有机化学人才网 | 最新人才 | 最新职位 | 技术交易 | 药物合成 |
   
全站搜索: |
  您当前位置:网站首页 >> 药物合成路线图解
 

药物详细合成路线

Name Orlistat;Orlipastat;Tetrahydrolipstatin;R-212;Ro-18-0647/002;Ro-18-0647;Xenical
Chemical Name N-Formyl-L-leucine 1(S)-[3(S)-hexyl-4-oxooxetan-2(S)-ylmethyl]dodecyl ester
CAS 96829-58-2
Related CAS
Formula C28H51NO5
Structure
Formula Weight 481.72237
Stage 上市-1998
Company Chugai (Originator), Roche (Originator)
Activity/Mechanism Antiobesity Drugs, METABOLIC DRUGS, Treatment of Nutritional Disorders, Fatty Acid Synthase Inhibitors
Syn. Route 11
Route 1
1) the condensation of (s)-l-malic acid (i) and cyclohexanone (ii) by means of boron trifluoride etherate gives the cyclic lactone (iii), which is reduced by borane and treated with tert-butyldiphenylchlorosilane yielding the silyl ether (iv). the transesterification of (iv) with sodium methoxide in methanol affords 4-(tert-butyldiphenylsilyloxy)-2(s)-hydroxybutyric acid methyl ester (v), which is reduced with borane as before and esterified with naphthalenesufonyl chloride to give the sulfonate (vi). the treatment of (vi) with sodium methoxide affords the epoxide (vii), which is alkylated with decyllithium yielding 1-(tert-butyldiphenylsilyloxy)tetradecan-3(r)-ol (viii). the benzylation of (viii) with benzyl trichloroacetimidate (bta) gives the benzyl ether (ix), which is desilylated with hf in acetonitrile yielding 3(r)-benzyloxytetradecan-1-ol (x). the oxidation of (x) with pdc gives 3(r)-benzyloxytetradecanal (xi), which is condensed with 1-(trimethylsilyl)-2(e)-nonene (xii) by means of a titanium dichloride complex yielding the diastereoisomeric mixture of alcohols (3r,4s,6r)- (xiii) and (3s,4s,6r)- (xiv), which are separated by column chromatography. the silylation of both isomers with tert-butyldimethylsilyl chloride affords both isomers (xv) and (xvi), which are ozonolyzed with o3 and oxidized with naclo2 to yield the corresponding acids (xvii) and (xviii). the desilylation of (xvii) and (xviii) with hf in acetonitrile gives the hydroxy acids (xix) and (xx), which are cyclized by means of benzenesulfonyl chloride and pyridine to the isomeric oxetanones (xxi) and (xxii). the unwanted isomer (xxii) can be isomerized by means of lithium diisopropylamide in thf to the correct isomer (xxi). the debenzylation of (xxi) by hydrogenation with h2 over pd/c affords (3s,4s)-3-hexyl-4-[2(r)-hydroxytridecyl]oxetan-2-one (xxiii), which is finally condensed with n-formyl-l-leucine (xxiv) by means of diethyl azodicarboxylate (dead) in thf.
List of intermediates No.
2,2,2-trifluoro-1,1-ethanediol (i)
(2r,3s)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol (ii)
(4s,5r)-4-isopropyl-5-(trifluoromethyl)-1,3-oxazolidin-2-one (iii)
(1r,2s,5r)-2-isopropyl-5-methylcyclohexyl (4s,5r)-4-isopropyl-2-oxo-5-(trifluoromethyl)-1,3-oxazolidine-3-carboxylate (iv)
(2s)-1-((2s)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid (v)
benzyl (1s)-2-methyl-1-[[(2s)-2-([[(1s,2r)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino]carbonyl)pyrrolidinyl]carbonyl]propylcarbamate (vi)
(2s)-1-[(2s)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-n-[(1s,2r)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]-2-pyrrolidinecarboxamide (vii)
1-[(2r,4s,5r)-5-([[3,4-bis(benzyloxy)benzyl]oxy]methyl)-4-hydroxytetrahydro-2-furanyl]-5-methyl-2,4(1h,3h)-pyrimidinedione (viii)
2-cyanoethyl n,n-diisopropylphosphoramidochloridite (ix)
5-o-(3,4-dibenzyloxybenzyl)-3-o-[2-cyanoethoxy(diisopropylamino)phosphinyl]thymidine; 5-o-(3,4-dibenzyloxybenzyl)-3-o-[2-cyanoethoxy(diisopropylamino)phosphinyl]thymidine (x)
phenyl (1r,2r)-2-hydroxy-1-(hydroxymethyl)-2-phenylethylcarbamate (xi)
(2r,3r)-3-hydroxy-2-[(phenoxycarbonyl)amino]-3-phenylpropyl methanesulfonate (xii)
phenyl (1r,2r)-2-hydroxy-2-phenyl-1-(1-pyrrolidinylmethyl)ethylcarbamate (xiii)
(1r,2r)-2-amino-1-phenyl-3-(1-pyrrolidinyl)-1-propanol (xiv)
1-chloro-2-undecanone (xv)
5-isoquinolinylamine; 5-isoquinolinamine (xvi)
2-methyl-2lambda(5)-isoquinolin-5-ylamine; 2-methyl-2lambda(5)-isoquinolin-5-amine (xvii)
2-methyl-1,2,3,4-tetrahydro-5-isoquinolinylamine; 2-methyl-1,2,3,4-tetrahydro-5-isoquinolinamine (xviii)
5-nitroisoquinoline (xix)
2-methyl-5-nitro-2lambda(5)-isoquinoline (xx)
Reference 1:
    barbier, p.; schneider, f.; widmer, u. (f. hoffmann-la roche ag); process for the preparation of oxetanones. ep 0189577 .
Reference 2:
    prous, j.; mealy, n.; castaner, j.; orlistat. drugs fut 1994, 19, 11, 1003.
Reference 3:
    tehim, a.; chen, p.; hanessian, s.; total synthesis of (-)-tetrahydrolipstatin. j org chem 1993, 58, 27, 7768-81.

