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药物详细合成路线

Name Amlodipine;UK-4834011;Norvasc(as besylate)
Chemical Name (±)-2-(2-Aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine
CAS 88150-42-9
Related CAS
Formula C20H25ClN2O5
Structure
Formula Weight 408.88565
Stage 上市-1990
Company Pfizer (Originator)
Activity/Mechanism Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Calcium Channel Blockers
Syn. Route 11
Route 1
the condensation of ethyl 4-chloroacetoacetate (i) with 2-azidoethanol (ii) by means of nah in thf gives ethyl 4-(2-azidoethoxy)acetoacetate (iii), which is submitted to a hantzsch cyclocondensation with methyl 3-aminocrotonate (iv) and 2-chlorobenzaldehyde (v) in refluxing methanol affording 3-ethyl 5-methyl 2-(2-azidoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate (vi), finally, this compound is reduced with zn and 3n hcl in methanol, or with h2 over pd/caco3 in ethanol.
List of intermediates No.
ethyl 2-[(3s)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2h-chromen-3-yl]acetate (iv)
3-amino-4-ethoxy-1h-1lambda(4),2,5-thiadiazol-1-one (i)
methyl n-(2-chloro-3-pyridinyl)ethanimidoate (ii)
n-(2-chloro-3-pyridinyl)-n-ethylamine; 2-chloro-n-ethyl-3-pyridinamine (iii)
n-(4-nitrophenyl)acetamide (v)
n-[4-(4h-1,2,4-triazol-4-yl)phenyl]acetamide (vi)
Reference 1:
    campbell, s.f.; cross, p.e.; stubbs, j.k. (pfizer inc.); 2-(secondary aminoalkoxymethyl)dihydropyridine derivatives as anti-ischaemic and antihypertensive agents. dd 218887; ep 0089167; jp 58167569; us 4572909 .
Reference 2:
    castaner, j.; prous, j.; amlodipine. drugs fut 1986, 11, 2, 89.

Route 2
preparation of a key intermediate in the synthesis of amlodipine:the reaction of ethyl 4-(2-phthalimidoethoxy)acetoacetate (i) with ammonium acetate in refluxing toluene gives the corresponding 3-aminocrotonic acid (ii), which is then cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (iii) in refluxing ethanol.
List of intermediates No.
(2s,3s,4r)-4-{[(cyanoimino)(phenoxy)methyl]amino}-2-(dimethoxymethyl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2h-chromene (i)
3-chloro-6-(1-piperazinyl)pyridazine (ii)
3-methoxy-4-hydroxybenzoic acid ethyl ester; 4-hydroxy-3-methoxybenzoic acid ethyl ester; ethyl 4-hydroxy-3-methoxybenzoate; ethyl vanillate; ethyl-3-methoxy-4-hydroxybenzoate; vanillic acid ethyl ester (iii)
ethyl 4-(3-chloropropoxy)-3-methoxybenzoate (iv)
Reference 1:
    campon pardo, j.; coppi, l.; gasanz guillen, y. (laboratorios del dr. esteve, sa); intermediate for the synthesis of amlodipine, preparation process and corresponding utilization. wo 0024714 .

Route 3
the reaction of ethyl 4-chloroacetoacetate (i) with 2-azidoethanol (ii) by means of nah in thf gives ethyl 4-(2-azidoethoxy)acetoacetate (ii), which is cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (iv) and ammonium acetate in refluxing ethanol to yield the azido-dihydropyridine (v). finally, the azido group of (v) is reduced with h2 over pd/c in ethanol to afford the target amlodipine.
List of intermediates No.
3-amino-4-ethoxy-1h-1lambda(4),2,5-thiadiazol-1-one (i)
methyl n-(2-chloro-3-pyridinyl)ethanimidoate (ii)
n-(2-chloro-3-pyridinyl)-n-ethylamine; 2-chloro-n-ethyl-3-pyridinamine (iii)
n-[4-(4h-1,2,4-triazol-4-yl)phenyl]acetamide (v)
3-methoxy-4-hydroxybenzoic acid ethyl ester; 4-hydroxy-3-methoxybenzoic acid ethyl ester; ethyl 4-hydroxy-3-methoxybenzoate; ethyl vanillate; ethyl-3-methoxy-4-hydroxybenzoate; vanillic acid ethyl ester (iv)
Reference 1:
    campbell, s.f.; cross, p.e.; stubbs, j.k. (pfizer inc.); 2-(secondary aminoalkoxymethyl)dihydropyridine derivatives as anti-ischaemic and antihypertensive agents. dd 218887; ep 0089167; jp 58167569; us 4572909 .

