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Name Mitiglinide calcium hydrate;S-21403;KAD-1229;Glufast
Chemical Name (-)-2(S)-Benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt dihydrate
CAS 207844-01-7
Related CAS 145525-41-3 (anhydrous), 145525-40-2 (anhydrous monoK salt), 145375-43-5 (anhydrous, free acid)
Formula C38H52CaN2O8
Structure
Formula Weight 704.92674
Stage 上市-2004
Company Kissei (Originator), Servier (Licensee), Takeda (Codevelopment)
Activity/Mechanism Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Secretagogues
Syn. Route 5
Route 1
the condensation of dimethyl succinate (i) with benzaldehyde (ii) by means of naome in refluxing methanol followed by hydrolysis with naoh in methanol/water gives 2-benzylidenesuccinic acid (iii). compound (iii) is treated with refluxing ac2o, yielding the corresponding anhydride (iv), which by reaction with cis-perhydroisoindole (v) in toluene affords the monoamide (vi). this amide is reduced with h2 over a chiral rhodium catalyst and treated with (r)-1-phenylethylamine (vii) to provide the chiral salt (viii) as a single diastereomer isolated by crystallization. finally, this salt is treated first with aqueous nh4oh and then with aqueous cacl2.
List of intermediates No.
2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran (vii)
methyl 3-[5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1h-thieno[2,3-e][1,4]diazepin-7-yl]propanoate (ii)
(4r)-4-[(7r,8s,9s,10s,13r,14s,17r)-7-(acetyloxy)-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3h-cyclopenta[a]phenanthren-17-yl]pentanoic acid (i)
(4r)-4-[(5s,7r,8r,9s,10s,13r,14s,17r)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoic acid (iii)
(iv)
(v)
(4r)-4-[(5r,7r,8r,9s,10s,13r,14s,17r)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoic acid (vi)
(4r)-4-[(7r,8s,9s,10r,13r,14s,17r)-7-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoic acid (viii)
Reference 1:
    castaner, r.m.; sorbera, l.a.; leeson, p.a.; castaner, j.; mitiglinide calcium hydrate. drugs fut 2000, 25, 10, 1034.
Reference 2:
    lecouve, j.-p.; souvie, j.-c.; fugier, c. (adir et cie.); method for preparing a substd. perhydroisoindole. fr 2765578; us 6133454; wo 9901430 .

Route 2
the condensation of diethyl succinate (ix) with benzaldehyde (ii) gives 2-benzylidenesuccinic acid (iii), which is treated with refluxing ac2o to yield the corresponding anhydride (iv). reaction of (iv) with cis-perhydroisoindole (v) in toluene affords the monoamide (vi), which is reduced with h2 over pd/c in ethanol to provide the racemic benzylsuccinamic acid (x). esterification of (x) with (s)-n-benzylmandelamide (xi) by means of dcc and dmap in dichloromethane gives a mixture of diastereomeric esters, which were separated by column chromatography on silica gel to provide the desired diastereomer (xii). the hydrolysis of (xii) with naoh in methanol yields the chiral acid (xiii), which is finally treated first with naoh and then with cacl2 in water.the preceding optical resolution of racemic acid (x) can also be performed with (r)-1-phenylethylamine (vii) or (r)-1-(1-naphthyl)ethylamine (xiv) by fractional crystallization of the corresponding diastereomeric salts and treatment with 2n hcl.
List of intermediates No.
2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran (vii)
methyl 3-[5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1h-thieno[2,3-e][1,4]diazepin-7-yl]propanoate (ii)
propylene oxide; 2-methyloxirane (ix)
(3ar,5r,6r,6as)-5-[(1s)-1,2-bis[(4-chlorobenzyl)oxy]ethyl]-2,2-dimethyl-6-propoxytetrahydrofuro[2,3-d][1,3]dioxole; (3ar,5r,6r,6as)-5-[(1s)-1,2-bis[(4-chlorobenzyl)oxy]ethyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl propyl ether (xiv)
(4r)-4-[(5s,7r,8r,9s,10s,13r,14s,17r)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoic acid (iii)
(iv)
(v)
(4r)-4-[(5r,7r,8r,9s,10s,13r,14s,17r)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoic acid (vi)
(3s,8s,9s,10r,13r,14s,17r)-17-[(1r,4z)-4-isopropyl-1-methyl-4-hexenyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-ol (x)
(3s,8s,9s,10r,13r,14s,17r)-17-[(1r,4z)-4-isopropyl-1-methyl-4-hexenyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl acetate (xi)
(3s,8s,9s,10r,13r,14s,17r)-17-[(1r)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl acetate (xiii)
(3s,8s,9s,10r,13r,14s,17r)-17-[(1r)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethyl-7-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl acetate (xii)
Reference 1:
    castaner, r.m.; sorbera, l.a.; leeson, p.a.; castaner, j.; mitiglinide calcium hydrate. drugs fut 2000, 25, 10, 1034.
Reference 2:
    yamaguchi, t.; et al.; preparation of optically active succinic acid derivatives. i. optical resolution of 2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)propionic acid. chem pharm bull 1997, 45, 9, 1518.

