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Name FTY-720A;FTY-720
Chemical Name 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride
CAS 162359-56-0
Related CAS 162359-55-9 (free base)
Formula C19H34ClNO2
Structure
Formula Weight 343.94133
Stage III 期临床
Company Mitsubishi Pharma (Originator), Taito (Originator), Novartis (Licensee)
Activity/Mechanism Immunologic Neuromuscular Disorders, Treatment of, IMMUNOMODULATING AGENTS, Immunosuppressants, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, Treatment of Transplant Rejection, Apoptosis Inducers, Lysophospholipid edg1 (S1P1) Receptor Agonists
Syn. Route 3
Route 1
the friedel-crafts condensation of phenethyl acetate (i) with octanoyl chloride (ii) by means of alcl3 in dichloroethane gives 2-(4-octanoylphenyl)ethyl acetate (iii), which is reduced with triethylsilane in tfa to afford 2-(4-octylphenyl)ethyl acetate (iv). the deprotection of (iv) with sodium ethoxide in ethanol gives 2-(4-octylphenyl)ethanol (v), which is treated with methanesulfonyl chloride followed by sodium iodide in refluxing 2-butanone yielding 2-(4-octylphenyl)ethyl iodide (vi). the condensation of (vi) with diethylacetamidomalonate (vii) by means of sodium ethoxide in ethanol/thf gives diethyl 2-acetamido-2-[2-(4-octylphenyl)ethyl]malonate (viii), which is reduced with lialh4 in thf and treated with acetic anhydride in pyridine to afford 2-acetamido-2-(acetoxymethyl)-4-(4-octylphenyl)butyl acetate (ix). the hydrolysis of (ix) with lithium hydroxide in refluxing methanol/water gives 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (x), which is finally treated with hcl in diethyl ether.
List of intermediates No.
benzyl (3r,4r)-4-(2,3-dimethylphenoxy)-3-hydroxy-1-piperidinecarboxylate (ii)
(6-amino-2,3-dichlorophenyl)methanol (i)
4-acetoxy-2-pyrrolidone; 5-oxo-3-pyrrolidinyl acetate (iii)
chloro(trimethyl)silane; trimethylsilyl chloride; trimethylchlorosilane (iv)
5-oxo-1-(trimethylsilyl)-3-pyrrolidinyl acetate (v)
1-(4-methoxybenzoyl)-1,5-dihydro-2h-pyrrol-2-one (vi)
4-[(4-methoxybenzoyl)amino]butyric acid (vii)
methyl 2-[(4-methoxybenzoyl)amino]benzoate (viii)
4-methoxy-n-[2-[2-(2-pyridinyl)acetyl]phenyl]benzamide (ix)
1,4,7,10-tetraoxa-13-azacyclopentadecane (x)
Reference 1:
    chiba, k.; adachi, k.; fty720. drugs fut 1997, 22, 1, 18.
Reference 2:
    fujita, t.; sasaki, s.; yoneta, m.; mishina, t.; adachi, k.; chiba, k. (taito co., ltd.; welfide corporation); 2-amino-1,3-propanediol compound and immunosuppressant. ep 0627406; jp 1994509845; us 5719176; wo 9408943 .
Reference 3:
    kiuchi, m.; adachi, k.; kohara, t.; et al.; synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols. j med chem 2000, 43, 15, 2946.

Route 2
a new synthesis of fty-720 has been described: the friedel crafts condensation of octylbenzene (i) with bromoacetyl chloride (ii) by means of alcl3 in dichloromethane gives the phenacyl bromide (iii), which is condensed with 2-acetamidomalonic acid diethyl ester (iv) by means of etona in ethanol/thf to yielding the ketone-malonic ester adduct (v). reduction of (v) with et3sih by means of ticl4 in dichloromethane affords compound (vi), which is then reduced with lialh4 in thf followed by acetylation with acetic anhydride and pyridine to provide the acetate (vii). finally, compound (vii) is hydrolyzed with lioh in refluxing methanol/water and treated with hcl in ethyl ether.
List of intermediates No.
4-[(4-methoxybenzoyl)amino]butyric acid (iv)
methyl 2-[(4-methoxybenzoyl)amino]benzoate (vi)
4-methoxy-n-[2-[2-(2-pyridinyl)acetyl]phenyl]benzamide (vii)
5-[2-(dibenzylamino)acetyl]-2-hydroxybenzamide; 5-(n,n-dibenzylglycyl)salicylamide (ii)
(2r,3r,4s,5r,6r)-3-(acetyloxy)-5-{[(3r,4s,5s,6r)-6-[(acetyloxy)methyl]-3,4,5-tris(benzyloxy)tetrahydro-2h-pyran-2-yl]oxy}-6-[(benzyloxy)methyl]-2-{[(1r,2r,3s,4r,5r)-3,4-bis(acetyloxy)-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}tetrahydro-2h-pyran-4-yl acetate (i)
(2r,3r,4s,5r,6r)-3-(acetyloxy)-5-({(2r,3r,4s,5s,6r)-6-[(acetyloxy)methyl]-3,4,5-trihydroxytetrahydro-2h-pyran-2-yl}oxy)-2-{[(1r,2r,3s,4r,5r)-3,4-bis(acetyloxy)-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-6-(hydroxymethyl)tetrahydro-2h-pyran-4-yl acetate (iii)
(2r,3r,4s,5s,6r)-2-{[(2r,3s,4r,5r,6s)-6-{[(1r,2s,3r,4r,5r)-3,4-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2h-pyran-3-yl]oxy}-6-(hydroxymethyl)tetrahydro-2h-pyran-3,4,5-triol (v)
Reference 1:
    renault, p.; durand, p.; peralba, p.; sierra, f.; a new efficient synthesis of the immunosuppressive agent fty-720. synthesis 2000, 4, 505.

Route 3
a new synthesis of fty-720 has been reported: condensation of 4-chlorobenzaldehyde (i) with octylzinc iodide (ii) by means of ni(0) gives 4-octylbenzaldehyde (iii), which is treated with vinylmagnesium bromide (iv) to yield the allyl alcohol (v). epoxidation of (v) with mcpba affords the epoxide (vi), which is opened by means of nano2 and mgso4 in refluxing methanol to provide 3-nitro-1-(4-octylphenyl)propane-1,2-diol (vii). reaction of diol (vii) with trimethylsilyl chloride and nai in acetonitrile gives 3-nitro-1-(4-octylphenyl)-1-propene (viii), which is hydrogenated with h2 over pd/c in ethanol yielding the corresponding nitropropane derivative (ix). the bis-formylation of compound (ix) with aqueous hcho in the presence of amberlyst a-21 in dichloromethane affords 2-nitro-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (x), which is finally reduced with h2 over ra-ni to provide fty-720.
List of intermediates No.
benzhydryl (6r,7r)-7-[((2r,3s)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxybutanoyl)amino]-3-[[(1-methyl-1h-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iv)
n-(2-ethoxybenzyl)[3-(4-methylphenoxy)phenyl]methanamine; n-(2-ethoxybenzyl)-n-[3-(4-methylphenoxy)benzyl]amine (i)
Reference 1:
    kalita, b.; barua, n.c.; bez, g; bezbarua, m.; synthesis of 2-nitro alcohols by regioselective ring opening of epoxides with mgso4/neoh/nano2 system: a short synthesis of immunosuppressive agent fty-720. synlett 2001, 9, 1411.

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盐酸芬戈莫德;英文名FTY-720A;FTY-720;CAS[162359-56-0]

 
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