Route 2
the chiral aldehyde (xi) can also be obtained as follows:the reaction of dodecanal (xxv) with allylmagnesium bromide (xxvi) in thf gives 1-pentadecen-4-ol (xxvii) as a racemic mixture, which is esterified with 2(r)-acetoxy-2-phenylacetic acid (xxviii) by means of dicyclohexylcarbodiimide (dcc) and dimethylaminopyridine (dmap) to yield the diastereoisomeric mixture of esters (xxix) and (xxx), which are separated by flash chromatography. the hydrolysis of (xxix) and (xxx) with koh in methanol affords the alcohols (xxxi) and (xxxii). the unwanted isomer (xxxii) can be isomerized to (xxxi) through the formation of the 4-nitrobenzoyl ester and hydrolysis with k2co3. the benzylation of (xxxi) with benzyl bromide and kh in thf gives the benzyl ether (xxxiii), which is finally ozonolyzed to the desired aldehyde (xi) with o3 in methanol-dichloromethane.
List of intermediates No.
4-methyl-2h-oxet-2-one (xxvi)
phenyl (1r,2r)-2-hydroxy-1-(hydroxymethyl)-2-phenylethylcarbamate (xi)
5-bromoisoquinoline (xxv)
5-bromo-2-methyl-8-nitro-2lambda(5)-isoquinoline (xxvii)
5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline (xxviii)
2-methyl-8-nitro-5-phenyl-1,2,3,4-tetrahydroisoquinoline (xxix)
2-methyl-5-phenyl-1,2,3,4-tetrahydro-8-isoquinolinylamine; 2-methyl-5-phenyl-1,2,3,4-tetrahydro-8-isoquinolinamine (xxx)
8-methyl-5-phenyl-6,7,8,9-tetrahydro-1h-pyrrolo[3,2-h]isoquinoline-2,3-dione (xxxi)
4-(8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro-1h-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonyl chloride (xxxii)
n,n-dimethyl-4-(8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro-1h-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonamide (xxxiii)
Reference 1:
    prous, j.; mealy, n.; castaner, j.; orlistat. drugs fut 1994, 19, 11, 1003.
Reference 2:
    tehim, a.; chen, p.; hanessian, s.; total synthesis of (-)-tetrahydrolipstatin. j org chem 1993, 58, 27, 7768-81.