Route 4
the reduction of 2,2-diethoxyacetic acid ethyl ester (i) with nabh4 in dimethoxyethane gives 2,2-diethoxyethanol (ii), which is condensed with ethyl 4-chloroacetoacetate (iii) by means of nah in hot thf to yield ethyl 4-(2,2-diethoxyethoxy)acetoacetate (iv). the condensation of (iv) with 2-chlorobenzaldehyde (v) by means of piperidine in refluxing toluene affords the acrylic ester (vi), which is cyclized with methyl 3-aminocrotonate (vii) in refluxing toluene to provide the dihydropyridine (viii). the reaction of (viii) with hydroxylamine in refluxing methanol/water gives the hydroxyimino derivative (ix), which is finally reduced to the target compound by means of h2 over pd/c in acetic acid or with nabh4 and nicl2 in methanol.alternatively, intermediate dihydropyridine (viii) can be obtained as follows: the reaction of acetoacetate (iv) with ammonium acetate in refluxing ethanol gives ethyl 3-amino-4-(2,2-diethoxyethoxy)crotonate (x), which is cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (xi) in refluxing toluene to yield the target intermediate the dihydropyridine (viii).
List of intermediates No.
ethyl 2-[(3s)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2h-chromen-3-yl]acetate (vii)
3-amino-4-ethoxy-1h-1lambda(4),2,5-thiadiazol-1-one (iii)
n-(4-nitrophenyl)acetamide (v)
methyl 3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzoate (i)
3-methoxy-4-hydroxybenzoic acid ethyl ester; 4-hydroxy-3-methoxybenzoic acid ethyl ester; ethyl 4-hydroxy-3-methoxybenzoate; ethyl vanillate; ethyl-3-methoxy-4-hydroxybenzoate; vanillic acid ethyl ester (xi)
2-(4-bromophenyl)-6-(4-morpholinyl)-4h-thiopyran-4-one (ii)
(iv)
2,2-dimethoxyadamantane; 2-methoxy-2-adamantyl methyl ether (vi)
(viii)
benzyl 2-amino-4-chlorobenzoate (x)
benzyl 4-chloro-2-[(phenoxycarbonyl)amino]benzoate (ix)
Reference 1:
    pedersen, s.b.; preikschat, h.f.; karup, g.l. (gea a/s farmaceutisk fabrik); process for the preparation of acetal derivs. of 1,4-dihydropyridines. wo 9925689 .
Reference 2:
    karup, g.l.; preikschat, h.f. (gea a/s farmaceutisk fabrik); process for the preparation of 1,4-dihydropyridines and cpds. used in this process. wo 9925688 .

Route 5
the protection of ethanolamine (i) with trityl chloride (ii) in isopropanol gives n-tritylethanolamine (iii), which is condensed with ethyl 4-chloroacetoacetate (iv) by means of nah in thf to yield ethyl 4-[2-(tritylamino)ethoxy]acetoacetate (v). the cyclization of (v) with 2-chlorobenzaldehyde (vi) and methyl 3-aminocrotonate (vii) in refluxing methanol affords the protected dihydropyridine (viii), which, without isolation, is finally detritylated by a treatment with aqueous benzenesulfonic acid.
List of intermediates No.
(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4-(acetoxy)-1,12,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate (i)
ethyl 2-[(3s)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2h-chromen-3-yl]acetate (vii)
3-amino-4-ethoxy-1h-1lambda(4),2,5-thiadiazol-1-one (iv)
n-(4-nitrophenyl)acetamide (vi)
tert-butyl 4-(aminosulfonyl)-2-{[(benzyloxy)carbonyl]amino}benzoate (ii)
tert-butyl 2-{[(benzyloxy)carbonyl]amino}-4-{[({2-[(benzyloxy)carbonyl]-5-chloroanilino}carbonyl)amino]sulfonyl}benzoate (iii)
2-{[({[3-amino-4-(tert-butoxycarbonyl)phenyl]sulfonyl}amino)carbonyl]amino}-4-chlorobenzoic acid (v)
tert-butyl 2-amino-4-{[7-chloro-2,4-dioxo-1,4-dihydro-3(2h)-quinazolinyl]sulfonyl}benzoate (viii)
Reference 1:
    furlan, b.; copar, a.; jeriha, a. (lek pharmaceutical and chemical co.); 3-ethyl 5-methyl (+)2-[2-(n-tritylamino)ethoxymethyl]-4-(2-chloro-phenyl)-1,4-dihydro-6-methyl-6-methyl-3, 5-pyridinedicarboxylate. ep 0599220; us 5389654 .

