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药物详细合成路线

Name Ioversol;MU-328(as syringe);MP-328;Optiject;Optiray
Chemical Name N,N-Bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)glycolamido]-2,4,6-triiodoisophthalamide
      N,N-Bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)(2-hydroxyethyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide
CAS 87771-40-2
Related CAS
Formula C18H24I3N3O9
Structure
Formula Weight 807.11988
Stage 上市
Company Mallinckrodt (Originator), Yamanouchi (Originator), Guerbet (Licensee)
Activity/Mechanism Contrast Mediums, DIAGNOSTIC AGENTS
Syn. Route 8
Route 1
chlorination of 5-amino-2,4,6-triiodoisophthalic acid (i) with socl2 in etoac or toluene affords acid chloride (ii). yields have been improved with the addition of benzyltriethylammonium chloride as a catalyst. acid chloride (ii) is then condensed with 3-amino-1,2-propanediol (iii) to produce diamide (iv). compound (iv) is converted to the tetraacetate ester (v) employing acetic anhydride in pyridine. subsequent acylation of the amino group of (v) with acetoxyacetyl chloride (vi) gives amide (vii). after saponification of the ester groups of (vii), the resultant hydroxy acetamide (viii) is alkylated by 2-chloroethanol (ix) to furnish the title compound. alternatively, amide (viii) is alkylated by bromoethyl acetate (x), producing (xi). hexa-ester (xi) is finally hydrolyzed with aqueous sulfuric acid. an improved procedure for this final hydrolysis step uses 1,1,2-trichloroethane as co-solvent.
List of intermediates No.
2,3,5,6-tetrachloro-1,4-benzoquinone; 2,3,5,6-tetrachlorobenzo-1,4-quinone; p-chloranil (x)
trimethyl[(2e)-2,4-pentadienyl]stannane (vi)
dichlorophoephoric acid 4-bromophenyl ester (iii)
(4-aminophenyl)methanol (i)
ethyl 1-benzyl-5-hydroxy-1,2,3,6-tetrahydro-4-pyridinecarboxylate (ii)
(e)-3-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-2-methyl-2-propenal (ix)
Reference 1:
    lin, y. (mallinckrodt medical inc.); cpds. suitable for x-ray visualisation methods. ep 0083964; us 4396598 .
Reference 2:
    dunn, t.j.; white, d.h.; kneller, m.t.; jones, m.m.; doran, n.o. iii; bailey, a.r. (mallinckrodt medical inc.); process for producing ioversol. wo 9727172 .
Reference 3:
    kneller, m.t.; bailey, a.r.; sathe, s.s.; spears, a.t.; wisneski, r.c. (mallinckrodt medical inc.); improved synthesis of ioversol. wo 9323365 .
Reference 4:
    villa, m.; castaldi, g.; pozzoli, c.; russo, l. (zambon group spa); process for the preparation of 5-amino-2,4,6-triiodoisophthalic acid dichloride by chlorination with thionyl chloride in the presence of a catalyst. wo 9636590 .
Reference 5:
    lin, y.; dean, r.t.; kneller, m.; wallace, r.a.; mccarthy, w.z.; white, d.h. (mallinckrodt medical inc.); process for production of ioversol. wo 9111431 .

Route 2
in a related method, the intermediate tetrahydroxy amine (i) is acylated by chloroacetyl chloride (ii) to produce the penta(chloroacetyl) derivative (iii). the chloroacetate ester groups are then hydrolyzed under basic conditions to afford the tetra-hydroxy chloroacetamide (iv). conversion of (iv) to the hydroxy acetamide (v) is accomplished by treatment with sodium acetate and naoh. amide (v) is finally alkylated with either chloroetanol (vi) or with ethylene oxide (vii) to furnish the title n-(hydroxyethyl) amide.
List of intermediates No.
2,3,5,6-tetrachloro-1,4-benzoquinone; 2,3,5,6-tetrachlorobenzo-1,4-quinone; p-chloranil (vi)
3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-4-phenyl-1,4-dihydropyridine (vii)
1-(methylamino)-3-tetracyclo[6.6.2.0(2,7).0(9,14)]hexadeca-2,4,6,9,11,13-hexaen-1-yl-2-propanol (ii)
Reference 1:
    dunn, t.j.; kneller, m.t.; white, d.h.; jones, m.m.; doran, n.o. (mallinckrodt medical inc.); process for producing ioversol. wo 9640286 .

