合成路线:Various new routes for the large-scale synthesis of Ro-31-8959 have been described:1) The condensation of N-protected-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) gives the keto ester (III),which is enantioselectively reduced with NaBH4 to yield the hydroxy ester (IV).The reaction of (IV) with 2,2-dimethoxypropane (V) by means of p-toluenesulfonic acid affords the oxazolidine (VI),which is hydrolyzed with NaOH in ethanol/water to the corresponding acid (VII).The treatment of (VII) with oxalyl chloride,mercaptopyridine-N-oxide (MPO) and bromotrichloromethane affords the bromomethyloxazolidine (VIII),which,without isolation,is treated with acetic acid to give the N-protected 3(S)-amino-2-bromo-4-phenyl-2(S)-butanol (IX).The reaction of (IX) with KOH in methanol yields the epoxide (X),which is condensed with (3S,4aS,8aS)-N-tert-butyldecahydroisoquinoline-3-carboxamide (XI),yielding the protected condensation product (XII).The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C affords the amino derivative (XIII),which is condensed with N-benzyloxycarbonyl-asparagine (XIV) in the usual way,giving the protected peptide (XV).The deprotection of (XV) as before yields compound (XVI),with a free amino group that is finally condensed with quinoline-2-carboxylic acid (XVII) by means of dicyclohexylcarbodiimide and hydroxybenzotriazole.
合成路线:2) The condensation of N-phthaloyl-L-phenylalaninyl chloride (XVIII) with 1,1,2-tris(trimethylsilyloxy)ethylene (TMS) (XIX) at 90-100 C followed by acidic hydrolysis with HCl gives the acid (XX),which,without isolation,is decarboxylated,yielding 1-hydroxy-3(S)-phthalimido-4-phenyl-2-butanone (XXI).Sequential protection of the OH- group with dihydropyran,reduction of the CO group with NaBH4,mesylation of the resulting OH group with methanesulfonyl chloride and deprotection of the primary OH group gives 2(R)-(methanesulfonyloxy)-4-phenyl-3(S)-phthalimido-1-butanol (XXII).The epoxidation of (XXII) with potassium tert-butoxide yields the epoxide (XXIII),which is condensed with the decahydroisoquinoline (XI) as before,affording the protected condensation product (XXIV).The elimination of the phthalimido group of (XXIV) with methylamine and HCl gives the amino derivative (XIII),already obtained in scheme 16810301a.
合成路线:3) The condensation of N-(tert-butoxycarbonyl)-L-phenylalaninal (XXV) with 2-(trimethylsilyl)thiazole (XXVI) by means of tetrabutylammonium fluoride gives the thiazole derivative (XXVII),which is cleaved by reaction with methyl iodide (formation of the thiazolium derivative) and treated with NaBH4 and HgCl2 to afford the protected 3(S)-amino-2(S)-hydroxy-4-phenylbutanal (XXVIII).Finally,this compound is reductocondensed with isoquinoline (XI) by means of sodium cyanoborohydride to yield the protected condensation product (XII),already obtained in scheme 16810301a.
合成路线:4) The selective esterification of 3(S)-azido-4-phenylbutane-1,2(S)-diol (XXIX) with 2,4,6-triiosopropylbenzenesulfonyl chloride (XXX) gives the sulfonate ester (XXXI),which by treatment with KOH is converted to the azido epoxide (XXXII).The condensation of (XXXII) with decahydroisoquinoline (XI) affords the azido condensation product (XXXIII),which is finally hydrogenated with H2 over Pd/C to the amino condensation product (XIII),already obtained in scheme 16810301a.5) The reaction of (XXIX) with SOCl2 and RuCl3 gives the dioxathiole dioxide (XXXIV),which is condensed with decahydroisoquinoline (XI) to afford the azido condensation product (XXXIII),already obtained.