Route 6
the two enantiomers of amlodipine have been obtained as follows:the reaction of 2-azidoethanol (i) with chloroacetic acid (ii) by means of nah in thf gives 2-(2-azidoethoxy)acetic acid (iii), which is condensed with meldrums acid (iv) and 3-hydroxypropionitrile (v) in dichloromethane to yield the 2-cyanoethyl acetoacetate (vi). the cyclization of (vi) with 2-chlorobenzaldehyde (vii) and methyl 3-aminocrotonate (viii) in refluxing ethanol affords the dihydropyridine (ix), which is selectively hydrolyzed at the 2-cyanoethylester with naoh to give the dihydropyridine monocarboxylic acid (x). the esterification of (x) with (s)-2-methoxy-2-phenylethanol (xi) by means of cdi in dichloromethane provides the ester (xii) as a diastereomeric mixture, which is separated by chromatography to furnish diastereomers (xxi a) and (xii b). the selective ethanolysis of (xii a) and (xii b) with sodium ethoxide in refluxing ethanol/diglyme gives enantiomers (+)-(xiii) and (-)-(xiii), which are finally reduced with h2 over pd/caco3 in ethanol to afford the (-)- and (+)-isomers, respectively, of the target compound.
List of intermediates No.
ethyl 2-[(3s)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2h-chromen-3-yl]acetate (viii)
5,6,9,10-tetrahydro-4h-pyrido[3,2,1-jk]carbazol-11(8h)-one (ii)
methyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (v)
tert-butyl (5s)-5-amino-6-([(1s)-1-[([(1s)-2-[[(1s)-1-(aminocarbonyl)-3-methylbutyl]amino]-1-[4-(tert-butoxy)benzyl]-2-oxoethyl]amino)carbonyl]-5-[(tert-butoxycarbonyl)amino]pentyl]amino)-6-oxohexylcarbamate (iv)
methyl n-(2-chloro-3-pyridinyl)ethanimidoate (i)
n-(4-nitrophenyl)acetamide (vii)
n-[4-(4h-1,2,4-triazol-4-yl)phenyl]acetamide (xiii)
1-(4-chlorophenyl)-3-(dimethylamino)-1-propanone (iii)
(vi)
(ix)
2,4-dichloroquinoline (x)
4-chloro-2-[3,4-dihydro-2(1h)-isoquinolinyl]quinoline (xi)
5-pyrimidinecarboxylic acid (xii)
Reference 1:
    arrowsmith, j.e.; et al.; long-acting dihydropyridine calcium antagonists. 1. 2-alkoxymethyl derivatives incorporating basic substituents. j med chem 1986, 29, 9, 1696.

