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              Name Avasimibe;CI-1011
              Chemical Name N-[2-(2,4,6-Triisopropylphenyl)acetyl]sulfamic acid 2,6-diisopropylphenyl ester
              CAS 166518-60-1
              Related CAS 166518-61-2 (sodium salt)
              Formula C29H43NO4S
              Structure
              Formula Weight 501.73436
              Stage III 期臨床
              Company Pfizer (Originator)
              Activity/Mechanism Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, ACAT Inhibitors
              Syn. Route 2
              Route 1
              1) synthesis of intermediate (v):the reduction of 2,4,6-triisopropylbenzoyl chloride (i) with lialh4 in ethyl ether gives 2,4,6-triisopropylbenzyl alcohol (ii) (1-4), which by reaction with socl2 in toluene is converted into 2,4,6-triisopropylbenzyl chloride (iii). the reaction of (iii) with nacn or kcn in dmso affords 2,4,6-triisopropylphenylacetonitrile (iv), which is hydrolyzed with aqueous h2so4 or koh in diethylene glycol/water, yielding the phenylacetic acid (v).2) synthesis of intermediate (iii):the intermediate benzyl chloride (iii) can also be obtained by direct chloromethylation of 1,3,5-triisopropylbenzene (xi) with paraformaldehyde/hcl in acetic acid.3) synthesis of intermediate (v):phenylacetic acid (v) can also be obtained by condensation of 1,3,5-triisopropylbenzene (xi) with glyoxylic acid (xiv) by means of h2so4 in refluxing acetic acid, yielding a mixture of acetoxyacetic acid (xv) and hydroxyacetic acid (xvi). this mixture is finally reduced with hi in acetic acid to the phenylacetic acid (v).4) synthesis of intermediate (iv):the acetonitrile (iv) can also be obtained by reaction of benzyl bromide (xii) with kcn in dmso.5) synthesis of intermediate (xiii):avasimibe can also be obtained by reaction of benzyl alcohol (ii) with pbr3 in ether to give the benzyl bromide (xii), which is treated with mg in thf to yield the corresponding grignard reagent (xiii).
              List of intermediates No.
              2-cyclopropyl-4-methoxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1h-benzimidazole-7-carbaldehyde (xi)
              4-[(3-bromopropyl)amino]-5-chloro-3(2h)-pyridazinone (xiv)
              (6r,7r)-3-[(acetoxy)methyl]-7-[[(2r)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (i)
              (6r,7r)-3-[(acetoxy)methyl]-7-[[(2r)-2-[[(4-hydroxy-6-methyl-3-pyridinyl)carbonyl]amino]-2-(4-hydroxyphenyl)ethanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (ii)
              2-[(8s,9s,10r,11s,13s,14s,16r,17r)-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate (iii)
              2-[(8s,9s,10r,11s,13s,14s,16r,17r)-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate (iv)
              (8s,9s,10r,11s,13s,14s,16r,17r)-17-glycoloyl-11,17-dihydroxy-10,13,16-trimethyl-8,9,10,11,12,13,14,15,16,17-decahydro-3h-cyclopenta[a]phenanthren-3-one (v)
              (8s,9s,10r,11s,13s,14s,16r,17r)-17-glycoloyl-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3h-cyclopenta[a]phenanthren-17-yl propionate (xii)
              (8s,9s,10r,11s,13s,14s,16r,17r)-11-hydroxy-10,13,16-trimethyl-3-oxo-17-[2-(propionyloxy)acetyl]-8,9,10,11,12,13,14,15,16,17-decahydro-3h-cyclopenta[a]phenanthren-17-yl propionate (xiii)
              2-[(8s,9s,10r,13s,14s,16r,17r)-17-hydroxy-10,13,16-trimethyl-3,11-dioxo-8,9,10,11,12,13,14,15,16,17-decahydro-3h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate (xv)
              (8s,9s,10r,13s,14s,16r,17r)-17-glycoloyl-17-hydroxy-10,13,16-trimethyl-9,10,12,13,14,15,16,17-octahydro-3h-cyclopenta[a]phenanthrene-3,11(8h)-dione (xvi)
              Reference 1:
                  sliskovic, d.r.; ci-1011: an atypical acat inhibitor with antiatherosclerotic activity. int symp med chem 1996, abst sr-06.2.
              Reference 2:
                  lee, h.t.; sliskovic, d.r.; picard, j.a.; et al.; inhibitors of acyl-coa:cholesterol o-acyl transferase (acat) as hypocholesterolemic agents. ci-1011: an acyl sulfamate with unique cholesterol-lowering activity in animals fed noncholesterol-supplemented diets. j med chem 1996, 39, 26, 5031.
              Reference 3:
                  sorbera, l.a.; rabasseda, x.; casta?er, j.; avasimibe . drugs fut 1999, 24, 1, 9.
              Reference 4:
                  lee, h.t.; picad, j.a.; sliskovic, d.r.; wierenga, w. (pfizer inc.); n-acyl sulfamic acid esters (or thioesters), n-acyl sulfonamides, and n-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents. ep 0698010; jp 1996510256; us 5491172; wo 9426702 .
              Reference 5:
                  dozeman, g.j.; et al.; chemical development of a pilot scale process for the acat inhibitor 2,6-diisopropylphenyl [(2,4,6-triisopropylphenyl)acetyl]sulfamate. org process res dev 1997, 1, 2, 137-48.

