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Name Isosorbide 5-mononitrate;TY-368-OD(sustained release);BM-22145;AHR-4698;IS-5-MN;Dilavenil;Uniket;Monicor;Monoket;Imdur(extended release);Ismo
Chemical Name 1,4:3,6-Dianhydro-D-glucitol 5-nitrate
CAS 16051-77-7
Related CAS
Formula C6H9NO6
Structure
Formula Weight 191.14173
Stage 上市-1981
Company Roche (Originator), AstraZeneca (Not Determined), Key Pharmaceuticals (Not Determined), Pierre Fabre (Not Determined), Lacer (Licensee), Wyeth Pharmaceuticals (Licensee)
Activity/Mechanism Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Heart Failure Therapy, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Nitrates
Syn. Route 2
Route 1
1. the nitration of isosorbide (i) with fuming hno3 in acetic acid/acetic anhydride gives the dinitrate (ii), which is selectively monoreduced by means of diisopropyltitanium tetrahydroborate (obtained by reaction of disopropyltitanium dichloride with benzyltriethylammonium borohydride) in dichloromethane to afford the isosorbide 5-nitrate.2. the reduction of dinitrate (ii) can also be performed with benzyl triethyl ammonium tetrathiomolibdate in dmf.3. the reduction of dinitrate (ii) can also be performed with h2 over pto2/c in methanol.4. the reduction of dinitrate (ii) can also be performed with cobalt phthalocyanine and nabh4 in methanol.5. the reduction of dinitrate (ii) can also be performed with zn and hoac in ethanol/water.6. the reduction of dinitrate (ii) can also be performed with h2 over pd/c and nicl2 in ethanol/water.7. the reaction of isosorbide (i) with 4-nitrobenzoyl chloride (iii) and pyridine in dichloromethane gives the isosorbide 2-o-(4-nitrobenzoate (iv), which is nitrated with hno3 in acetic acid/acetic anhydride to yield the isosorbide 5-o-nitrate-2-o-(4-nitrobenzoate) (v). finally, this compound is selectively hydrolyzed with koh in methanol/dichloromethane.
List of intermediates No.
1-[(e)-3-chloro-1-propenyl]-3-methoxy-2-nitrobenzene; 3-[(e)-3-chloro-1-propenyl]-2-nitrophenyl methyl ether (iii)
Reference 1:
    bhar, d.; chandrasekaran, s.; a highly chemoselective reduction of isosorbide-2,5-dinitrate mediated by tetrathiomolybdate. indian j chem 1997, 36b, 9, 793.
Reference 2:
    ravikumar, k.s.; chandrasekaran, s.; highly chemoselective reduction of 2,5-dinitro-1,4:3,6-dianhydro-d-glucitol with titanium(iii) tetrahydroborates: efficient synthesis of isomerically pure 2- and 5-nitro-1,4:3,6-dianhydro-d-glucitols. synthesis (stuttgart) 1994, 10, 1032.
Reference 3:
    brown, c.; et al.; new preparative routes to isosorbide 5-mononitrate. j chem soc - perkins trans i 2000, 12, 1809.
Reference 4:
    camera, e.; filipuzzi, f.; de lucchi, o.; modena, g. (consiglio nazionale delle ricerche); process for the preparation of isosorbide-5-mononitrate. ep 0201067; us 4713466 .
Reference 5:
    gallardo carrera, a. (fordonal sl); process for the preparation of isosorbide-5-nitrate. es 8402305 .
Reference 6:
    roberts, s.m.; marston, r.w.; quigley, p.f.; brown, c.m.; cross, s.j.; synthesis of isosorbide mononitrate. ep 1248788; wo 0149692 .

Route 2
8. the enantioselective monoacetylation of isosorbide (i) by means of vinyl acetate (vi) catalyzed by pig liver esterase in dichloromethane gives isosorbide 2-o-acetate (vii), which is nitrated with hno3 in acetic anhydride to yield isosorbide 2-o-acetate-5-o-nitrate (viii). finally, this compound is deacetylated by means of k2co3 in methanol.9. the enantioselective monoacylation of isosorbide (i) by means of vinyl butyrate (ix) catalyzed by chiraclec-bl in thf or carlsberg subtilisin in tert-butanol gives isosorbide 2-o-butyrate (x), which is nitrated with hno3 in acetic anhydride to yield isosorbide 2-o-butyrate-5-o-nitrate (xi). finally, this compound is deacylated by means of k2co3 in methanol.10. the acylation of isosorbide (i) with acetic anhydride and pyridine gives the diacetate (xii), which is enantioselectively monodeacetylated by means of lipase from pseudomonas fluorescens in thf to yield isosorbide 2-o-acetate (vii). this compound is then nitrated to (viii) and finally deacetylated as already described.11. the acylation of isosorbide (i) with hoac and ac2o gives (after purification by crystallization) isosorbide 2-o-acetate (vii), which is nitrated to (viii) and finally deacetylated as already described.12. the acylation of isosorbide (i) with isobutyric acid (xiii) by means of sulfuric acid in refluxing chlorobenzene/toluene gives isosorbide 2-o-isobutyrate (xiv), which is nitrated with hno3/h2so4 to yield isosorbide 2-o-isobutyrate-5-o-nitrate (xv). finally, this compound is deacylated by means of naoh in toluene/water.13. the nitration of isosorbide (i) by means of hno3 in hoac/ac2o gives a 3.5/1 mixture of isosorbide-5-o-nitrate and isosorbide 2-o-nitrate that is separated by column chromatography over alumina.14. the nitration of isosorbide (i) with hno3 in benzene/hoac/ac2o, followed by a purification step yields the target isosorbide-5-o-nitrate.
List of intermediates No.
(z)-2-butene-1,4-diol (vi)
ethyl 2-[[(benzyloxy)imino]methyl]hexanoate (xiii)
Reference 1:
    stoss, p.; process for the preparation of isosorbide-5-nitrate. de 3102947; ep 0057847; us 4371703 .
Reference 2:
    ito, t.; ishibashi, k.; ishiguro, s.; shimada, f.; a method for the preparation of isosorbide-5-nitrate and sodium isosorbide-5-nitrate hydrate as a precursor thereof. ep 0143507; us 4584391 .
Reference 3:
    dvonch, w.; alburn, h.e. (wyeth); mononitrate esters of 1,4:3,6-dianhydro-d-glucitol. de 2221080; gb 1356374; us 3886186 .
Reference 4:
    lauer, k.; kiegel, e. (boehringer ingelheim gmbh); process for the preparation of 1,4:3,6-dianhydro-d-glucite 5-nitrate (isosorbide-5-nitrate). de 3028873; ep 0045076; us 4431829 .
Reference 5:
    schonafinger, k. (cassella ag); process for the preparation of 5-isosorbide nitrate. de 3117612; ep 0064194; us 4431830 .
Reference 6:
    roberts, s.m.; marston, r.w.; quigley, p.f.; brown, c.m.; synthesis of isosorbide cpds.. gb 2358859 .

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5-單硝酸異山梨酯;英文名Isosorbide 5-mononitrate;TY-368-OD(sustained release);BM-22145;AHR-4698;IS-5-MN;Dilavenil;Uniket;Monicor;Monoket;Imdur(extended release);Ismo;CAS[16051-77-7]

 
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