Route 7
the reaction of ethyl 4-bromoacetoacetate (i) with 2-chloroethanol (ii) by means of nah in thf gives ethyl 4-(2-chloroethoxy)acetoacetate (iii), which is treated with nai in refluxing acetone to yield the corresponding 2-iodoethoxy derivative (iv). the condensation of (iv) with 2-chlorobenzaldehyde (v) by means of piperidine acetate in isopropanol affords ethyl 2-(2-chlorobenzylidene)-4-(2-iodoethoxy)acetoacetate (vi), which is cyclized with methyl 3-aminocrotonate (vii) in refluxing isopropanol to provide the dihydropyridine (viii). the reaction of (viii) with hexamethylenetetramine (ix) in hot acetonitrile gives the aminium salt (x), which is finally treated with benzenesulfonic acid in refluxing butanol (methanol)/water.alternatively, the intermediate dihydropyridine (viii) can be obtained as follows: the condensation of ethyl 4-(2-chloroethoxy)acetoacetate (iii) with the aldehyde (v) by means of piperidine acetate in isopropanol gives ethyl 2-(2-chlorobenzylidene)-4-(2-chloroethoxy)acetoacetate (xi), which is cyclized with methyl 3-aminocrotonate (vii) in refluxing isopropanol to yield the corresponding dihydropyridine (xii). finally, this compound is treated with nai in refluxing isopropanol to afford the target intermediate dihydropyridine (viii).
List of intermediates No.
2,3,5,6-tetrachloro-1,4-benzoquinone; 2,3,5,6-tetrachlorobenzo-1,4-quinone; p-chloranil (ii)
ethyl 2-[(3s)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2h-chromen-3-yl]acetate (vii)
n-(4-nitrophenyl)acetamide (v)
2,3,6,7-tetrachloro-5-nitroquinoxaline (ix)
n-[3-([5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazol-4-yl]methoxy)benzyl]hydroxylamine; 4-([3-[(hydroxyamino)methyl]phenoxy]methyl)-5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazole (i)
1,4,5,6-tetrahydro-5-pyrimidinecarboxylic acid (iii)
methyl 1,4,5,6-tetrahydro-5-pyrimidinecarboxylate (iv)
methyl 1-trityl-1,4,5,6-tetrahydro-5-pyrimidinecarboxylate (vi)
n-hydroxypropanimidamide (viii)
5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1-trityl-1,4,5,6-tetrahydropyrimidine (x)
3-(1-adamantyl)-4-{[tert-butyl(dimethyl)silyl]oxy}phenylboronic acid (xi)
6-(3-(1-adamantyl)-4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)nicotinaldehyde (xii)
Reference 1:
    németh, n.; vereczkey, g.d.; krasznai, g.; koványi, g.; német, g.; blask, g.; t?mpe, p.; nagy, k.; bozsing, d.; simig, g. (egis pharmaceuticals ltd.); a process and intermediate cpds. for the preparation of amlodipine benzene sulphonate. ep 0902016 .

Route 8
the reaction of 4,5-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (i) with ethyl 4-chloroacetoacetate (ii) gives the bis adduct (iii), which is cyclized with 2-chlorobenzaldehyde (iv) and methyl 3-aminocrotonate (v) in refluxing ethanol to yield the dimeric dihydropyridine (vi). the cleavage of the dioxolane ring of (vi) by means of ts-oh in methanol affords the vicinal diol (vii), which is cleaved by means of naio4 in methanol to provide the acetaldehyde derivative (viii). the reaction of (viii) with hydroxylamine and tea in methanol affords the corresponding oxime (ix), which is finally reduced to the target compound with pd(oh)2/carbon and ammonium formate in refluxing methanol. alternatively, the reductive amination of acetaldehyde (viii) with ammonium acetate and sodium cyanoborohydride in methanol yields also the target compound.
List of intermediates No.
ethyl 2-[(3s)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2h-chromen-3-yl]acetate (v)
3-amino-4-ethoxy-1h-1lambda(4),2,5-thiadiazol-1-one (ii)
n-(4-nitrophenyl)acetamide (iv)
benzyl 4-chloro-2-[(phenoxycarbonyl)amino]benzoate (ix)
6-[3-(1-adamantyl)-4-hydroxyphenyl]nicotinaldehyde (i)
6-bromonicotinaldehyde (iii)
boc-d-alpha-phenylglycine (vi)
3,5-dichloro-n-{(z,6r)-2-[(1r)-1-(3,4-dichlorophenyl)-4-methyl-3-pentenyl]-8-hydroxy-10,10-dimethyl-5-oxo-6-phenyl-4,9-dioxa-3,7-diaza-2-undecen-1-yl}-n-methylbenzamide (vii)
3,5-dichloro-n-((3r)-3-(3,4-dichlorophenyl)-2-{[(2,2-dimethylpropanoyl)oxy]imino}-6-methyl-5-heptenyl)-n-methylbenzamide (viii)
Reference 1:
    karimian, k.; leung-toung, r.c.s.h.; tam, t.f. (apotex inc.); 1,4-dihydropyridines, n-substd. bicyclic 4-hydropyridines, and bicyclic n-substd. 4,5-dihydropyridines. us 5723618 .

