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Name Thalidomide;NSC-66847;K-17;Talizer;Thalomid;Synovir
Chemical Name (±)-2-(2,6-Dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione;(±)-N-(2,6-Dioxopiperidin-3-yl)phthalimide;(±)-alpha-(N-Phthalimido)glutarimide
CAS 50-35-1
Related CAS
Formula C13H10N2O4
Structure
Formula Weight 258.23565
Stage 上市-1998
Company Celgene (Orphan Drug), Andrulis (Originator), EntreMed (Originator), University of Minnesota (Not Determined), Celgene (Licensee), Penn (Licensee), Pharmion (Licensee), National Cancer Institute (Codevelopment), Pfizer (Codevelopment)
Activity/Mechanism AIDS Medicines, Antiarthritic Drugs, ANTIINFECTIVE THERAPY, Antimycobacterial Agents, Brain Cancer Therapy, Breast Cancer Therapy, Cognition Disorders, Treatment of, Colorectal Cancer Therapy, GASTROINTESTINAL DRUGS, Glioblastoma MultiformeTherapy, Immunologic Neuromuscular Disorders, Treatment of, Inflammatory Bowel Disease, Agents for, Kaposis Sarcoma Therapy, Leukemia Therapy, Liver Cancer Therapy, Lung Cancer Therapy, Multiple Myeloma Therapy, Multiple Sclerosis, Agents for, Myelodysplastic Syndrome Therapy, NEUROLOGIC DRUGS, Non-Small Cell Lung Cancer Therapy, OCULAR MEDICATIONS, Oncolytic Drugs, Ophthalmic Drugs, Prostate Cancer Therapy, Renal Cancer Therapy, Scleroderma, Agents for, Treatment of Age-Related Macular Degeneration, Treatment of AIDS-Associated Malignancies, Treatment of Cachexia, Treatment of Leprosy, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Other Autoimmune Disorders, Angiogenesis Inhibitors, TNF-alpha Production Inhibitors, TNF-alp
Syn. Route 6
Route 1
a new scaleable two-step synthesis of thalidomide was reported: the reaction of l-glutamine (i) with n-(ethoxycarbonyl)phthalimide (ii) gives the n-phthaloyl-l-glutamine (iii), which is finally cyclized by means of carbonyldimidazole (cdi) and dimethylaminopyridine.
List of intermediates No.
[2-[(e)-(6-amino-9h-purin-9-yl)methylidene]cyclopropyl]methyl benzoate (ii)
methyl (z)-7-((2r,4r,5s)-4-[[(e)-2-(anilinocarbothioyl)hydrazono]methyl]-2-methyl-1,3-dioxan-5-yl)-5-heptenoate (i)
(1s,3z,8s,9s,10r,11r)-9-(benzyloxy)-11,13-bis[[tert-butyl(dimethyl)silyl]oxy]-8,10,12,12-tetramethyl-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-tridecenyl acetate (iii)
Reference 1:
    muller, g.w.; et al.; a two step synthesis of thalidomide. 217th acs natl meet (march 21 1999, anaheim) 1999, abst orgn 079.
Reference 2:
    muller, g.w.; et al.; a concise two-step synthesis of thalidomide. org process res dev 1999, 3, 2, 139.

Route 2
a new direct synthesis of thalidomide has been reported: reaction of the commercially available n-phthaloyl-l-glutamic acid (i) with either urea (ii) or thiourea (iii) under microwave irradiation (1000 w output) provides thalidomide in 63 or 85% yield, respectively.
List of intermediates No.
methyl (1s,3as,4s,5s,7as)-4-(cyanomethyl)-7a-methyl-5-[(1r,3r,6r)-3-methyl-2-oxo-7-oxabicyclo[4.1.0]hept-3-yl]octahydro-1h-indene-1-carboxylate (iii)
[1,1-biphenyl]-4-yl(phenyl)methanone (ii)
Reference 1:
    vazquez-tato, m.p.; pacios-lopez, b.; martinez, m.m.; gonzalez-bando, c.; seijas, j.a.; microwave promoted synthesis of a rehabilitated drug: thalidomide. synthesis (stuttgart) 2001, 7, 999.

Route 3
a novel solid-phase synthesis of thalidomide has been described: the coupling of phthalic anhydride (i) with hydroxymethyl polystyrene resin (ii) by means of triethylamine and 4-dimethylaminopyridine (dmap) in dmf affords the resin-linked acid (iii), which is then condensed with alpha-aminoglutarimide (iv) by means of diisopropylcarbodiimide (dic) and n-hydroxybenzotriazole (hobt) in dmf to provide amide (v). finally, thalidomide is obtained by treatment of resin (v) with tfa in refluxing toluene.
List of intermediates No.
2-isopropoxy-1-ethanol (i)
ethyl 4,5-dimethoxy-2-nitrobenzoate (iv)
Reference 1:
    schaefer, k.; li, p.-k.; xiao, z.; firestine, s.; solid-phase synthesis of thalidomide and its analogues. j comb chem 2002, 4, 2, 149.