合成路线:The intermediate (3R,4S)-4-[N-(tert-butoxycarbonyl)-N-methylamino]-5-phenyl-3-(tert-butyldimethylsilyloxy)pentanoic acid (VII) has been obtained as follows: The condensation of N-(tert-butoxycarbonyl)-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) by means of CDI gives the beta-ketoester (III),which is reduced with NaBH4 to yield (3R,4S)-4-(tert-butoxycarbonylamino)-3-hydroxy-5-phenylpentanoic acid ethyl ester (IV).The protection of the OH group of (IV) with Tbdms-Cl and imidazole in DMF affords the silylated ester (V),which is hydrolyzed with NaOH to provide the corresponding carboxylic acid (VI).Finally,this compound is N-methylated by means of Me-I and NaH in THF to obtain the target intermediate (VII).
参考文献标题:Studies toward the large-scale synthesis of the HIV proteinase inhibitor Ro 31-8959
文献作者:Parkes,K.E.B.; Bushnell,D.J.; Crackett,P.H.; et al.
参考来源:J Org Chem 1994,59(13),3656
合成路线:[14C]-Saquinavir: The cyclization of [ring-14C]-aniline (I) with crotonic aldehyde (II) by means of HCl and acetic anhydride gives labeled 2-methylquinoline (III),which is brominated with Br2 in acetic acid yielding the tribromo derivative (IV).The hydrolysis of (IV) with hot sulfuric acid afforded labeled quinoline-2-carboxylic acid (V),which is finally condensed with Ro-32-0445 (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC) in THF.
合成路线:Pentadeuterated saquinavir: The nitration of hexadeuterobenzene (VII) with HNO3/H2SO4 gives pentadeuteronitrobenzene (VIII),which is hydrogenated with deuterium/Pt in D1-methanol yielding heptadeuteroaniline (IX).The cyclization of (IX) with crotonic aldehyde (II) by means of DCI/D2O and acetic anhydride as before affords hexadeuterated quinoline (X),which is brominated with Br2 as before giving the tribromo derivative (XI).The hydrolysis of (XI) with sulfuric acid as before yields the acid (XII),which is finally condensed with Ro-32-0445 (VI) as before.
合成路线:Tetradeuterated saquinavir: The cyclization of heptadeuteroaniline (IX) with crotonic aldehyde (II) by means of HCl and acetic anhydride as before gives the tetradeuteroquinoline (XIII),which is brominated as described yielding the tribromo derivative (XIV).The hydrolysis of (XIV) with sulfuric acid affords tetradeuterated acid (XV),which is finally condensed with Ro-32-0445 (VI) as indicated.
合成路线:Tritiated saquinavir: The cyclization of 4-bromoaniline (XVI) with crotonic aldehyde (II) by means of ZnCl2/HCl gives 6-bromo-4-methylquinoline (XVII),which is brominated as before giving tetrabromo derivative (XVIII).The hydrolysis of (XVIII) with sulfuric cid affords 6-bromoquinoline-2-carboxylic acid (XIX),which is condensed with Ro-32-0445 (VI) by means of HOBT and DCC as indicated giving the bromo derivative of saquinavir (XX).Finally,this compound is tritiated with T2 over Pd/C in ethanol.
合成路线:5)[15N,13C,2H]-Saquinavir: The nitration of [13C6]-benzene (XXI) with [15N]-nitric acid gives the corresponding nitrobenzene (XXII),which is reduced with Sn/HCl to the aniline (XXIII).The cyclization of (XXIII) with crotonic aldehyde (II) by means of ClD/D2O and acetic ahydride yields the tetradeuterated quinoline (XXIV),which is brominated as before givig the tribromo derivative (XXV).The hydrolysis of (XXV) with sulfuric acid as usual affords the [15N,13C6,2H3]-labeled quinoline-2-carboxylic acid (XXVI),which is finally condensed with Ro-32-0445 (VI) by means of HOBT and CDI as indicated.
参考文献标题:The synthesis of labelled forms of saquinavir
文献作者:Wiltshire,H.R.; et al.
参考来源:J Label Compd Radiopharm 1998,41(12),1103
产品链接: CAS No. 149845-06-7›› 产品链接: CAS No.127779-20-8››