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藥物詳細合成路線

Name Pranoprofen;Y-8004;Pransus;Niflan
Chemical Name alpha-Methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid
CAS 52549-17-4
Related CAS
Formula C15H13NO3
Structure
Formula Weight 255.27576
Stage 上市-1982
Company Mitsubishi Pharma (Originator), Senju (Originator), SSP (Originator)
Activity/Mechanism Antiinflammatory Ophthalmic Agents, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Non-Steroidal Antiinflammatory Drugs
Syn. Route 4
Route 1
1) by reduction of 2-(5-oxo-5h[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid (i) with nabh4 in basic water.2) by treating with co2 the grignard compound prepared from 7-(1-bromoethyl)-5h[1]benzopyrane[2,3-b]pyridine (ii) with mg in thf.3) by oxidation of 2-(5h[1]benzopyrane[2,3b]pyridin-7-yl)propionaldehyde (iii) with silver oxide in basic ethanol.4) by reduction of 2-(5h[1]benzopyrane[2,3-b]pyridin-7-yl)acrylic acid (iv) or 2-(5h[1]benzopyrane[2,3b]pyridin-7-yl)-2-chloropropionic acid (v) with h2 over raney-ni in aqueous naoh.
List of intermediates No.
(2r)-n-[(z,2s,6z,9s,10e)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-2-methoxy-1-pyrrolidinamine; n-[(z,2s,6z,9s,10e)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-n-[(2r)-2-methoxypyrrolidinyl]amine (i)
(2s,6z,9s,10e)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienenitrile (ii)
(3s,6r,7s,8s,12z,15s,16e)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid (iii)
tert-butyl(dimethyl)silyl (3s,6r,7s,8s,12z,15s,16e)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate (iv)
(6s)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanol (v)
Reference 1:
    nakanishi, m.; oe, t.; tsuruda, m.; substituted alkanoic acids and derivatives. de 2337052; fr 2193593; gb 1403487; us 3931205 .
Reference 2:
    nakanishi, m.; et al.; jp 7493398 .
Reference 3:
    tsuruda, m.; et al.; jp 7505399 .
Reference 4:
    roberts, p.; castaner, j.; y 8004. drugs fut 1977, 2, 3, 217.

Route 2
1) by cyclization of 2-[p-(alpha-carboxyethyl)phenoxy]nicotinic acid (xiii) with phosphoric acid at 130-40 c.2) by cyclization of 2-[3-(2-chloronicotinoyl)-4-hydroxyphenyl]propionic acid (xiv) hy means of cu - cu2i2 in aqueous naoh.3) by oxidation of 2-(5-oxo-5h[1]benzopyrano[2,3-b]-pyridin-7-yl)propionaldehyde (xv) with kmno4 in pyridine-water.
List of intermediates No.
(1s,3z,8s,9s,10r,11r)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8,10,12,12-pentamethyl-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-oxo-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate (xiii)
(4r,6r,7r,8s,9s,16s)-8-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-5,5,7,9,13-pentamethyl-16-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecen-2-one (xiv)
(4s,6r,7r,8s,9s,16s)-8-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-5,5,7,9,13-pentamethyl-16-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecen-2-one (xv)
Reference 1:
    nakanishi, m.; oe, t.; tsuruda, m.; substituted alkanoic acids and derivatives. de 2337052; fr 2193593; gb 1403487; us 3931205 .
Reference 2:
    nakanishi, m.; et al.; jp 7505398 .
Reference 3:
    roberts, p.; castaner, j.; y 8004. drugs fut 1977, 2, 3, 217.

