (xxii), which was further esterified with chloroacetyl chloride to afford 2-phenylcyclohexyl chloroacetate (xxiii). enantioselective hydrolysis of the racemic ester (xxiii) by means of pseudomonas fluorescens lipase provided pure (1r,2s)-2-phenylcyclohexanol (xxiv), which was again esterified with chloroacetyl chloride, yielding the chiral ester (xxvi). darzens condensation of chloro ester (xxvi) with anisaldehyde (x) led to the chiral glycidic ester (xxvii). epoxide ring opening in (xxvii) with 2-aminothiophenol (vii) furnished amino ester (xxviii). intermediate thiazepinone (viii) was then obtained by cyclization of (xxviii) using p-toluenesulfonic acid in refluxing xylene. alternatively, amino ester (xxviii) was first hydrolyzed to amino acid (xxix), which was subsequently cyclized with p-toluenesulfonic acid as above (11). the final cyclization of amino acid (xxix) to the intermediate thiazepinone (viii) has also been carried out in the presence of trichloroacetic acid
List of intermediates No.
4-(dimethylamino)-n-(2,6-dimethylphenyl)-4-piperidinecarboxamide (xxiv)
(2r,3r,4s,5s,6r)-3,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromo-2-cyanotetrahydro-2h-pyran-4-yl acetate (xxi)
[(2r,3s,5r)-5-(6-hydroxy-9h-purin-9-yl)-3-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl acetate (vii)
methyl 2-phenoxyacetate (x)
4-{4-[4-(benzyloxy)phenyl]-1-piperazinyl}aniline; 4-{4-[4-(benzyloxy)phenyl]-1-piperazinyl}phenylamine (+/--xxii)
Reference 1:
    plaum, m.j.m.; boesten, w.h.j.; process for the preparation of a benzothiazepine. ep 0796853; jp 1998007667; us 5859241 .

Route 6
a different strategy to reach the amino ester precursor (xxix) was developed starting from the chiral diol (xxx), readily accessible by asymmetric dihydroxylation of cinnamate (i). reaction of diol (xxx) with socl2 produced the cyclic sulfite (xxxi) (12,14). optionally, diol (xxx) was condensed with phosgene to produce the cyclic carbonate (xxxii) (12). opening of either sulfite (xxxi) or carbonate (xxxii) with 2-aminothiophenol (viii) proceeded with retention of the configuration, leading to the desired intermediate aminoacid (xxix)
List of intermediates No.
[(2r,3s,5r)-5-(6-hydroxy-9h-purin-9-yl)-3-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl acetate (viii)
Reference 1:
    lohray, b.b.; jayachandran, b.; bhushan, v.; nandanan, e.; ravindranathan, t.; anchimeric assisted unprecedented sn(i)-type cleavage of cyclic sulfite: application in the synthesis of the calcium channel blocker diltiazem. j org chem 1995, 60, 18, 5983.
Reference 2:
    hulshof, l.a.; kuilman, t.; process for preparing 1,5-benzothiazepin derivs.. ep 0450705 .

Route 7
the racemic thiazepinone (xxxiii) has been converted to the pure enantiomer (viii) through a different strategy. oxidation of hydroxy lactam (xxxiii) by means of dmso and ac2o produced the enol ester (xxxv). basic hydrolysis of (xxxi) gave rise to the keto lactam (xxxv). this was then subjected to asymmetric reduction utilizing a reducing reagent generated in situ from nabh4 and (s)-tert-leucine to afford the intermediate thiazepinone (viii)
List of intermediates No.
(1r,2r)-3-(acetoxy)-1-(4-methoxyphenyl)-2-methylpropyl acetate
Reference 1:
    yamada, s.; mori, y.; morimatsu, k.; ishizu, y.; ozaki, y.; yoshioka, r.; nakatani, t.; seko, h.; asymmetric reduction of a 1,5-benzothiazepine derivative with sodium borohydride-(s)-alpha-amino acids: an efficient synthesis of a key intermediate of diltiazem. j org chem 1996, 61, 24, 8586.