Route 9
the reaction of 2,2-dimethyl-1,3-dioxolane-4-methanol (x) with ethyl 4-chloroacetoacetate (ii) gives the adduct (xi), which is cyclized with 2-chlorobenzaldehyde (iv) and methyl 3-aminocrotonate (v) in refluxing ethanol to yield the dihydropyridine (xii). the cleavage of the dioxolane ring of (xii) by means of ts-oh in methanol affords the vicinal diol (xiii), which is cleaved by means of naio4 in methanol to provide the already reported acetaldehyde derivative (viii).
List of intermediates No.
ethyl 2-[(3s)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2h-chromen-3-yl]acetate (v)
3-methyl-5,7-dinitro-1-benzothiophene (x)
3-amino-4-ethoxy-1h-1lambda(4),2,5-thiadiazol-1-one (ii)
n-(4-nitrophenyl)acetamide (iv)
benzyl 4-chloro-2-[(phenoxycarbonyl)amino]benzoate (ix)
3,5-dichloro-n-((3r)-3-(3,4-dichlorophenyl)-2-{[(2,2-dimethylpropanoyl)oxy]imino}-6-methyl-5-heptenyl)-n-methylbenzamide (viii)
methyl 4-[(4r)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutanoate (xi)
methyl (3r)-3-{[(4r)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-5-cyanopentanoate (xii)
methyl (3r)-6-amino-3-{[(4r)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}hexanoate (xiii)
Reference 1:
    karimian, k.; leung-toung, r.c.s.h.; tam, t.f. (apotex inc.); 1,4-dihydropyridines, n-substd. bicyclic 4-hydropyridines, and bicyclic n-substd. 4,5-dihydropyridines. us 5723618 .

Route 10
the cyclization of 2-butynoic acid methyl ester (i) with 2-(2-chlorobenzylidene)-3-oxobutyric acid ethyl ester (ii) and benzylamine (iii) in refluxing toluene gives the n-benzylated dihydropyridine (iv), which is debenzylated by reduction with formic acid over pd/c in refluxing methanol to yield the dihydropyridine (v). the bromination of (v) with c5h5nh+ hbr3- in dichloromethane affords the bromomethyl compound (vi), which is condensed with 2-azidoethanol (vii) by means of nah in ethyl ether to provide the 2-azidoethoxymethyl compound (viii). finally, the azido group of (viii) is reduced with zn and hcl in methanol to furnish the desired 2-aminoethoxymethyl compound.
List of intermediates No.
1-(2,6-dihydroxyphenyl)-1-ethanone (ii)
methyl n-(2-chloro-3-pyridinyl)ethanimidoate (vii)
1,3,8-triazaspiro[4.5]decan-4-one (i)
8-[4-(4-fluorophenyl)-4-oxobutyl]-1,3,8-triazaspiro[4.5]decan-4-one (iii)
(4-methoxybenzyl)(triphenyl)phosphonium bromide (iv)
1-nitrosoethane (v)
[(2r)-2-(2,4-difluorophenyl)oxiranyl]methanol (vi)
(rac)-(1s,2s)-2-methoxycyclohexanol (viii)
Reference 1:
    kim, s.-c.; et al.; synthesis of amlodipine using aza diels-alder reaction. bull korean chem soc 2002, 23, 1, 143.

Route 11
the condensation of 4-(2-phthalimidoethoxy)acetoacetic acid ethyl ester (i) with 2-chlorobenzaldehyde (ii) by means of piperidine in isopropanol gives 2-(2-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetic acid ethyl ester (iii), which is cyclized with 3-aminocrotonic acid methyl ester (iv) in hot isopropanol to yield the phthalimido amlodipine (v). finally, this compound is deprotected by means of aqueous methylamine to afford the target amlodipine.
List of intermediates No.
ethyl 2-[(3s)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2h-chromen-3-yl]acetate (iv)
n-(4-nitrophenyl)acetamide (ii)
(2s,3s,4r)-4-{[(cyanoimino)(phenoxy)methyl]amino}-2-(dimethoxymethyl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2h-chromene (i)
ethyl 4-(3-chloropropoxy)-3-methoxybenzoate (v)
Reference 1:
    benneker, f.b.g.; peters, t.h.a.; slanina, p.; bartl, j.; process for making amlodipine, derivs. thereof, and precursors therefor. wo 0253535 .

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氨氯地平;英文名Amlodipine;UK-4834011;Norvasc(as besylate);CAS[88150-42-9]

 
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