Route 3
the oxetanone (xxiii) can also be obtained as follows:the condensation of 3(r)-benzyloxytetradecanal (xi) with octanoic acid (xxxiv) by means of lithium diisopropylamide gives 5(r)-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid (xxxv), which is deprotected by hydrogenation with h2 over pd/c yielding the dihydroxy acid (xxxvi). the lactonization of (xxxvi) with p-toluenesulfonic acid affords the hydroxy lactone (xxxvii), which is oxidized with cro3 h2so4 to 3-hexyl-6(r)-undecyltetrahydropyran-2,4-dione (xxxviii). hydrogenation of (xxxviii) with h2 over pto2/c in ethylacetate gives (3s,4s,6r)-3-hexyl-4-hydroxy-6-undecyltetrahydropyran-2-one (xxxix), which is benzylated with benzyl trichloroacetimidate to the 4-benzyloxy derivative (xl). ring opening of (xl) with koh in dioxane-water yields the hydroxy acid (xli), which is esterified with benzyl bromide to the benzyl ester (xlii). the reaction of (xlii) with dihydropyran (dhp) by means of p-toluenesulfonic acid in dichloromethane affords (2s,3s,5r)-3-benzyloxy-2-hexyl-5-(tetrahydropyran-2-yloxy)hexadecanoic acid benzyl ester (xliii), which is debenzylated by hydrogenation with h2 over pd/c in thf to the hydroxy acid (xliv). the cyclization of (xliv) with p-toluenesulfonyl chloride in pyridine gives (3s,4s)-3-hexyl-4-[2(r)-(tetrahydropyran-2-yloxy)tridecyl]oxetan-2-one (xlv), which is finally deprotected with pyridinium p-toluenesulfonate in ethanol to afford the oxetanone (xxiii), already obtained in scheme 11082301a.
List of intermediates No.
3-bromodihydro-2(3h)-furanone (xxxiv)
2-[(2-oxotetrahydro-3-furanyl)oxy]-1h-isoindole-1,3(2h)-dione (xxxv)
3-(aminooxy)dihydro-2(3h)-furanone (xxxvi)
n,n-dimethyl-4-(8-methyl-2-oxo-3-[[(2-oxotetrahydro-3-furanyl)oxy]imino]-1,2,6,7,8,9-hexahydro-3h-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonamide (xxxvii)
6-formyl-2,3-dimethoxybenzoic acid (xxxviii)
7,8-dimethoxy-1(2h)-phthalazinone (xxxix)
1-chloro-7,8-dimethoxyphthalazine; 4-chloro-5-methoxy-6-phthalazinyl methyl ether (xl)
4-([[tert-butyl(dimethyl)silyl]oxy]methyl)pyridine; tert-butyl(dimethyl)silyl 4-pyridinylmethyl ether (xli)
ethyl 4-fluorobenzoate (xlii)
2-[[tert-butyl(dimethyl)silyl]oxy]-1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone (xliii)
4-methoxy-2,6-pyridinediamine; 6-amino-4-methoxy-2-pyridinylamine (xliv)
2,5-dihydro-1h-pyrrole (xlv)
Reference 1:
    barbier, p.; schneider, f.; synthesis of tetrahydrolipstatin and tetrahydroesterastin, compounds with beta-lactone moiety. stereoselective hydrogenation of a beta-keto delta-lactone and conversion of the delta-lactone into a beta-lactone. j org chem 1988, 53, 6, 1218-21.
Reference 2:
    prous, j.; mealy, n.; castaner, j.; orlistat. drugs fut 1994, 19, 11, 1003.

Route 4
oxetanone (xlv) can also be obtained as follows:the reaction of 3(r)-hydroxytetradecanoic acid tert-butyl ester (xlvi) with dhp and p-toluenesulfonic acid gives the corresponding tetrahydropyranyl ether (xlvii), which is reduced with dibutylaluminum hydride (dibal) in toluene to the aldehyde (xi), already obtained. compound (xi) is condensed with 2-(p-toluenesulfinyl)acetic acid tert-butyl ester (xlviii) by means of tert-butylmagnesium bromide in ether-thf affording the sulfinylhydroxy ester (ii), which is treated with aluminum amalgam in thf-water to yield the hydroxy ester (l). the alkylation of (l) with hexyl bromide (li) by means of butyllithium and diisopropylamine in thf-hexane affords 2-hexyl-3(s)-hydroxy-5(r)-(tetrahydropyranyloxy)hexadecanoic acid tert-butyl ester (lii), which is hydrolyzed with koh in methanol to the corresponding free acid (liii). the lactonization of (liii) with pyridinium p-toluenesulfonate in hot ethanol affords oxetanone (liv) as a diastereomeric mixture, which is separated by column chromatography, finally yielding oxetanone (xlv), previously obtained in scheme 11082301c.
List of intermediates No.
2,5-dihydro-1h-pyrrole (xlv)
tert-butyl 2,5-dihydro-1h-pyrrole-1-carboxylate (xlvi)
tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (xlvii)
tert-butyl (3r,4r)-3-azido-4-hydroxy-1-pyrrolidinecarboxylate (xlviii)
tert-butyl (3r,4r)-3-amino-4-hydroxy-1-pyrrolidinecarboxylate (il)
(2s)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid (l)
tert-butyl 3-[((2s)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]-4-hydroxy-1-pyrrolidinecarboxylate (li)
benzyl (1s)-1-[[(4-hydroxy-3-pyrrolidinyl)amino]carbonyl]-3-methylbutylcarbamate (lii)
benzyl (1s)-1-([3-[((2s)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]-4-hydroxy-1-pyrrolidinyl]carbonyl)-3-methylbutylcarbamate (liii)
Reference 1:
    barbier, p.; schneider, f.; synthesis of tetrahydrolipstatin and tetrahydroesterastin, compounds with beta-lactone moiety. stereoselective hydrogenation of a beta-keto delta-lactone and conversion of the delta-lactone into a beta-lactone. j org chem 1988, 53, 6, 1218-21.
Reference 2:
    prous, j.; mealy, n.; castaner, j.; orlistat. drugs fut 1994, 19, 11, 1003.