Route 8
the precursor cis-cinnamate (xxxix) can be obtained by several synthetic routes. bromination of ethyl trans-4-methoxycinnamate (i) afforded the dibromo ester (xxxvi), which underwent dehydrohalogenation and hydrolysis to the arylpropiolic acid (xxxvii) upon treatment with ethanolic koh. acid (xxxvii) was converted to the corresponding isopropyl ester (xxxviii) by dcc-mediated coupling with isopropanol. semihydrogenation of (xxxviii) in the presence of lindlar catalyst led to the required cis cinnamate (xxxix). alternatively, anisaldehyde (x) was converted to the gem-dibromostyrene (xl) by condensation with cbr4 in the presence of pph3. reaction of (xl) with buli, followed by addition of isopropyl chloroformate to the resultant lithium acetylide, furnished the arylpropiolate (xxxviii). in another method to obtain the cis-cinnamate (xxxix), trans-4-methoxycinnamic acid (xli) was converted to the isopropyl ester (xlii), which was then photochemically isomerized to the desired cis-cinnamate (xxxix)
List of intermediates No.
methyl 2-phenoxyacetate (x)
2-[(2r)-4-benzoyl-2-(3,4-difluorophenyl)morpholinyl]ethyl benzoate (xli)
Reference 1:
    jacobsen, e.n.; deng, l.; furukawa, y.; martinez, l.e.; enantioselective catalytic epoxidation of cinnamate esters. tetrahedron 1994, 50, 15, 4323.

Route 9
the key cis glycidate ester (xliii) was prepared by (salen)mn(iii)-catalyzed asymmetric epoxidation of the cis cinnamate (xxxix). epoxide opening in (xliii) with 2-nitrothiophenol (xliv), with inversion of the configuration, led to the nitro ester adduct (xlv). the nitro group of (xlv) was then reduced to the aniline derivative (xlvi) by means of feso4. subsequent isopropyl ester group saponification in (xlvi) furnished amino acid (xxix). this was then cyclized to the target thiazepinone (viii) in refluxing xylene
List of intermediates No.
Reference 1:
    jacobsen, e.n.; deng, l.; furukawa, y.; martinez, l.e.; enantioselective catalytic epoxidation of cinnamate esters. tetrahedron 1994, 50, 15, 4323.

Route 10
in a variation of the preceding methods, the chiral glycidic amide (xlvii) was used as the synthetic precursor. amide (xlvii) was either prepared by treatment of the chiral glycidic ester (vi) with ammonia, or by enzymatic resolution of (xii), followed by amidation. iron-catalyzed addition of 2-aminothiophenol (vii) to the glycidamide (xlvii) in refluxing chlorobenzene yielded the desired threo adduct (xlviii) as the major isomer. cyclization of amino amide (xlviii) under acidic conditions furnished thiazepinone (viii)
List of intermediates No.
1-hydrazinecarboxamide (xii)
[(2r,3s,5r)-5-(6-hydroxy-9h-purin-9-yl)-3-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl acetate (vii)
Reference 1:
    yamada, s.; tsujioka, i.; shibatini, t.; yoshioka, r.; efficient alterative synthetic route to diltiazem via (2r,3s)-3-(4-methoxyphenyl)glycidamide. chem pharm bull 1999, 47, 2, 146.

Route 11
aldol condensation of anisaldehyde (x) with the lithium enolate of the n-acyl oxazolidinone (xlix) gave adduct (l). dehydration of alcohol (l) was accomplished by formation of the corresponding mesylate (li), which underwent elimination in the presence of dbu, to produce a 4:1 mixture of z and e olefins. after chromatographic isolation of the major z isomer (lii), diastereoselective michael addition using a 1:2 mixture of 2-aminothiophenol (vii) and the corresponding lithium thiophenoxide furnished (liii) as the major diastereoisomer. intramolecular cyclization of the amino imide (liii) to the benzothiazepinone (liv) was accomplished in the presence of trimethylaluminium in refluxing ch2cl2. the methoxymethyl group of (liv) was then removed by treatment with ticl4, leading to the key precursor the thiazepinone (viii)
List of intermediates No.
[(2r,3s,5r)-5-(6-hydroxy-9h-purin-9-yl)-3-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl acetate (vii)
methyl 2-phenoxyacetate (x)
Reference 1:
    miyata, o.; shinada, t.; ninomiya, i.; naito, t.; asymmetric construction of two contiguous stereocenters by diastereoface differentiating addition reaction of thiols to chiral imides: formal synthesis of (+)-diltiazem. tetrahedron 1997, 53, 7, 2421.
Reference 2:
    miyata, o.; shinada, t.; ninomiya, i.; naito, t.; asymmetric induction at two contiguous stereogenic centers by diastereoface differentiating nucleophilic addition reaction. tetrahedron lett 1991, 32, 29, 3519.

