合成路线1

The benzylation of 4-hydroxymandelic acid (I) with benzyl alcohol (II) and K2CO3 in methanol gives 4-benzyloxymandelic acid (III), which is condensed with 2-(3,4-dimethoxyphenyl)ethylamine (IV) by means of (C2H5O)2PON3 in THF to afford N-(3,4-dimethoxyphenylethyl)-4-benzyloxymandelamide (V). The reduction of (V) with diborane in THF yields the final product protected at the phenolic hydroxyl (VI) This compound is finally deprotected by hydrogenolysis with H2 over Pd/C.

合成路线2

The reaction of 1-cyclopentenylpyrrolidino (I) with methyl 2-acetylamino-3-chloropropionate (II) in DMF gives methyl 2-acetylamino-3-(2-oxocyclopentyl)propionate (III), which is cyclized in refluxing concentrated HCl and reduced with H2 over Pd/C in acetic acid yielding cis,endo-2-azabicyclo[3.3.0]octan-3-carboxylic acid (IV). Esterification of (IV) with SOCl2 and benzyl alcohol affords the corresponding benzyl ester (V), which is condensed with N-(1-ethoxycarbonyl-3-phenylpropyl)alanine (VI) by means of dicyclohexylcarbodiirnide (DCC) in DMF affording benzyl N-(1-ethoxycarbonyl-3-phenylpropyl)alanyl-cis,endo-2-azabicyclo[3.3.0]octan-3-carboxylate (VII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol.

合成路线3

The cyclization of 2-amino-3-chloropyrazine (I) with chloroacetone (II) by means of triethylamine at 100 C gives 8-chloro-2-methylimidazo[1,2-a]pyrazine (III), which is treated with benzyl alcohol and NaOH in DMF to yield 8-benzyloxy-2-methylimidazo[1,2-a]pyrazine (IV). The nitrosation of (V) with butyl nitrite in refluxing dioxane affords 8-benzyloxy-3-nitroso-2-methylimidazo[1,2-a]pyrazine (V), which is finally reduced with Zn in acetic acid, and treated with HCl.

合成路线4

The condensation of alanine tert-butyl ester (I) with ethyl 2-bromo-4-phenylbutanoate (II) by means of triethylamine in hot DMF gives ethyl 2-[[1-(tert-butoxycarbonyl)ethyl]amino]-4-phenylbutanoate (III), which is partially hydrolyzed with trifluoroacetic acid yielding ethyl 2-[[1-carboxyethyl]amino]-4-phenylbutanoate (IV). The condensation of (IV) with benzyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (V) [prepared from the corresponding acid (VI) and benzyl alcohol (A) by means of polyphosphoric acid] by means of triethylamine and 1-hydroxybenzotriazole affords benzyl 2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (VII), which is finally debenzylated by hydrogenolysis with H2 over Pd/C in THF.

合成路线5

Protection of 2-hydroxyisovaleric acid (XIX) with tert-butyldimethylsilyl chloride and imidazole in DMF, followed by condensation with Meldrum's acid (XX) by use of diethyl phosphorocyanidate (DEPC) and Et3N in THF, furnishes derivative (XXI), which is then subjected to reaction with benzyl alcohol (XXII) in refluxing benzene to afford beta-keto ester (XXIII). Next, derivative (XXIII) is methylated with MeI and NaH and its benzyl group is removed by hydrogenation over Pd/C in THF to yield carboxylic acid (XXIV). Coupling between H-Pro-OBzl.HCl (XXV) and Boc-Leu-OH (XXVI) by means of DEPC and Et3N in DMF affords dipeptide (XXVII), which is then converted into fragment (XXVIII) by first condensation with carboxylic acid (XXIV) by means of DCC, HOBt and NMM in THF/DMF and treatment with tetrabutylammonium fluoride for TBDMS protecting group removal. Coupling of fragment (XXVIII) with fragment (XVIII) by means of DCC and DMAP in CH2Cl2 furnishes linear peptide (XXIX), which is hydrogenated over Pd/C in THF and then subjected to cyclization by means of BOPCl and Et3N in CH2Cl2 to give macrolide (XXX). Next, deprotection of (XXX) with TMSOTf affords intermediate (XXXI) (didemnin A).

合成路线6

The esterification of bromoacetic acid (I) with benzyl alcohol (II) gives the corresponding ester (III), which by reaction with triphenylphosphine (IV) in hot toluene yields the phosphonium bromide (V). The reaction of (V) with NaOH in water-dichloromethane affords benzyl(triphenylphosphoranylidene) acetate (VI), which is submitted to a Wittig condensation with 5-(hydroxymethyl)-2-pyrrolidone (VII) in the presence of Dess-Martin periodinane (DMPI) giving benzyl 3-(5-oxo-2-pyrrolidinyl)-2(E) propenoate (VIII). The acylation of (VIII) with 4-methoxybenzoyl chloride (IX) by means of triethylamine in hot toluene yields the corresponding amide (X), which is finally hydrogenated and deprotected with H2 over Pd/C in THF.