Route 5
a new synthesis of orlistat has been described:the ozonolysis of 3(r)-(tetrahydropyranyloxy)-6-heptenoic acid ethyl ester (lv) with o3 gives the corresponding terminal aldehyde (lvi), which is submitted to a wittig condensation with octyl triphenylphosphonium bromide (lvii) and butyllithium in ether-thf yielding 3(r)-(tetrahydropyranyloxy)-6(z)-tetradecenoic acid ethyl ester (lviii). the reduction of (lviii) with dibal in toluene-dichloromethane affords the corresponding aldehyde (lix), which is condensed with octanoic acid (xxxiv) by means of butyllithium and diisopropylamine in thf to give 2-hexyl-3-hydroxy-5(r)-(tetrahydropyranyloxy)-8(z)-hexadecenoic acid (lx), which is lactonized with benzenesulfonyl chloride in pyridine to the protected oxetanone (lxi). the deprotection of (lxi) with pyridinium p-toluenesulfonate in hot ethanol affords 3-hexyl-4-[2(r)-hydroxy-5(z)-tridecenyl]oxetan-2-one (lxii) as a mixture of diastereomers, which are separated by column chromatography yielding the (3s,4s,2r)-isomer (lxiii). the condensation of (lxiii) with n-formyl-l-leucine (xxiv) as before gives dihydrolipstatin (lxiv), which is finally hydrogenated with h2 over pd/c in thf.
List of intermediates No.
5-methyl-n-[4-(trifluoromethoxy)phenyl]-4-isoxazolecarboxamide (xxiv)
3-bromodihydro-2(3h)-furanone (xxxiv)
(7r)-7-acetyl-7-hydroxy-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,10,10a,10b,11,12-tetradecahydro-5-chrysenyl 2,2-dichloroacetate (lv)
(1r)-1-acetyl-11-[(2,2-dichloroacetyl)oxy]-10a,12a-dimethyl-8-oxo-1,2,3,4,4a,4b,5,6,8,10a,10b,11,12,12a-tetradecahydro-1-chrysenyl butyrate (lvi)
5-amino-4,6-dichloropyrimidine; 4,6-dichloro-5-pyrimidinylamine; 4,6-dichloro-5-pyrimidinamine (lvii)
5-amino-1-pentanol (lviii)
5-[(5-amino-6-chloro-4-pyrimidinyl)amino]-1-pentanol (lix)
5-(6-chloro-9h-purin-9-yl)-1-pentanol (lx)
9-(5-hydroxypentyl)-9h-purin-6-ol (lxi)
9-[5-[(chlorocarbonyl)oxy]pentyl]-6-hydroxy-9h-purine (lxii)
arginine; 2-amino-5-guanidinopentanoic acid (lxiii)
benzyl 3,6-dihydro-1(2h)-pyridinecarboxylate (lxiv)
Reference 1:
    barbier, p.; schneider, f.; syntheses of tetrahydrolipstatin and absolute configuration of tetrahydrolipstatin and lipstatin. helv chim acta 1987, 70, 196-202.
Reference 2:
    prous, j.; mealy, n.; castaner, j.; orlistat. drugs fut 1994, 19, 11, 1003.

Route 6
the esterification of optical active (-)-n-methylephedrine (lxv) with octanoyl chloride (lxvi) in tert-butyl methyl ether gives the corresponding ester (lxvii), which is treated with trimethylsilyl chloride and butyllithium-diisopropylamine in thf to yield the enolic trimethylsilyl ether (lxviii). the condensation of (lxviii) with the previously obtained aldehyde, 3(r)-(benzyloxy)tetradecanal (xi) (scheme 11082301a), by means of ticl4 in dichloromethane affords, after chromatography, (2s,3s,5r)-5-(benzyloxy)-2-hexyl-3-hydroxyhexadecanoic acid 2(s)-(dimethylamino)-1(r)-phenylpropyl ester (lxix), which is finally hydrolyzed with methanolic koh to (2s,3s,5r)-5-(benzyloxy)-2-hexyl-3-hydroxy-hexadecanoic acid (xix), obtained in scheme 11082301a.the previously obtained 3(r)-(benzyloxy)tetradecanal (xi) can also be obtained by benzylation of 3(r)-hydroxytetradecanoic acid methyl ester (lxx) as usual, to the protected (lxxi), which is then reduced with dibal as before.tetrahydrolipstatin can also be obtained from natural lipstatin by hydrogenation with h2 over pd/c in ethanol.
List of intermediates No.
benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (lxv)
benzyl (3r,4r)-4-(2,3-dimethylphenoxy)-3-hydroxy-1-piperidinecarboxylate (lxvi)
benzyl (4r)-4-(2,3-dimethylphenoxy)-3-oxo-1-piperidinecarboxylate (lxvii)
benzyl (3s,4r)-4-(2,3-dimethylphenoxy)-3-hydroxy-1-piperidinecarboxylate (lxviii)
8-(bromomethyl)-2-phenyl-4h-chromen-4-one (lxxix)
2-(4-oxo-2-phenyl-4h-chromen-8-yl)acetonitrile (lxx)
2-(4-oxo-2-phenyl-4h-chromen-8-yl)acetic acid (lxxi)
Reference 1:
    barbier, p.; widmer, u.; schneider, f.; stereoselective syntheses of tetrahydrolipstatin and of an analogue, potent pancreatic-lipase inhibitors containing a beta-lactone moiety. helv chim acta 1987, 70, 1412-8.
Reference 2:
    prous, j.; mealy, n.; castaner, j.; orlistat. drugs fut 1994, 19, 11, 1003.