Route 3
the bromination of 7-methyl-5-oxo-5h[1]benzopyrane[2,3-b]pyridine (xvi) with nbs in ccl4 gives 7-bromomethyl-5-oxo-5h[1]benzopyrane[2,3-b] pyridine (xvii), which is treated with nacn in dmf yielding 7-cyanomethyl-5-oxo-5h[1]benzopyrane[2,3b]pyridine (xviii). the reaction of (xviii) with diethyl carbonate (a) by means of sodium ethoxide in ethanol affords ethyl 2-cyano-2-(5-oxo-5h[1]benzopyrane[2,3b]pyridine-7-yl)acetate (xix), which, without isolation, is methylated with mei giving ethyl 2-cyano-2-(5-oxo-5h[1]benzopyrane[2,3b]pyridine-7-yl)propionate (xx); finally this product is hydrolyzed and decarboxylated with dry hcl in refluxing acetic acid.an alternative way starting from the cyano derivative (xviii) is its methylation with nanh2 and mei giving 7-(1-cyanoethyl)-5-oxo-5h[1]benzopyrane[2,3-b]pyridine (xxi), which is hydrolyzed with dry hcl in refluxing acetic acid.
List of intermediates No.
tert-butyl (1r,2r,4s)-2-(6-methoxy-3-pyridinyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (a)
(2r)-n-[(z,2s,6z,9s,10e)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-2-methoxy-1-pyrrolidinamine; n-[(z,2s,6z,9s,10e)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-n-[(2r)-2-methoxypyrrolidinyl]amine (i)
(6r,7r,8s,9s,16s)-8-[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-6-[(triphenylsilyl)oxy]oxa-13-cyclohexadecene-2,4-dione (xvi)
(4s,6r,7s,8s,9s,16s)-8-[[tert-butyl(dimethyl)silyl]oxy]-4,6-dihydroxy-5,5,7,9,13-pentamethyl-16-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecen-2-one (xvii)
(4s,6r,7s,8s,9s,16s)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxy-5,5,7,9,13-pentamethyl-16-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecen-2-one (xviii)
propyl (2z,5s,6e)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate (xix)
(2s)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-propanol (xx)
4-((1e,3s,5z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-iodo-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1s,3z)-5-iodo-4-methyl-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether (xxi)
Reference 1:
    nakanishi, m.; oe, t.; tsuruda, m.; substituted alkanoic acids and derivatives. de 2337052; fr 2193593; gb 1403487; us 3931205 .
Reference 2:
    nakanishi, m.; et al.; jp 7535196 .
Reference 3:
    roberts, p.; castaner, j.; y 8004. drugs fut 1977, 2, 3, 217.

Route 4
the reduction of 5-oxo-5h[1]benzopyrane[2,3-b]pyridine (vi) affords 5-hydroxy-5h[1]benzopyrane[2,3-b]pyridine (vii), which is reduced again with refluxing isopropanol and hcl giving 5h[1]benzopyrane[2,3b]pyridine (viii). this product is chloromethylated with hcho and hcl in h2so4 to yield 7-chloromethyl-5h[1]benzopyrane[2,3-b]pyridine (ix), which is treated with kcn in dmf-water to afford 7-cyanomethyl-5h[1]benzopyrane[2,3-b]pyridine (x). the reaction of (x) with diethyl carbonate (a) in ethanol containing sodium ethoxide gives ethyl 2-cyano-2-(5h[1]benzopyrano[2,3-b]pyridine-7-yl)acetate (xi), which, without isolation, is methylated with mei to ethyl 2-cyano-2-(5h[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate (xii). finally, (xii) is hydrolyzed and decarboxylated with dry hcl in refluxing acetic acid.
List of intermediates No.
tert-butyl (1r,2r,4s)-2-(6-methoxy-3-pyridinyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (a)
(6s)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanone (vi)
ethyl(triphenyl)phosphonium iodide (vii)
tert-butyl(dimethyl)silyl (1s,3e)-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1e,3s,5e)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-heptadienyl)-2-methyl-1,3-thiazole (viii)
(1e,3s,5z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-heptadien-3-ol (ix)
(1s,3z)-4-iodo-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl acetate (x)
phenyl (3s,6r,7s,8s,12z,15s,16e)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate (xi)
(1s,3z,8s,9s,10r,11r)-9-[[tert-butyl(dimethyl)silyl]oxy]-13,13-dimethoxy-4,8,10,12,12-pentamethyl-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-11-[(triphenylsilyl)oxy]-3-tridecenyl acetate (xii)
Reference 1:
    kato, y.; et al.; studies on anti-inflammatory agents. xxxii. absorption, excretion, distribution and metabolism of 2-(5h-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionic acid (y-8004) in rats and mice. yakugaku zasshi 1976, 96, 819.
Reference 2:
    takanori, o.; et al.; substituted alkanoic acids and derivatives. de 2337052; fr 2193593; gb 1403487; us 3931205 .
Reference 3:
    nakanishi, m.; et al.; jp 7493398 .
Reference 4:
    roberts, p.; castaner, j.; y 8004. drugs fut 1977, 2, 3, 217.

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普拉洛芬;英文名Pranoprofen;Y-8004;Pransus;Niflan;CAS[52549-17-4]

 
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