Route 3
in an alternative procedure, the intermediate amino tetraacetate (i) is acylated by chloroacetyl chloride (ii), yielding chloroacetamide (iii). the amide n is then alkylated with bromoethyl acetate (iv) to produce (v). simultaneous hydrolysis of the acetate esters and the chloro group in aqueous sulfuric acid furnishes the title compound.
List of intermediates No.
1-(methylamino)-3-tetracyclo[6.6.2.0(2,7).0(9,14)]hexadeca-2,4,6,9,11,13-hexaen-1-yl-2-propanol (ii)
(e)-3-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-2-methyl-2-propenal (iv)
Reference 1:
    mccarthy, w.z.; kneller, m.t.; lin, y.; white, d.h. (mallinckrodt medical inc.); synthesis of ioversol using chloroacetyl chloride. wo 9301840 .

Route 4
similarly, the tetrahydroxy amine (i) is acylated by chloroacetyl chloride (ii) to produce the tetraester amide (iii). after amide alkylation with bromoethyl acetate (iv), the resultant penta-ester (v) is hydrolyzed to the title compound using aqueous sulfuric acid.
List of intermediates No.
1-(methylamino)-3-tetracyclo[6.6.2.0(2,7).0(9,14)]hexadeca-2,4,6,9,11,13-hexaen-1-yl-2-propanol (ii)
(e)-3-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-2-methyl-2-propenal (iv)
Reference 1:
    mccarthy, w.z.; kneller, m.t.; lin, y.; white, d.h. (mallinckrodt medical inc.); synthesis of ioversol using chloroacetyl chloride. wo 9301840 .

Route 5
a further synthetic variation for the title compound is based on the acylation of intermediate (i) with acetoxyacetyl chloride (ii) to afford (iii). amide alkylation with bromoethyl acetate (iv) furnishes (v). the ester groups of (v) are finally hydrolyzed in aqueous sulfuric acid.
List of intermediates No.
trimethyl[(2e)-2,4-pentadienyl]stannane (ii)
(e)-3-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-2-methyl-2-propenal (iv)
Reference 1:
    lin, y.; wallace, r.a.; mccarthy, w.z.; kneller, m.t.; white, d.h. (mallinckrodt medical inc.); synthesis of ioversol using a minimal excessof acetoxyacetylchloride. us 5371278 .

Route 6
an improved method for the preparation of the iodinated precursor (ii) has been reported. thus, iodination of the amino isophthalamide (i) with iodine monochloride is performed with co-addition of phosphoric acid, to yield a higher purity triiodo derivative (ii).
List of intermediates No.
Reference 1:
    leibner, j.e. (mallinckrodt medical inc.); improved synthesis of ioversol using phosphoric acid modified co-addition. wo 9535122 .

Route 7
in a different strategy, the target n-aryl hydroxy acetamide has been obtained by smiles rearrangement of the aryloxy acetamide (i) under basic conditions.
List of intermediates No.
Reference 1:
    anelli, p.l.; et al.; smiles rearrangement as a tool for the preparation of 5-[(2-hydroxyacyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamides: main pathway and side reactions. tetrahedron 1997, 53, 34, 11919.
Reference 2:
    musu, c.; felder, e.; fumagalli, l.; piva, r.; uggeri, f.; smiles rearrangement, a new synthetic pathway to the synthesis of 5-(hydroxyacyl)-amino-2,4,6-triiodoisophthalamides. invest radiol 1990, 25, suppl. 1, s100-1.

Route 8
in an improved method, the acetamido isophthalamide (i) is treated with boric acid and koh to form the cyclic diborate tripotassium salt (ii). subsequent alkylation of (ii) with 2-chloroethanol (iii) yields regioselectively the n-alkylated acetamide (iv). the borate groups of (iv) are finally removed upon quenching with diluted hcl.
List of intermediates No.
2,3,5,6-tetrachloro-1,4-benzoquinone; 2,3,5,6-tetrachlorobenzo-1,4-quinone; p-chloranil (iii)
Reference 1:
    bjoersvik, h.-r.; et al.; a selective process for n-alkylation in competition with o-alkylation: boric acid, borax, and metaborate as a cheap and effective protecting group applicable for industrial-scale synthetic processes. org process res dev 2001, 5, 5, 472.
Reference 2:
    priebe, h. (amersham plc); an n-alkylation. gb 2331098 .

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碘氟醇;英文名Ioversol;MU-328(as syringe);MP-328;Optiject;Optiray;CAS[87771-40-2]

 
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