Route 4
the reaction of 2-(phthalimido)glutaric acid (i) with acetic anhydride and socl2 gives 2-(phthalimido)glutaric anhydride (ii), which is treated with urea at 180 c to yield the target thalidomide.alternatively, anhydride (ii) can also be treated with ammonia in dioxane at 180 c in a pressure vessel.
List of intermediates No.
Reference 1:
    (grunenthal gmbh); novel products of the amino-piperidine-2,6-dione series. gb 0768821 .
Reference 2:
    frankus, e.; graudums, i.; muckter, h. (grunenthal gmbh); derivs. of phthalimidines. gb 1185273 .

Route 5
the esterification of n-(tert-butoxycarbonyl)-d-glutamic acid 5-o-benzyl ester (i) with phenol by means of dcc and pyridine in ethyl acetate gives the mixed ester (ii), which is treated with h2 over pd/c in methanol to yield the n-(tert-butoxycarbonyl)-d-glutamic acid 1-o-phenyl ester (iii). the cyclization of (iii) with o-benzylhydroxylamine (iv) by means of edc, hobt and tea in dichloromethane affords n-[1-(benzyloxy)-2,6-dioxopiperidin-3(r)-yl]carbamic acid tert-butyl ester (v), which is treated with hcl gas in dichloromethane to provide 3(r)-amino-1-(benzyloxy)piperidine-2,6-dione (vi). the reaction of (vi) with phthalic anhydride (vii) by means of tea in thf gives the phthalimido derivative (viii), which is debenzylated with h2 over pd/c in methanol to yield 1-hydroxy-3-(r)-(phthalimido)piperidine-2,6-dione (ix). finally, the oh group of (ix) is eliminated by reaction with phenacyl bromide (x) and tea in acetonitrile to afford the phenacyl ether (xi), which is submitted to a nucleophilic cleavage by means of dmap as the base to obtain the target (r)-thalidomide.
List of intermediates No.
3,4-dimethoxy-5-propylbenzoic acid (x)
2-isopropoxy-1-ethanol (vii)
ethyl 3-[3-(3-ethoxy-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propanoate (iv)
Reference 1:
    robin, s.; et al.; a convenient asymmetric synthesis of thalidomide. tetrahedron asymmetry 1995, 6, 6, 1249.

Route 6
the esterification of n-(tert-butoxycarbonyl)-l-glutamic acid 5-o-benzyl ester (i) with phenol by means of dcc and pyridine in ethyl acetate gives the mixed ester (ii), which is treated with h2 over pd/c in methanol to yield the n-(tert-butoxycarbonyl)-l-glutamic acid 1-o-phenyl ester (iii). the cyclization of (iii) with o-benzylhydroxylamine (iv) by means of edc, hobt and tea in dichloromethane affords n-[1-(benzyloxy)-2,6-dioxopiperidin-3(s)-yl]carbamic acid tert-butyl ester (v), which is treated with hcl gas in dichloromethane to provide 3(s)-amino-1-(benzyloxy)piperidine-2,6-dione (vi). the reaction of (vi) with phthalic anhydride (vii) by means of tea in thf gives the phthalimido derivative (viii), which is debenzylated with h2 over pd/c in methanol to yield 1-hydroxy-3-(s)-(phthalimido)piperidine-2,6-dione (ix). finally the oh group of (ix) is eliminated by reaction with phenacyl bromide (x) and tea in acetonitrile to afford the phenacyl ether (xi), which is submitted to a nucleophilic cleavage by means of dmap as the base to obtain the target (s)-thalidomide.alternatively, the phthalimido derivative (viii) can also be obtained by reaction of 2(s)-(phthalimido)glutaric anhydride (xii) with o-benzylhydroxylamine (iv) by means of dcc and pyridine in dichloromethane.
List of intermediates No.
3,4-dimethoxy-5-propylbenzoic acid (x)
2-isopropoxy-1-ethanol (vii)
ethyl 3-[3-(3-ethoxy-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propanoate (iv)
3-(2-methyl-2-nitropropyl)-1h-indole (i)
Reference 1:
    robin, s.; et al.; a convenient asymmetric synthesis of thalidomide. tetrahedron asymmetry 1995, 6, 6, 1249.

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沙利度胺;英文名Thalidomide;NSC-66847;K-17;Talizer;Thalomid;Synovir;CAS[50-35-1]

 
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