合成路线7

The partial hydrolysis of perhydropyrrolizine-3,5-dione (I) in the presence of benzyl alcohol (II) by means of aqueous concentrated HCl at 98 C gives benzyl 5-oxopyrrolidine-2-propenoate (III), which is condensed with 4-methoxybenzoyl chloride (IV) by means of triethylamine in hot THF to afford benzyl 1-(4-methoxybenzoyl)-5-oxopyrrolidine-3-propanoate (V). Finally, this compound ls debenzylated by hydrogenolysis with H2 over Pd/C in THF.

合成路线8

The reaction of epichlorohydrin (I) with benzyl alcohol (II) by means of NaOH in water gives 1,3-di-O-benzylglycerol (III), which is condensed with paraformaldehyde by means of HCl in methylene chloride to yield 1,3-di-O-benzyl-2-O-(chloromethyl)glycerol (IV). Acetylation of (IV) with potassium acetate in acetone affords 1,3-di-O-benzyl-2-O-(acetoxymethyl)glycerol (V), which is condensed with diacetylguanine (VI) by means of p-toluenesulfonic acid in sulfolane giving N2-acetyl-9-[[1,3-bis(benzyloxy)-2-propoxy]methyl]guanine (VII). Finally, this compound is deprotected by a treatment with palladium hydroxide in refluxing cyclohexane.

合成路线9

The esterification of (3aR,7aS)-octahydroindole-2(S)-carboxylic acid (I) with benzyl alcohol (II) by means of SOCl2 gives the corresponding benzyl ester (III), which is condensed with N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (IV) by means of 1-hydroxybenzotriazole, N-ethylmorpholine and dicyclohexylcarbodiimide (DCC) in DMF giving the benzyl ester (V) of the desired product. Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol.

合成路线10

The synthesis of ring labeled [14C]-atorvastatin has been described: The Grignard reaction of phenylmagnesium chloride (I) with [14C]-labeled CO2 (II) in THF/ethyl ether gives the benzoic acid (III), which is reduced with LiAlH4 in ethyl ether to the benzyl alcohol (IV). The oxidation of (IV) with pyridinium dichromate affords the benzaldehyde (V), which is condensed with the isobutyrylacetamide (VI) by means of beta-alanine in acetic acid yielding a mixture of the cis- and trans-benzylidene derivatives (VII). The condensation of (VII) with 4-fluorobenzaldehyde (VIII) by means of triethylamine and a thiazolium bromide catalyst affords the 1,4-dione (IX), which is cyclized with the chiral amino ester (X) in hot heptane/toluene/THF providing the protected pyrroloheptanoic ester (XI). The deprotection of (XI) in acidic medium, followed by the hydrolysis of the ester group with NaOH affords the sodium salt (XII), which is finally treated with calcium acetate in THF/water.

合成路线11

The esterification of indole-2-carboxylic acid (I) with benzyl alcohol and CDI gives the corresponding benzyl ester (II), which is alkylated with methyl bromoacetate (III) by means of NaH in DMF yielding 1-(methoxycarbonylmethyl)-1H-indole-2-carboxylic acid benzyl ester (IV). The debenzylation of (IV) with H2 over Pd/C in ethanol/DMF affords the free acid (V), which is condensed with 4-(2-chlorophenyl)thiazol-2-amine (VI) by means of benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) in DMF to give the carboxamide (VII). Finally, the ester group of (VII) is hydrolyzed with NaOH or KOH in methanol/water.

合成路线12

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.

合成路线13

The reaction of 3-tetrahydrofuroic acid (I) with diphenyl phosphoryl azide (DPPA) in refluxing dioxane gave the intermediate isocyanate (II), which was treated with benzyl alcohol (III) to yield carbamate (IV). Subsequent hydrogenolysis in the presence of Pd/C afforded racemic amine (V), which was resolved by treatment with S-(+)-10-camphorsulfonyl chloride (VI) in pyridine, followed by column chromatography and recrystallization from acetone of the resulting sulfonamide (VII). Then, hydrolysis in HCl-AcOH provided the S-amine (VIII). Condensation of amine (VIII) with 6-chloropurine riboside (IX) in the presence of triethylamine in refluxing MeOH furnished the title compound.

