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药物详细合成路线

Name Habekacin;Arbekacin;Habekacin
Chemical Name 1-N-[(S)-4-Amino-2-hydroxybutyryl]dibekacin;1-N-[(S)-4-Amino-2-hydroxybutyryl]-3,4-dideoxykanamycin B;O-3-Amino-3-deoxy-alpha-D-glucopyranosyl-(1--4)-O-[2,6-diamino-2,3,4,6-tetradeoxy-alpha-D-erythro-hexopyranosyl-(1--6)]-N-[(2S)-4-amino-2-hydroxybutyryl]-2-deoxy-L-streptamine
CAS 51025-85-5
Related CAS 75282-65-4 (carbonate(1:2) salt)
Formula C22H44N6O10
Structure
Formula Weight 552.63018
Stage 上市-1990
Company Meiji Seika (Originator)
Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY, Aminoglycosides
Syn. Route 5
Route 1
the acylation of 3,4-dideoxykanamycin b (dibekacin) (i) with n-benzyloxycarbonyloxysuccinimide (ii) and zinc acetate in dmso gives 3,2,6-tri-n-benzyloxycarbonydibekacin (iii), which is then treated with the n-hydroxysuccinimide ester of 2-hydroxy-4-aminobutyric acid (iv) and finally deprotected by hydrogenation with h2 over pd/c in acidic water dioxane.
List of intermediates No.
(4-chlorophenyl)methanesulfonyl chloride (i)
(ii)
(iii)
(iv)
Reference 1:
    umezawa, h.; umezawa, s.; tsuchiya, t.; takagi, y.; jikihara, t. (microbial chemistry research foundation); production of a selectively protected n-acylated derivative of an aminoglycosidic antibiotic. be 0879925; de 2945010; fr 2441631; fr 2482109; gb 2036020; gb 2065123; jp 80164696; jp 8064598; us 4297485 .
Reference 2:
    serradell, m.n.; castaner, j.; blancafort, p.; habekacin. drugs fut 1983, 8, 5, 410.

Route 2
the acylation of 3,4-dideoxykanamycin b (dibekacin) (i) with benzyloxycarbonyl chloride in water gives 6-n-benzyloxycarbonyldibekacin (v), which is then acylated with (iv) as before and deprotected by hydrogenolysis with h2 over pd/c in water - acetic acid.
List of intermediates No.
[5-[3-benzoyl-2,4-dioxo-5-vinyl-3,4-dihydro-1(2h)-pyrimidinyl]-3-(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate
(4-chlorophenyl)methanesulfonyl chloride (i)
(iv)
(v)
Reference 1:
    umezawa, h.; umezawa, s.; maeda, k.; tsuchiya, o.; kondo, s.; fukatsu, s. (microbial chemistry research foundation); 1-n-[(s)-alpha-hydroxy-omega-aminoacyl]. de 2530169; fr 2201875; gb 1426908; jp 7462442; jp 7480039; jp 7494648; jp 7733629; jp 8003357; us 4001208; us 4107424 .
Reference 2:
    serradell, m.n.; castaner, j.; blancafort, p.; habekacin. drugs fut 1983, 8, 5, 410.

Route 3
the acylation of 3,2,6-tri-n-benzyloxycarbonydibekacin (iii) with ethyl trifluoroacetate and k2co3 gives 3,2,6-tri-n-benzyloxycarbonyl-3-trifluoroacetyldibekacin (vi), which is acylated again with (iv) yielding the protected habekacin (vii). finally, this compound is deprotected by hydrolysis with ammonia in aqueous thf, followed by hydrogenolysis with h2 over pd/c.
List of intermediates No.
(4-chlorophenyl)methanesulfonyl chloride (i)
(ii)
(iii)
(iv)
5-iodo-3-thiophenecarbaldehyde (vi)
(5-iodo-3-thienyl)methanol (vii)
Reference 1:
    tsuchiya, t.; takagi, y.; umezawa, s.; 1-n-acylation of aminocyclitol antibiotics via zinc chelation and regiospecific n-trifluoroacetylation. tetrahedron lett 1979, 51, 4951-54.
Reference 2:
    serradell, m.n.; castaner, j.; blancafort, p.; habekacin. drugs fut 1983, 8, 5, 410.

Route 4
the acylation of 3,4-dideoxykanamycin b (dibekacin) (i) with tert-butyl-s-(4,6-dimethylpyrimid-2-yl)thiocarbonate (viii) by means of triethylamine in isopropanol gives 3,2,6-tri-n-tert-butyloxycarbonyldibekacin (ix), which is acylated again with 4-benzyloxycarbonylamino-2-hydroxybutyric acid n-hydroxysuccinimide ester (x) in the yielding the protected habekacin (xi). finally, this compound is deprotected by a treatment with trifluoroacetic acid, followed by hydrogenolysis with h2 over pd/c in methanol - acetic acid.
List of intermediates No.
(4-chlorophenyl)methanesulfonyl chloride (i)
(viii)
(ix)
(x)
(xi)
Reference 1:
    umezawa, h.; kondo, s. (microbial chemistry research foundation); process for the preparation of 1-n-isoseryl- or 1-n-(l-4-amino-2-hydroxybutyryl)-3,4-dideoxykanamycin b and intermediates thereof. de 2950020; fr 2444046; gb 2038329; gb 2072676; gb 2072677; jp 55081897; us 4268664 .
Reference 2:
    serradell, m.n.; castaner, j.; blancafort, p.; habekacin. drugs fut 1983, 8, 5, 410.

Route 5
the acylation of 3,4-dideoxy-3,4-didehydrokanamycin b (xii) with tert-butyl-s-(4,6-dimethylpyrimid-2-yl)thiocarbonate (viii) as before gives 3,2,6-tri-n-butoxycarbonyl-3,4-dideoxy-3,4-didehydrokanamycin b (xiii), which is acylated again with (x) as before yielding the fully protected 3,4-didehydrohabekacin (xiv). partial deprotection of (xiv) with trifluoroacetic acid affords 1-n-(4-benzyloxycarbonylamino-2-hydroxybutyryl)-3,4-dideoxy-3,4-didehydrokanamycin b (xv), which is finally debenzylated and reduced by a treatment with h2 over pto2 in aqueous acetic acid.
List of intermediates No.
(viii)
(x)
(xii)
(xiii)
(5r,6s)-6-[4-(propylsulfonyl)-1,2,5-thiadiazol-3-yl]-1-azabicyclo[3.2.1]octane; 4-[(5r,6s)-1-azabicyclo[3.2.1]oct-6-yl]-1,2,5-thiadiazol-3-yl propyl sulfone (xiv)
4-[(5r,6s)-1-azabicyclo[3.2.1]oct-6-yl]-1,2,5-thiadiazole-3-thiol; 4-[(5r,6s)-1-azabicyclo[3.2.1]oct-6-yl]-1,2,5-thiadiazol-3-ylhydrosulfide (xv)
Reference 1:
    serradell, m.n.; castaner, j.; blancafort, p.; habekacin. drugs fut 1983, 8, 5, 410.

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贝卡星;英文名Habekacin;Arbekacin;Habekacin;CAS[51025-85-5]

 
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