Route 7
a new asymmetric synthesis of orlistat has been described: reaction of the chiral aminoindanol (i) with octanoyl chloride (ii) in pyridine gives the chiral ester (iii), which is condensed with cinnamaldehyde (iv) by means of ticl4, diea and bu2botf in dichloromethane yielding, after chromatographic purification, the anti-aldol adduct (v). hydrolysis of the chiral auxiliary of (v) with lithium hydroperoxide affords the beta-hydroxy acid (vi), which is protected as the 1,3-dioxan-4-one (viii) by reaction with pivalaldehyde (vii), tms-otf and isopropoxytrimethylsilane (tms-o-i-pr). ozonolysis of (viii) with o3 in dichloromethane yields the aldehyde (ix), which is condensed with 1-nitrododecane (x) by means of tbaf in dmf to provide the nitroaldol (xi). the dehydration of (xi) with dcc and cucl in hot acetonitrile gives the nitroalkene (xii), which is reduced with zn/hoac to oxime (xiii). oxidative hydrolysis of (xiii) with ceric ammonium nitrate (can) and hno3 yields diketone (xiv), which is hydrolyzed with hcl in thf providing the beta-hydroxy acid (xv). esterification of (xv) with benzyl iodide and csco3 gives the benzyl ester (xvi), which is estereoselectively reduced with me4nb(oac)3h in hoac/acetonitrile yielding the chiral anti-1,3-diol (xvii). the selective protection of (xvii) with tips-otf and 2,6-lutidine affords the monosilylated ester (xviii), which is treated with h2 over pd(oh)2 in ethyl acetate/methanol to furnish the free beta-hydroxy acid (xix). cyclization of acid (xix) by means of phso2cl in pyridine affords the beta-lactone (xx), which is desilylated with tbaf and hoac in thf giving lactone (xxi). finally, lactone (xxi) is esterified under mitsunobu conditions with n-formyl-l-leucine (xxii) by means of diad and pph3 in thf.
List of intermediates No.
5-methyl-n-[4-(trifluoromethoxy)phenyl]-4-isoxazolecarboxamide (xxii)
3-bromodihydro-2(3h)-furanone (ii)
hydroxylamine (vii)
(1-methyl-1h-pyrazol-5-yl)(phenyl)methanol; 5-(alpha-hydroxybenzyl)-1-methyl-1h-pyrazole (i)
n,n-dimethyl-2-[(1-methyl-1h-pyrazol-5-yl)(phenyl)methoxy]-1-ethanamine; n,n-dimethyl-n-{2-[(1-methyl-1h-pyrazol-5-yl)(phenyl)methoxy]ethyl}amine (iii)
n,n-dimethyl-2-{[(r)-(1-methyl-1h-pyrazol-5-yl)(phenyl)methyl]oxy}-1-ethanamine; n,n-dimethyl-n-(2-{[(r)-(1-methyl-1h-pyrazol-5-yl)(phenyl)methyl]oxy}ethyl)amine (iv)
n,n-dimethyl-2-{[(s)-(1-methyl-1h-pyrazol-5-yl)(phenyl)methyl]oxy}-1-ethanamine; n,n-dimethyl-n-(2-{[(s)-(1-methyl-1h-pyrazol-5-yl)(phenyl)methyl]oxy}ethyl)amine (v)
(r)-(1-methyl-1h-pyrazol-5-yl)(phenyl)methanol (vi)
(s)-(1-methyl-1h-pyrazol-5-yl)(phenyl)methanol (viii)
(s)-(1-methyl-1h-pyrazol-5-yl)(phenyl)methyl acetate (ix)
(1-methyl-1h-pyrazol-5-yl)(phenyl)methanone (x)
ethyl (2r)-2-hydroxy-2-phenylethanoate (xi)
(2r)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethanal (xii)
(e,4s)-4-{[tert-butyl(dimethyl)silyl]oxy}-4-phenyl-2-buten-1-ol (xiii)
(e,4s)-4-{[tert-butyl(dimethyl)silyl]oxy}-4-phenyl-2-butenal (xiv)
tert-butyl(dimethyl)silyl (r)-(1-methyl-4,5-dihydro-1h-pyrazol-5-yl)(phenyl)methyl ether; 5-[(r)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-1-methyl-4,5-dihydro-1h-pyrazole (xv)
tert-butyl (1s)-1-(sec-butyl)-2-oxo-4-pentenylcarbamate (xvi)
tert-butyl (1s,2r)-1-(sec-butyl)-2-hydroxy-4-pentenylcarbamate (xvii)
tert-butyl (1s,2r)-1-(sec-butyl)-2-methoxy-4-pentenyl(methyl)carbamate (xviii)
(3r,4s)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid (xix)
Reference 1:
    ghosh, a.k.; fidanze, s.; asymmetric synthesis of (-)-tetrahydrolipstatin: an anti-aldol-based strategy. org lett 2000, 2, 16, 2405.

