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药物详细合成路线

Name Iguratimod;T-614;Careram
Chemical Name 3-(Formylamino)-7-(methylsulfonamido)-6-phenoxy-4H-1-benzopyran-4-one
CAS 123663-49-0
Related CAS
Formula C17H14N2O6S
Structure
Formula Weight 374.37493
Stage 预注册
Company Toyama (Originator), Dong-A (Licensee), Eisai (Licensee)
Activity/Mechanism Antiarthritic Drugs, Disease-Modifying Drugs, Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, NF-kappaB (NFKB) Activation Inhibitors
Syn. Route 2
Route 1
the reduction of 3-nitro-4-phenoxyphenol (i) with fe, aqueous hcl gives 3-amino-4-phenoxyphenol (ii), which is acylated with methanesulfonyl chloride by means of pyridine in dichloromethane affording 3-(methylsulfonamido)-4-phenoxyphenol (iii). the condensation of (iii) with 3-chloropropionic acid (iv) by means of naoh in water gives 3-[3-(methylsulfonamido)-4-phenoxyphenoxy]propionic acid (v), which is cyclized by means of polyphosphoric acid at 65-70 c yielding 7-(methylsulfonamido)-6-phenoxy-3,4-dihydro-2h-1-benzopyran-4-one (vi). the bromination of (vi) with br2 in chcl3 affords 3-bromo-7-(methylsulfonamido)-6-phenoxy-3,4-dihydro-2h-1-benzopyran-4-one (vii), which is treated with sodium azide in dmf at 70-75 c giving 3-amino-7-(methylsulfonamido)-6-phenoxy-2h-1-benzopyran-4-one (viii). finally, this compound is formylated with formic acid in acetic anhydride.
List of intermediates No.
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether (i)
7-methoxy-1,2,3,4-tetrahydro-6-isoquinolinol (ii)
2-(3,4-dimethoxyphenyl)-7-[6-hydroxy-7-methoxy-3,4-dihydro-2(1h)-isoquinolinyl]-2-[(4-methylphenyl)sulfanyl]heptanenitrile (iii)
7-[6-(2-chloroethoxy)-7-methoxy-3,4-dihydro-2(1h)-isoquinolinyl]-2-(3,4-dimethoxyphenyl)-2-[(4-methylphenyl)sulfanyl]heptanenitrile (iv)
5-bromo-2-methyl-7-nitro-1,2,3,4-tetrahydro-8-isoquinolinylamine; 5-bromo-2-methyl-7-nitro-1,2,3,4-tetrahydro-8-isoquinolinamine (v)
ethyl 2-amino-5-bromo-3-nitro-6-vinylbenzyl(methyl)carbamate (vi)
ethyl 2,3-diamino-6-ethylbenzyl(methyl)carbamate (vii)
(6-ethyl-2,3-dioxo-1,2,3,4-tetrahydro-5-quinoxalinyl)methyl(methyl)carbamic acid (viii)
Reference 1:
    takano, s.; yoshida, c.; inaba, t.; tanaka, k.; takeno, r.; nagaki, h.; shimotori, t.; makino, s. (toyama chemical co., ltd.); 4h-benzopyran-4-one derivs. and their salts, their processes of production and pharmaceutical compsns. containing them. au 8823489; ch 679397; fr 2621585; gb 2210879; jp 1995267943; us 4954518 .
Reference 2:
    mealy, n.; prous, j.; castaner, j.; t-614. drugs fut 1993, 18, 8, 714.

Route 2
a preparative-scale synthetic route for t-614 has been reported:the reaction of 4-chloro-3-nitroanisole (i) with potassium phenolate in hot dmf gives 4-phenoxy-3-nitroanisole (ii), which is reduced to the corresponding 3-amino compound (iii) by treatment with fe and hcl. the reaction of (iii) with mesyl chloride in pyridine affords the sulfonamide (iv), which is acylated with 2-aminoacetonitrile (v) and alcl3 in nitrobenzene/hcl giving the 2-aminoacetophenone (vi). formylation of (vi) at the nh2 with acetic formic anhydride yields the formamide (vii), which is demethylated with alcl3 and nai in acetonitrile affording the phenol (viii). finally, this compound is cyclized with dimethylformamide dimethylacetal in dmf.
List of intermediates No.
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1h-indol-3-yl]acetyl chloride (ix)
1-[4-(tert-butyl)phenyl]-n-[(2s)-2-(4-methylphenyl)propyl]-5-oxo-3-pyrrolidinecarboxamide (i)
(2r,3r,4s)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylic acid (ii)
ethyl (2r,3r,4s)-4-(1,3-benzodioxol-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate (iii)
ethyl (2r,3r,4s)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate (iv)
1-(4-pyridinyl)-4-piperidinecarbaldehyde (vi)
(vii)
(viii)
n-(2-aminoethyl)-2-bromo-n-{[1-(4-pyridinyl)-4-piperidinyl]methyl}acetamide (v)
Reference 1:
    yoshida, c.; tanaka, k.; nagaki, h.; takeno, r.; inaba, t.; takano, s.; synthesis and antiinflammatory activities of 7-methanesulfonylamino-6-phenoxychromones. antiarthritic effect of the 3-formylamino compound (t-614) in chronic inflammatory disease models. chem pharm bull 2000, 48, 1, 131.

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艾拉莫德;英文名Iguratimod;T-614;Careram;CAS[123663-49-0]

 
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