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药物详细合成路线

Name Albaconazole;UR-9825
Chemical Name (1R,2R)-7-Chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one
CAS 187949-02-6
Related CAS
Formula C20H16ClF2N5O2
Structure
Formula Weight 431.83262
Stage I 期临床
Company Uriach (Originator)
Activity/Mechanism Antifungal Agents, ANTIINFECTIVE THERAPY
Syn. Route 2
Route 1
the condensation of the chiral oxazolidinone (i) with 2,4-difluorophenacyl bromide (ii) by means of nahmds in thf/et2 o gives the chiral oxirane (iii), which is treated with lioh and h2o2 to eliminate the chiral auxiliary, yielding the carboxylic acid (iv). the cleavage of the oxirane ring of (iv) with 1,2,4-triazole (v) and nah in hot dmf affords the chiral hydroxyacid (vi), which is submitted to curtius rearrangement by means of dppa in hot pyridine to provide the chiral oxazolidinone (vii). the cleavage of the oxazolidinone ring of (vii) by means of refluxing aq. hcl gives the chiral aminoalcohol (viii), which is condensed with 2-amino-4-chlorobenzoic acid (ix) by means of dcc and hobt to yield the corresponding amide (x). finally, this compound is cyclized to the target quinazolinone by reaction with triethyl orthoformate in hot dioxane/nmp.
List of intermediates No.
5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione (v)
2-(benzyloxy)-5-nitro-1h-isoindole-1,3(2h)-dione (i)
1-[(2r,3r,4r,5r)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydro-2-furanyl]-5-(5h-dibenzo[a,d]cyclohepten-5-yl)-4-thioxo-3,4-dihydro-2(1h)-pyrimidinone (ii)
Reference 1:
    bartroli, j.; et al.; aldol condensation of evans chiral enolates with acetophenones. its application to the stereoselective synthesis of homochiral antifungal agents. j org chem 1995, 60, 10, 3000.
Reference 2:
    bartroli, j.; et al.; new azole antigungals. 3. synthesis and antifungal activity of 3-substituted-4(3h)-quinazolinones. j med chem 1998, 41, 11, 1869.
Reference 3:
    bartrolí, j.; turmo, e.; anguita, m. (j. uriach & cía., sa); new pyrimidone derivs. with antifungal activity. ep 0783501; es 2107376; es 2120885; jp 1998508317; us 5807854; wo 9705130 .

Route 2
the condensation of (r)-lactic acid (i) with morpholine (ii) gives the corresponding morpholide (iii), which is protected at the hydroxyl position with dihydropyran (iv) to yield the tetrahydropyranyl ether (v). the grignard reaction of (v) with 2,4-difluorophenylmagnesium bromide (vi) affords the chiral 1-propanone (vii), which by a coreys diastereoselective epoxidation with trimethylsulfoxonium iodide is converted into the oxirane (viii). the opening of the oxirane ring of (viii) by means of 1,2,4-triazole (ix) and nah provides the tertiary alcohol (x), which is treated with pyridine p-toluenesulfonate to give the deprotected diol (xi) as a (2r,3r) and (2r,3s) 4:1 diastereomeric mixture, from which the desired (2r,3r)-isomer (xii) was isolated by crystallization. the reaction of (xii) with ms-cl and tea, followed by cyclization with naome, yields the oxirane (xiii), which is finally condensed with 7-chloroquinazolin-4(3h)-one (xiv) by means of k2co3 in hot nmp.
List of intermediates No.
2-(4-benzhydryl-1-piperazinyl)ethyl (z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate (ii)
(2r)-2-[([(2s)-1-[(2s,5s,8r,11s,14s,17r,20r)-20-(4-chlorobenzyl)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-14-(hydroxymethyl)-5-isobutyl-24,24-dimethyl-4,7,10,13,16,19,22-heptaoxo-17-(3-pyridinylmethyl)-23-oxa-3,6, (i)
4-([[3-(4-morpholinyl)propyl]imino]methyl)-2-pyrimidinamine (xii)
5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione (ix)
methyl (2s,3s,4s,5r,6r)-6-[5-(4-[[2,4-dimethyl-7-oxo-6,7-dihydropyrido[2,3-d]pyrimidin-8(5h)-yl]methyl][1,1-biphenyl]-2-yl)-2h-1,2,3,4-tetraazol-2-yl]-3,4,5-trihydroxytetrahydro-2h-pyran-2-carboxylate (iv)
2-[(dichlorophosphoryl)oxy]benzoyl chloride (vi)
(2r)-5-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid (xiii)
methyl 2-[3-(3-bromopropoxy)phenyl]acetate (v)
2-bromoethyl trifluoromethanesulfonate (xiv)
Reference 1:
    tasaka, a.; tamura, n.; matsushita, y.; teranishi, k.; hayashi, r.; okonogi, k.; itoh, k.; optically active antifungal azoles. i. synthesis and antifungal activity of (2r,3r)-2-(2,4-difluorophenyl)-3-mercapto-1-(1h-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. chem pharm bull 1993, 41, 6, 1035-42.
Reference 2:
    bartroli orpi, j.; anguita lopez, m. (j. uriach & cia., sa); method for preparing pyrimidone derivs. with antifungal activity. es 2159488; wo 0166519 .

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阿巴康唑;英文名Albaconazole;UR-9825;CAS[187949-02-6]

 
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