Route 8
synthesis of (3s,4s)-3-hexyl-4-[2(s)-hydroxytridecyl]oxetan-2-one (vi), a key intermediate in the synthesis of orlistat has been reported: reaction of methyl 3(s)-hydroxytetradecanoate (i) with 2-methoxypropene (ii) by means of pyridinium p-toluenesulfonate gives the protected ester (iii), which is reduced with dibal to the aldehyde (iv). finally, aldehyde (iv) is condensed with the lithium amide-enolate (v) generated from 1-octanoylbenzotriazole and lihmds, resulting in a 4:1 mixture of diastereomeric oxetanones (vi) and (vii) separated by flash chromatography.
List of intermediates No.
2-amino-2-imino-n-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]ethanimidamide (ii)
tert-butyl (2s)-2-[(1r,2s)-1-methoxy-2-methyl-3-butenyl]-1-pyrrolidinecarboxylate (i)
benzyl (1s)-2-amino-1-benzyl-2-oxoethylcarbamate (iii)
benzyl (1s)-2-phenyl-1-(1,3-thiazolidin-2-yl)ethylcarbamate (iv)
benzyl (1s)-2-phenyl-1-(1,3-thiazol-2-yl)ethylcarbamate (v)
benzyl (1s)-2-amino-1-benzyl-2-thioxoethylcarbamate (vi)
(1s)-2-phenyl-1-(1,3-thiazol-2-yl)-1-ethanamine; (1s)-2-phenyl-1-(1,3-thiazol-2-yl)ethylamine (vii)
Reference 1:
    wedler, c.; et al.; synthesis of enantiomerically pure beta-lactones by the tandem aldol - lactonization. a highly efficient access to (3s,4s)-3-hexyl-4-[(2s)-2-hydroxytridencyl]oxetan-2-one, the key intermediate for the enzyme inhibitors tetrahydrolipstatin and tetrahydroes. j org chem 1999, 64, 14, 5301.