Route 12
alkylation of the lactam n of thiazepinone (i) with 2-(dimethylamino)ethyl chloride (ii) in the presence of k2co3 or under phase-transfer conditions gave thiazeinone (iii). subsequent esterification of (iii) with acetic anhydride furnished the title compound.alternatively, diltiazem has been prepared by acetylation of thiazeinone (i) with ac2o to yield the lactam acetate ester (iv), which is then alkylated with chloride (ii) under phase-transfer conditions
List of intermediates No.
ethyl (z)-3-(2-methoxy-4-pyridinyl)-2-propenoate (ii)
Reference 1:
    coffen, d.l.; madan, p.b.; schwartz, a. (f. hoffmann-la roche ag); process for the preparation of optically pure aminophenylthio- and aminonaphthalenylthio-propanoic acids. ep 0343474 .
Reference 2:
    honma, t.; igarashi, k. (shionogi & co. ltd.); process for production of diltiazem hydrochloride. us 4552695 .
Reference 3:
    murthy, k.; weeratunga, g.; burchat, a. (acic (canada) inc.); method for the manufacture of benzothiazepine derivs.. wo 9638429 .
Reference 4:
    piselli, f.l.; boschi, p.; navoni, c.; a process for the preparation of diltiazem. ep 0594101 .
Reference 5:
    bhushan, l.b.; jayachandran, b.e.; bhushan, l.v.; thottappillil, r. (council of scientific and industrial research); process for preparing diltiazem. us 5869697 .
Reference 6:
    hytonen, m. (orion corporation); process for the manufacture of diltiazem. ep 0728751; jp 1996253464; us 5644054 .
Reference 7:
    hulshof, l.a.; kuilman, t.; process for preparing 1,5-benzothiazepin derivs.. ep 0450705 .
Reference 8:
    manghisi, e.; cascio, g. (lusofarmaco); process for the optical resolution of the dl-alpha-hydroxy-3-(4-methoxyphenyl)-3-(2-aminophenylthio)propionic acid. us 4533748 .
Reference 9:
    simonovitch, h.; hoffmann, t.; sassoon, s. (abic, ltd.); a process for the preparation of benzothiazepin derivs.. ep 0158303 .
Reference 10:
    hytonen, m. (orion corporation); method for the preparation of pharmaceutically active benzothiazepine derivs.. ep 0702009 .
Reference 11:
    manghisi, e.; perego, b.; a process for the preparation of diltiazem. wo 9210485 .

Route 13
similarly, thiazepinone (i) was transesterified with isopropenyl acetate (v) to afford acetate ester (iv). subsequent alkylation of the lactam n of (iv) with 2-(dimethylamino)ethyl mesylate (vi) in the presence of k2co3 furnished diltiazem.similarly, thiazepinone (i) was transesterified with isopropenyl acetate (v) to afford acetate ester (iv). subsequent alkylation of the lactam n of (iv) with 2-(dimethylamino)ethyl mesylate (vi) in the presence of k2co3 furnished diltiazem.
List of intermediates No.
4,5-diethyl-2,4-dihydro-3h-1,2,4-triazol-3-one (v)
Reference 1:
    harsanyi, k.; gizur, t.; demeter, a.; aracs, z.; felmeri, j.; berki, k.; trischeler, f.; vincze, z. (gedeon richter ltd.); process for the preparation of benzothiazepin-4(5h)-one derivs.. es 2001146; jp 1987108872 .

Route 14
several related procedures utilize racemic intermediates that are resolved in more advanced synthetic steps. the racemic trans-glycidic ester (ix) was prepared by darzens condensation between anisaldehyde (vii) and methyl chloroacetate (viii). opening of the epoxide group of (ix) with 2-aminothiophenol (x) in hot chlorobenzene in the presence of fecl3 gave rise to the racemic threo adduct (xi) which, without isolation, was cyclized to the cis-lactam (xii) by addition of methanesulfonic acid and then heating to reflux. alkylation of the lactam n of (xii) with 2-(dimethylamino)ethyl chloride (ii) led to the racemic precursor (xiii). resolution of (xiii) to provide the (s,s)-isomer (vii) was then accomplished by preferential crystallization of supersaturated solutions of several sulfonate salts of (xiii) upon seeding with the desired enantiomer. racemic diltiazem (xiv), obtained by acetylation of (xiii), has been resolved via formation of the corresponding diastereoisomeric salts with (s)-naproxen
List of intermediates No.
(3r,4r)-4-(difluoromethyl)-1-(4-methoxyphenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone (viii)
1-hydrazinecarboxamide (ix)
ethyl (z)-3-(2-methoxy-4-pyridinyl)-2-propenoate (ii)
[(2r,3s,5r)-5-(6-hydroxy-9h-purin-9-yl)-3-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl acetate (x)
methyl 2-phenoxyacetate (vii)
Reference 1:
    gizur, t.; harsanyi, k.; fogassy, e.; studies of the resolution of racemates in the synthesis of diltiazem. j prakt chem chem-ztg 1994, 336, 7, 628.
Reference 2:
    yamada, s.; yoshioka, r.; shibatani, t.; optical resolution of a 1,5-benzothiazepine derivative,a synthetic intermediate of diltiazem, by preferential crystallization and diastereomeric salt formation. chem pharm bull 1997, 45, 12, 1922.