Route 3
the optical resolution of racemic 2-benzylsuccinic acid (xv) using the chiral amines (r)-1-phenylethylamine (vii), (r)-1-(1-naphthyl)ethylamine (xiv) or (s)-1-phenyl-2-(4-tolyl)ethylamine (xvi) is carried out by fractional crystallization of the corresponding diastereomeric salts and treatment with 2n hcl, providing the desired enantiomer 2(s)-benzylsuccinic acid (xvii). reaction of (xvii) with socl2 gives the corresponding acyl chloride (xviii), which is treated with 4-nitrophenol (xix) and tea in dichloromethane to yield the activated diester (xx). the regioselective reaction of (xx) with cis-perhydroisoindole (v) in dichloromethane affords the monoamide (xxi), which by reaction with hcl and methanol provides the corresponding methyl ester (xxii). this ester is hydrolyzed with naoh to the previously described chiral succinamic acid (xiii), which is finally converted into its calcium salt.
List of intermediates No.
2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran (vii)
benzhydryl 2-[3,4-bis(acetoxy)phenyl]-2-[(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)oxy]acetate (xix)
(3ar,5r,6r,6as)-5-[(1s)-1,2-bis[(4-chlorobenzyl)oxy]ethyl]-2,2-dimethyl-6-propoxytetrahydrofuro[2,3-d][1,3]dioxole; (3ar,5r,6r,6as)-5-[(1s)-1,2-bis[(4-chlorobenzyl)oxy]ethyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl propyl ether (xiv)
(v)
(3s,8s,9s,10r,13r,14s,17r)-17-[(1r)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl acetate (xiii)
(3s,5s,7r,8r,9s,10s,13r,14s,17r)-7-hydroxy-17-[(1r)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-1h-cyclopenta[a]phenanthren-3-yl acetate (xv)
(3s,5s,7r,8r,9s,10s,13r,14s,17r)-17-[(1r)-1,5-dimethyl-4-oxohexyl]-7-hydroxy-10,13-dimethylhexadecahydro-1h-cyclopenta[a]phenanthren-3-yl acetate (xvi)
(5s,7r,8r,9s,10s,13r,14s,17r)-7-hydroxy-17-[(1r)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-3h-cyclopenta[a]phenanthren-3-one (xvii)
(5s,7r,8r,9s,10s,13r,14s,17r)-7-(benzyloxy)-17-[(1r)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-3h-cyclopenta[a]phenanthren-3-one (xviii)
tert-butyl 3-({(3s,5r,7r,8r,9s,10s,13r,14s,17r)-7-(benzyloxy)-17-[(1r)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-1h-cyclopenta[a]phenanthren-3-yl}amino)propyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate (xx)
tert-butyl 3-({(3s,5r,7r,8r,9s,10s,13r,14s,17r)-7-(benzyloxy)-17-[(1r)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1h-cyclopenta[a]phenanthren-3-yl}amino)propyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate (xxi)
tert-butyl 3-({(3s,5r,7r,8r,9s,10s,13r,14s,17r)-7-(benzyloxy)-17-[(1r)-1,5-dimethyl-4-(sulfooxy)hexyl]-10,13-dimethylhexadecahydro-1h-cyclopenta[a]phenanthren-3-yl}amino)propyl{4-[(tert-butoxycarbonyl)amino]butyl}carbamate (xxii)
Reference 1:
    castaner, r.m.; sorbera, l.a.; leeson, p.a.; castaner, j.; mitiglinide calcium hydrate. drugs fut 2000, 25, 10, 1034.
Reference 2:
    mukaiyama, y.; hokari, h.; kamijo, t.; yanagi, t.; yamaguchi, t.; yamamoto, i.; preparation of optically active succinic acid derivatives. ii. efficient and practical synthesis of kad-1229. chem pharm bull 1998, 46, 2, 337-340.
Reference 3:
    yamaguchi, t.; et al.; synthesis of kad-1229, a succinic acid derivative with optical activity. 118th annu meet pharmaceut soc jpn (march 31 1998, kyoto) 1998, abst 31(xp)9-9.
Reference 4:
    yamaguchi, t.; kamijo, t.; yanagi, t. (kissei pharmaceutical co., ltd.); process for producing optically active benzylsuccinic acid and intermediate therefor. wo 9832727 .