Route 9
the kecks enantioselective allylation of dodecanal (i) with allyl bromide (ii) employing a catalytic amount of (r)-binol and titanium tetraisopropoxide furnishes the chiral alcohol (iii), which is esterified with acryloyl chloride (iv), tea and dmap to give the acrylate (v). the olefin metathesis of (v) by means of grubbs catalyst and ti(o-ipr)4 in refluxing dichloromethane yields the dihydropyranone (vi), which is epoxidized with h2o2 and naoh to afford the chiral epoxide (vii). the reductive cleavage of (vii) with diphenyl diselenide and nabh4 gives the chiral tetrahydropyranone (viii), which is silylated with tbdms-cl and diea, yielding the silyl ether (ix). opening of the lactone ring of (ix) with tea and methanol affords the hydroxyester (x), which is treated with dihydropyran and ppts to provide the tetrahydropyranyl ether (xi). the desilylation of (xi) with tbaf in thf gives the beta-hydroxyester (xii), which is alkylated with hexyl iodide and lda in thf, yielding the adduct (xiii). the cyclization of (xiii) by hydrolysis with lioh, followed by treatment with ph-so2-cl, affords the beta-lactone (xiv), which is treated with ppts to eliminate the tetrahydropyranyl-protecting group and yield the secondary alcohol (xv). the esterification of (xv) with n-(benzyloxycarbonyl)-l-leucine (xvi) by means of dcc and dmap affords the leucinate (xvii), which is deprotected with h2 over pd/c, affording (xviii) with a free amino group that is formylated with acetic formic mixed anhydride to furnish the target (-)-tetrahydrolipstatin.
List of intermediates No.
5-bromoisoquinoline (i)
4-(8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro-1h-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonyl chloride (iii)
tert-butyl (2r)-2-[[(methylsulfonyl)oxy]methyl]-1-pyrrolidinecarboxylate (ii)
4-(4-fluorophenyl)-1-[4-(1h-1,2,4-triazol-1-yl)butyl]-4-piperidinol (iv)
(2r)-2-[(1r,3s)-1-[(1s)-1-amino-2-(5-hydroxy-2,4-dimethoxy-3-methylphenyl)ethyl]-8-hydroxy-5,7-dimethoxy-2,6-dimethyl-1,2,3,4-tetrahydro-3-isoquinolinyl]-2-(4-morpholinyl)ethanenitrile (xvi)
(2s,3s,4r,6r)-6-{[(3r,4s,5r,6r,7r,9r,11r,12r,13s,14r)-6-{[(2s,3r,4s,6r)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2h-pyran-2-yl]oxy}-12-(allyloxy)-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy}-4- (v)
1-(3-butenyl)-4-phenyl-1h-imidazole (vi)
(2s,3s,4r,6r)-6-[((3r,4s,5r,6r,7r,9r,11r,12r,13s,14r)-6-{[(2s,3r,4s,6r)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2h-pyran-2-yl]oxy}-14-ethyl-13-hydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-12-{[(e)-5-(4-phenyl-1h-imidazol-1-yl)-2- (vii)
methyl 3-(4-iodophenyl)-3-methyl-2-oxiranecarboxylate (viii)
3-(4-iodophenyl)-3-methyl-2-oxiranecarboxylic acid (ix)
2-(4-iodophenyl)propanal (x)
(xi)
2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid (xii)
4-acetylbenzenediazonium (xiii)
1-[4-(3-methyl-2-thienyl)phenyl]-1-ethanone (xiv)
methyl 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylate (xv)
3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylic acid (xvii)
2-[4-(3-methyl-2-thienyl)phenyl]propanal (xviii)
Reference 1:
    ghosh, a.k.; liu, c.; a stereoselective synthesis of (-)-tetrahydrolipstatin. chem commun (london) 1999, 1743.

Route 10
the reaction of cyclohexane-1,3,5-triol (i) with trimethyl orthobenzoate (ii) by means of bf3/et2o gives the cyclic orthoester (iii), which is partially reduced with borane in thf to yield the alcohol (iv). oxidation with dess-martin periodinane affords cyclohexanone (v), which is enantioselectively deprotonated with the chiral lithium (s,s)-alpha,alpha-dimethyldibenzylamide (vi) in the presence of tms-cl in thf to provide the chiral silylated enol ether (vii). ozonolysis of the double bond of (vii) gives the 6-oxohexanoic acid (viii), which is reduced with nabh4 to the corresponding hydroxyacid (ix). the methylation of (ix) with methyl iodide and k2co3 yields the hydroxyester (x), which is oxidized with oxalyl chloride in dmso to afford the oxoester (xi). the wittig condensation of (xi) with decyltriphenylphosphonium bromide (xii) by means of buli in thf provides the unsaturated hexadecenoic ester (xiii), which is finally reduced, deprotected and cyclized by treatment with h2 over pd/c in acetic acid to furnish the target (4s,6s)-4-hydroxy-6-undecyltetrahydrofuran-2-one (xiv).the conversion of (xiv) into tetrahydrolipstatin has already been described in scheme 11082304a.
List of intermediates No.
5-quinolinol (i)
(3,5-diaminophenyl)methanol (ii)
methyl 3-(4-iodophenyl)-3-methyl-2-oxiranecarboxylate (xiv)
methyl 2,3-dimethyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylate (iii)
3-[4-(3-methyl-2-thienyl)phenyl]-2-butanone (iv)
2-methyl-2-[4-(3-methyl-2-thienyl)phenyl]oxirane (v)
5-methyl-5-[4-(3-methyl-2-thienyl)phenyl]-2,4-imidazolidinedione (vi)
2-[4-(3-methyl-2-thienyl)phenyl]alanine (vii)
n,n-dimethyl-2-[4-(3-methyl-2-thienyl)phenyl]alanine (viii)
1-ethoxy-2-[4-(3-methyl-2-thienyl)phenyl]-2-propanol (ix)
2-(4-bromophenyl)-3-methylthiophene (x)
chloro[4-(3-methyl-2-thienyl)phenyl]zinc (xi)
ethyl 2-[4-(3-methyl-2-thienyl)phenyl]propanoate (xiii)
3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarbonitrile (xii)
Reference 1:
    ono, s.; endo, k.; honda, t.; construction of an enatiomerically pure 6-substituted 3,5-syn-dihydroxyhexanoic acid system by an enatioselective deprotonation strategy: formal synthesis of an antiobesity agent, (-)-tetrahydrolipstatin. chem pharm bull 2000, 48, 10, 1545.
Reference 2:
    ghosh, a.k.; liu, c.; a stereoselective synthesis of (-)-tetrahydrolipstatin. chem commun (london) 1999, 1743.