Route 15
. 4-hydroxycinnamic acid (xv) was acetylated with ac2o in pyridine, and the resultant 4-acetoxycinnamic acid (xvi) was converted to the cinnamyl alcohol (xviii) via conversion to the mixed anhydride (xvii) and subsequent reduction with nabh4. sharpless asymmetric epoxidation of (xviii) furnished the chiral epoxide alcohol (xix). after oxidation of alcohol (xix) to the glycidic acid (xx) by means of ruo2/naio4, treatment with dimethyl sulfate and et3n gave rise to the corresponding methyl ester (xxi). epoxide opening in (xxi) with hcl and pyridine hydrochloride produced chlorohydrin (xxii) as a mixture of the desired (2s,3r)-isomer and minor amounts of the corresponding 3-chloro epimer. condensation of (xxii) with 2-nitrothiophenol (xxiii) provided, after recrystallization from etoh, the pure (s,s)-thioether adduct (xxiv). the hydroxyl group of (xxiv) was then protected as the methoxymethyl ether (xxv) by means of methylal in the presence of p2o5
List of intermediates No.
2-fluoro-5-(trifluoromethyl)phenol (xv)
Reference 1:
    honma, t.; igarashi, k. (shionogi & co. ltd.); process for production of diltiazem hydrochloride. us 4552695 .

Route 16
selective hydrolysis of the acetate ester of (xxv) using benzylamine in thf led to phenol (xxvi), which was further methylated by means of diazomethane, yielding methyl ether (xxvii). reduction of the nitro group (xxvii) to the corresponding aniline (xxviii) was then performed employing ferrous sulfate and ammonium hydroxide. subsequent saponification of the methyl ester group of (xxviii) gave amino acid (xxix). cyclization of (xxix) with ethyl chloroformate and triethylamine furnished lactam (xxx). the lactam n of (xxx) was then alkylated by 2-(dimethylamino)ethyl chloride (ii) to produce (xxxi). finally, deprotection of the methoxymethyl group of (xxxi) and concomitant o-acetylation was accomplished by treatment with acetyl chloride and ticl4
List of intermediates No.
ethyl (z)-3-(2-methoxy-4-pyridinyl)-2-propenoate (ii)
Reference 1:
    honma, t.; igarashi, k. (shionogi & co. ltd.); process for production of diltiazem hydrochloride. us 4552695 .

Route 17
the racemic precursor threo-hydroxy nitro ester (iii), prepared by addition of 2-nitrothiophenol (ii) to the racemic trans-glycidate (i), has been optically resolved by enantioselective lipase-catalyzed esterification of the (r,r)-isomer, producing the (r,r)-acetate (iv), while leaving unaltered the target intermediate, the (s,s)-hydroxy nitroester enantiomer (v). the racemic hydroxy nitro ester (iii) has also been resolved through formation of the diastereoisomeric salts with l-lysine
List of intermediates No.
ethyl (z)-3-(2-methoxy-4-pyridinyl)-2-propenoate (i)
Reference 1:
    kanerva, l.t.; sundholm, o.; lipase catalysis in the resolution of racemic intermediates of diltiazem synthesis in organic solvents. j chem soc - perkins trans i 1993, 13, 1385.
Reference 2:
    senuma, m.; shibazaki, m.; nishimoto, s.; shibata,k.; okamura, k.; date, t.; the practical resolution of (2rs,3rs)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylthio)propionic acid, a key intermediate for diltiazem, with l-lysine. chem pharm bull 1989, 37, 12, 3204.

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鹽酸地爾硫卓;英文名Diltiazem hydrochloride;CRD-401;MK-793(maleate);SLV-324;Milptin;Teczem(Comb. with enalapril);Tiazac(slow-release);Herbesser;Adizem;Dilzem;Cardizem;Slozem;Cardizem XL;Masdil;Uni-Masdil;Anoheal;Lacerol;Cardizem LA;Tildiem;CAS[33286-22-5]

 
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