              Route 2
              1) the reaction of (v) with socl2 or (cocl)2 in dmf affords the expected acyl chloride (vi), which is finally condensed with 2,6-diisopropylphenyl sulfamate (vii) by means of triethylamine in hot toluene to obtain avasimibe.2) the sulfamate (vii) can be obtained by condensation of 2,6-diisopropylphenol (viii) with chlorosulfonyl isocyanate (ix) in refluxing toluene to give the isocyanate (x), which is hydrolyzed with water to the sulfamate (vii). compound is condensed with the previously described isocyanate (x) in refluxing thf to obtain avasimibe.3) avasimibe can also be obtained by condensation of isocyanate (x) with grignard reagent (xiii).
              List of intermediates No.
              methyl (2r,3s)-3-azido-3-cyclopropyl-2-hydroxypropanoate (ix)
              (8s,9s,10r,11s,13s,14s,16r,17r)-17-glycoloyl-11,17-dihydroxy-10,13,16-trimethyl-8,9,10,11,12,13,14,15,16,17-decahydro-3h-cyclopenta[a]phenanthren-3-one (v)
              (8s,9s,10r,11s,13s,14s,16r,17r)-11-hydroxy-10,13,16-trimethyl-3-oxo-17-[2-(propionyloxy)acetyl]-8,9,10,11,12,13,14,15,16,17-decahydro-3h-cyclopenta[a]phenanthren-17-yl propionate (xiii)
              2-ethoxy-2-ethyl-16alpha-methylspiro[androsta-1,4,6-triene-17(r),4-[1,3]dioxane]-3,5,11-trione (vi)
              (8s,9s,10r,13s,14s,16r,17r)-17-glycoloyl-10,13,16-trimethyl-3,11-dioxo-8,9,10,11,12,13,14,15,16,17-decahydro-3h-cyclopenta[a]phenanthren-17-yl propionate (vii)
              2-oxo-2-[(8s,9s,10r,13s,14s,16r,17r)-10,13,16-trimethyl-3,11-dioxo-17-(propionyloxy)-8,9,10,11,12,13,14,15,16,17-decahydro-3h-cyclopenta[a]phenanthren-17-yl]ethyl propionate (viii)
              2-bromopropane (x)
              Reference 1:
                  sorbera, l.a.; rabasseda, x.; casta?er, j.; avasimibe . drugs fut 1999, 24, 1, 9.
              Reference 2:
                  lee, h.t.; picad, j.a.; sliskovic, d.r.; wierenga, w. (pfizer inc.); n-acyl sulfamic acid esters (or thioesters), n-acyl sulfonamides, and n-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents. ep 0698010; jp 1996510256; us 5491172; wo 9426702 .

              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阿伐麥布;英文名Avasimibe;CI-1011;CAS[166518-60-1]

               
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