Route 11
the hydrolysis of methyl (2e, 4e)-hexadecadienoate (i) with koh in thf gives the corresponding free acid (ii), which is treated with (cocl)2 in dichloromethane to yield the acid chloride (iii). the esterification of (iii) with trichloroethanol (iv), tea and dmap affords the trichloroethyl ester (v), which is stereospecifically dihydroxylated by means of ad-mix-alpha, methanesulfonamide and nahco3 in t-butanol/water to provide the dihydroxyester (vi). the reaction of (vi) with socl2 in refluxing ccl4 gives the cyclic sulfite (vii), which is alkylated by means of cucn, li-c6h13 and bf3/et2o in thf to give 5(s)-hydroxy-2(s)-hexyl-3(e)-hexadecanoic acid trichloroethyl ester (viii). the cleavage of the ester group of (viii) by means of zn/acoh yields the corresponding free acid (ix), which is submitted to cyclization by reaction with br2 in ccl4/meoh in the presence of nahco3 to afford the brominated beta lactone (x). radical debromination of (x) by means of di-tert-butyl peroxide (dbpo), ph2se2, and bu3snh in toluene provides the beta lactone (xi), which is condensed with n-(benzyloxycarbonyl)-l-leucine (xii) by means of dcc and dmap in dichloromethane to furnish the ester (xiii). the cleavage of the boc group of (xiii) by means of h2 over pd/c in thf gives the free amino acid ester (xiv), which is finally n-formylated by means of acetic formic anhydride (xv) in ethyl ether to yield the target tetrahydrolipstatin.
List of intermediates No.
(2r)-2-[(1r,3s)-1-[(1s)-1-amino-2-(5-hydroxy-2,4-dimethoxy-3-methylphenyl)ethyl]-8-hydroxy-5,7-dimethoxy-2,6-dimethyl-1,2,3,4-tetrahydro-3-isoquinolinyl]-2-(4-morpholinyl)ethanenitrile (xii)
2-[(dimethylamino)methyl]-6,7-dimethyl-3,4-dihydro-1(2h)-naphthalenone (xv)
methyl 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylate (xi)
3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylic acid (xiii)
2-[4-(3-methyl-2-thienyl)phenyl]propanal (xiv)
[(2r,3r,4s)-4-fluoro-3-(formyloxy)-5-hydroxytetrahydro-2-furanyl]methyl benzoate (iv)
Reference 1:
    bodkin, j.a.; humphries, e.j.; mcleod, m.d.; the total synthesis of (-)-tetrahydrolipstatin. tetrahedron lett 2003, 44, 14, 2869.

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奥利司他;英文名Orlistat;Orlipastat;Tetrahydrolipstatin;R-212;Ro-18-0647/002;Ro-18-0647;Xenical;CAS[96829-58-2]

 
推荐VIP企业
无锡景耀生物科技有限公司
杭州卢普生物科技有限公司
宁波赛伦化工有限公司
苏州昊赛生物科技有限公司
北京嘉盛扬医药科技有限公司
上海泽涵生物医药科技有限公司
河北固安三利化工公司
郑州凯普瑞生物技术有限公司
上海药谷药业有限公司
兰州康寓信生物科技有限公司
湖北朗昕生化药业有限公司
武汉福鑫化工有限公司
嘉兴市英南化工有限公司
苏州迪飞医药科技有限公司
唐山盛源泽兴化工有限公司
上海盛中医药化工有限公司
连云港天和化学有限公司
南京晨瑞医药科技有限公司
南京苏如化工有限公司
常州瑞盛化工有限公司
热门文章
作物抗病基因工程新进展——利用
安道麦与辉丰强强联手,加深合作
2019年农药市场谁主沉浮?
用药拌干稻种可减轻恶苗病和干尖
原药登记中环境试验项目:环境归
2018年我国农药发展回顾与对
苏北沿海化企复产,前路还有多长
因抗药性,这些农药已失效了,怎
当前我国小麦主要病虫害发生面积
林丹,硫丹,全氟辛基磺酰氟,禁
检察机关:农资打假绝不手软!
颖泰/快达2018年业绩向好
草甘膦再评审即将开始!欧盟提议
干、抗、防!拜耳又一创新产品横
安道麦推出新产品,并将致力于完
环保压力不减,原药行情持续盘整
农业农村部×中化集团:携手共促
必须知道!这些问题在农药登记申
关于“三个时代”下我国农药发展
联化科技2019年第一季度净利
 友情链接
有机化学人才网  
首页 | 广告服务 | 建站服务 | 关于我们 | 联系我们 | 版权声明