Route 4
the reaction of 2(s)-benzylsuccinic acid 1-benzyl monoester (xxiii) with cis-perhydroisoindole (v) by means of isobutyl chloroformate and nmm in thf gives the succinamic ester (xxiv), which is hydrogenated with h2 over pd/c in ethanol, yielding the already described succinamic acid (xiii). finally, this compound is converted into its calcium salt.
List of intermediates No.
(v)
(3s,8s,9s,10r,13r,14s,17r)-17-[(1r)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl acetate (xiii)
(4r)-4-[(3s,5r,7r,8r,9s,10s,13r,14s,17r)-3-({3-[(4-aminobutyl)amino]propyl}amino)-7-(benzyloxy)-10,13-dimethylhexadecahydro-1h-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate (xxiii)
(3s,8s,9s,10r,13s,14s)-17-[(e)ethylidene]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl acetate (xxiv)
Reference 1:
    castaner, r.m.; sorbera, l.a.; leeson, p.a.; castaner, j.; mitiglinide calcium hydrate. drugs fut 2000, 25, 10, 1034.
Reference 2:
    sato, f.; tsubaki, a.; hokari, h.; tanaka, n.; saito, m.; akahane, k.; kobayashi, m. (kissei pharmaceutical co., ltd.); succinic acid cpds.. ep 0507534; jp 1992330055; jp 1992356459; jp 1993230019; us 5202335 .

Route 5
the condensation of 2(s)-benzylsuccinic acid (xvii) with cis-perhydroisoindole (v) by means of imidazole, socl2 and tea in ethyl acetate gives the succinamic acid (xiii), which is esterified with benzyl bromide (xxv) and k2co3 in ethyl acetate or with benzyl alcohol (xxvi) and dcc in the same solvent, yielding the succinamic ester (xxiv). finally, this compound is treated with naoh or with h2 over pd/c and reacted with cacl2, yielding high purity mitiglinide calcium.the one-pot sequential reaction of imidazole with socl2, 2(s)-benzylsuccinic acid (xvii) and cis-perhydroisoindole (v), followed by hydrolysis with hcl, gives succinamic acid (xiii), which is finally treated with 2n naoh and cacl2.
List of intermediates No.
2,6-dichloro-3-cyano-1,4-quinoxalinediiumdiolate (xxv)
4,5-dimethyl-1,3-dioxol-2-one (xxvi)
(v)
(3s,8s,9s,10r,13r,14s,17r)-17-[(1r)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl acetate (xiii)
(5s,7r,8r,9s,10s,13r,14s,17r)-7-hydroxy-17-[(1r)-3-(2-isopropyl-1,3-dioxolan-2-yl)-1-methylpropyl]-10,13-dimethylhexadecahydro-3h-cyclopenta[a]phenanthren-3-one (xvii)
(3s,8s,9s,10r,13s,14s)-17-[(e)ethylidene]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl acetate (xxiv)
Reference 1:
    castaner, r.m.; sorbera, l.a.; leeson, p.a.; castaner, j.; mitiglinide calcium hydrate. drugs fut 2000, 25, 10, 1034.
Reference 2:
    yamaguchi, t.; yanagi, t.; yamamoto, i.; mukaiyama, y.; kamijo, t.; hokari, h.; preparation of optically active succinic acid derivatives. iii. regioselective condensation reactions of optically active 2-substituted succinic acids with diimidazolide. yakugaku zasshi 1998, 118, 6, 248-255.
Reference 3:
    yamaguchi, t.; et al.; synthesis of kad-1229, a succinic acid derivative with optical activity (1). 118th annu meet pharmaceut soc jpn (march 31 1998, kyoto) 1998, abst 01(xd)13-1.
Reference 4:
    yanagi, t.; kamijo, t.; yamaguchi, t. (kissei pharmaceutical co., ltd.); process for producing benzylsuccinic acid derivs.. ep 0967204; wo 9832736 .

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米格列奈鈣;英文名Mitiglinide calcium hydrate;S-21403;KAD-1229;Glufast;CAS[207844-01-7]

 
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