合成路线14

Reaction of 2-nitro-5-chlorophenylhidrazyne (I) with ethyl 2-cyano-3-ethoxypropenoate (II) in EtOH and catalytic AcOH affords derivative (III), which is simultaneously hydrolyzed and cyclized to the triazine system (IV) in aqueous NaOH. Treatment of (IV) with SOCl2, followed by addition of alcohol (V) in chloroform, allows obtention of the desired product.

合成路线15

The reaction of malononitrile (I) with benzyl alcohol (II) and HCl in ethyl ether gives 2-cyanoacetimidic acid benzyl ester (III), which is condensed with phenoxycarbonyl isothiocyanate (IV) to yield 2-cyano-3-mercapto-3-(phenoxycarbonylamino)acrylimidic acid benzyl ester (V). Compound (V) is cyclized by means of pyridine and Br2 in acetonitrile to afford the isothiazole derivative (VI). The reaction of (VI) with conc. H2SO4 provides the isothiazole carboxamide (VII), which is condensed with 4-bromo-2,6-difluorophenol (VIII) by means of PPh3 and DEAD in THF to give the aromatic ether (IX). Finally, the carbamic ester group of (IX) is treated with 4-(1-pyrrolidinyl)butylamine (X) to yield the target urea derivative.

合成路线16

Treatment of protected derivative (I) with ethyl chloroformate (II) and DMAP in dichloromethane yields (III), which is then protected by Mitsunobu reaction with benzyl alcohol (IV) in the presence of PPh3 and DEAD to provide (V). Coumarin (V) undergoes Mitsunobu reaction with noviose (VI) to afford alpha-glycoside (VII), which is converted into (VIII) by protection in 3'-OH by means of TESCl, imidazole and DIEA in dichloromethane (chromatographic separation of 3'- and 2'-TES-protected regioisomers is needed), followed by protection of the 2'-OH by treatment with DHP and catalytic TsOH in dichloromethane. Hydrogenolysis of (VIII) over Pd/C followed by desilylation with TBAF in THF affords intermediate (IX), which is then converted into N'-alkoxycarbamate (XII) by reaction with (X) and DMAP in dichloromethane to yield the corresponding p-nitrophenylcarbonate activated form, followed by reaction with hydroxylamine (XI) in DMF and catalysis of DMAP. Exchange of the 3-ester group in (XII) by hydroxylamine (XIII) in pyridine gives coumarin-3-hydroxamate derivative (XIV), which is finally deprotected of its THP form in MeOH and catalysis of TsOH.

合成路线17

Addition of benzyl alcohol (C) to isocyanate (XVIII) gave rise to carbamate (XIX), which was further N-alkylated with iodomethane and NaH. Hydrogenolysis of carbamate (XX) over Pd/C produced methyl amine (XXI). This was then converted to the target triazolylmethyl derivative by alkylation with N-formyl-2-chloroacetamidrazone (XXII), followed by thermal cyclization in refluxing xylene.

合成路线18

The alkylation of diethyl (R)(+)-2-hydroxysuccinate (I) with 2-methylallyl bromide (II) by means of LiHMDS in THF gives the alkylated diester (III), which is hydrolyzed with KOH in dioxane/water to yield the chiral succinic acid (IV). The regioselective monoesterification of (IV) with benzyl alcohol (V), trifluoroacetic anhydride, TEA and DMAP affords the monobenzyl ester (VI). The lactonization of (VI) by means of bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC) in dichloromethane provides the beta lactone (VII), which is hydrogenolyzed at the benzyl ester group by means of H2 over Pd/C in ethanol to give the carboxylic acid (VIII). Finally this compound is condensed with the dipeptide N2-(tert-butoxycarbonyl-L-alanyl)-N1-(1-naphthylmethyl)-L-lysinamide (IX) by means of DCC and HOBt in dichloromethane to yield the target dipeptide derivative.

合成路线19

The condensation of phenyl dichlorophosphonate (I) with 2-chloroethylamine hydrochloride (II) in the presence of Et3N in cold CH2Cl2 provides phenyl N,N ’-bis(2-chloroethyl)phosphorodiamidate (III), which is finally converted to the corresponding phosphorodiamidic acid by catalytic hydrogenation over PtO2 in EtOH . In an alternative method, acylation of benzyl alcohol (IV) with POCl3 in the presence of Et3N in cold acetonitrile gives benzyl dichlorophosphonate (V), which is further condensed with 2-chloroethylamine hydrochloride (II) in the presence of Et3N to yield benzyl N,N’-bis(2-chloroethyl)phosphorodiamidate (VI). Finally, benzyl ester (VI) is then submitted to hydrogenolysis over Pd/C in acetonitrile .

合成路线20