合成路线1

The reaction of dihydrolysergol (I) with BrCN in DMF gives the N-cyano derivative (II), which is treated with NaOH in ethylene glycol yielding the demethylated compound (III). The reductive alkylation of (III) with propionaldehyde (IV) and formic acid in DMF affords the propyl derivative (V), which is mesylated with MsCl and pyridine giving the mesylate (VI). Finally, this compound is treated with sodium methylthiolate and MsOH.

合成路线2

By condensation of 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (I) with 3-formylcrotonic acid butyl ester (II) by means of NaH in DMF to yield 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraen-1-oic acid butyl ester (III), which is then hydrolyzed with KOH in refluxing ethanol - water. The starting products (I) and (II) are obtained as follows: 1) The methylation of 2,3,5-trimethylphenol (IV) with KOH and methyl iodide in refluxing aqueous ethanol gives 2,3,5-trimethylanisole (V), which is then carbonylated with POCl3 and DMF (A) to afford 4-methoxy-2,3,6-trimethylbenzaldehyde (VI). The condensation of (VI) with acetone (B) by means of NaOH gives 4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one (VII), which by a Grignard reaction with ethynylmagnesium bromide (C) in THF is converted into 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-4-penten-1-yne (VIII). The controlled hydrogenation of (VIII) with H2 over a Pd catalyst in hexane yields 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-3-hydroxy-1,4-pentadiene (IX), which is finally treated with triphenylphosphonium bromide in benzene at 60 C to give the phosphonium salt (I). 2) The oxidation of dibutyl L-(+)-tartrate (X) with lead tetraacetate in benzene gives butyl glyoxalate (XI), which is then condensed with propionic aldehyde (D) by means of dibutylamine (E) to afford ester (II).

合成路线3

The methylation of 2,3,5-trimethylphenol (I) with MeI and KOH in 10% aqueous ethanol gives 2,3,5-trimethylanisole (II), which is formylated with DMF and POCl3 yielding 2,3,6-trimethyl-p-anisylaldehyde (III). The condensation of (III) with acetone (B) by means of NaOH affords 4-(4-methoxy-2,3,6-trimethylphenyl)but-3-en-2-one (IV), which by a Grignard reaction with ethynylmagnesium bromide (C) in THF is converted into the acetylenic alcohol (V). Partial hydrogenation of (V) with H2 over Pd/C in hexane gives dienic alcohol (VI), which is condensed with triphenylphosphine hydrobromide in benzene affording 5-(4-methoxy-2,3,6 trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphosphonium bromide (VII). A Wittig condensation of (VII) with butyl 3-formylcrotonate (VIII) by means of NaH in DMF gives butyl 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate (IX), which is hydrolyzed with KOH in refluxing ethanol-water yielding the corresponding free acid (X). This acid is converted into the acyl chloride (XI) by treatment with PCl3 in refluxing benzene. Finally, this compound is treated with ethylamine (E) in ether. The butyl 3-formylcrotonate (VIII) is obtained as follows: The oxidation of dibutyl tartrate (XII) with lead tetraacetate in benzene gives butyl glyoxalate (XIII), which is then condensed with propionaldehyde (XIV) by heating at 110 C with dibutyl-amine (D).

合成路线4

Free NH group of (XI) is alkylated by reductocondensation with propionaldehyde (XII) and H2 over Pd/C, giving the N-propyl derivative (XIII). The reaction of the ester group of (XIII) with hydrazine yields the corresponding hydrazide (XIV), which is submitted to degradation with nitrosyl chloride in THF to afford the amine (XV). The condensation of (XV) with N,N-diethylsulfamoyl chloride (XVI) by means of TEA in chloroform gives the sulfamide (XVII), which is finally demethylated by a treatment with BBr3 in dichloromethane.

合成路线5

The condensation of the acetylenic tetrahydropyranyl ether (I) with propionaldehyde (II) by means of BuLi in THF gives 6-(tetrahydropyranyloxy)-4-hexyn-3-ol (III), which by reduction with H2 over Lindlar catalyst in hexane yields compound (IV). The Swern oxidation of (IV) with oxalyl chloride in dichloromethane affords enone (V), which is condensed with the lithium enolate (VI) in THF to afford the addition keto ester (VII). Cyclization of (VII) by means of potassium tert-butoxide, followed by acylation with pivaloyl chloride gives the cyclohexenone (VIII). Elimination of the tetrahydropyranyl protecting group of (VIII) with TsOH in methanol yields the carbinol (IX), which is oxidized with oxalyl chloride and TEA in dichloromethane to afford the carbaldehyde (X). The enolization of the aldehyde group of (X) with TIPSOTf, DBU and DMAP in dichloromethane provides exclusively the (E)-enol ether (XI), which is submitted to a Sharpless' asymetric dihydroxylation using DHQ-PHN as a chiral ligand to give the chiral alpha-hydroxy aldehyde (XII). Elimination of the pivaloyl group of (XII) with N,N'-dimethylethylenediamine and potassium methoxide in refluxing benzene, followed by reprotection with TIPSCl in THF provides aldehyde (XIII). The reaction of the ketonic group of (XIII) with PhSCH(Li)TMS in THF affords the dienol silyl ether (XIV), which by condensation with 2-bromo-4,5-dihydrobenzaldehyde dibenzyl acetal (XV) by means of t-BuLi in the presence of t-BuMgCl furnishes the expected addition compound (XVI) as a single isomer. Protection of the vicinal diol of (XVI) with trimethyl borate and pyridine in benzene gives the boronic ester (XVII), which is cyclized by means of (i-PrO)2TiCl2 in dichloromethane to yield the polycyclic compound (XVIII). The hydrolysis of the boronic ester of (XVIII) with pinacol and DMAP in benzene, followed by silylation with t-Bu2SiHCl and BuLi in THF affords the cyclic silyl ether (XIX). Reduction of the ketonic group of (XIX) with DIBAL in dichloromethane, followed by silylation with TBDMS-OTf affords the silyl ether (XX), which is dihydroxylated by oxidation with O2 and light using TPP as catalyst, and desulfurized by treatment with Bu3SnH and AIBN in refluxing benzene to provide diol (XXI).

合成路线6

The reaction of 4-benzoyloxycyclohexanone (I) with pyrrolidine (II) by means of p-toluenesulfonic acid in refluxing benzene gives the corresponding enamine (III), which is cyclized with acrylamide (IV) in refluxing dioxane yielding the mixture of hexahydroquinolones (V) and (VI). Benzylation of this mixture with benzylbromide (A) and NaH in THF affords the mixture of N-benzylquinolones (VII) and (VIII), which is reduced with LiAlH4 to the mixture of N-benzylhexahydroquinolines (IX) and (X). The reduction of this mixture with sodium cyanoborohydride in THF affords trans-1-benzyl-6-hydroxydecahydro quinoline (XI), which by reaction with BN in CH2Cl2 is converted to trans-1-cyano-6-hydroxydecahydro quinoline (XII). Oxidation of (XII) with CrO3/pyridine in CH2Cl2 gives the corresponding quinolone (XIII), which by reaction with dimethylformamide dimethyl acetal (XIV) in refluxing benzene is converted to 1-cyano-6-oxo-7-(dimethylaminomethylene)decahydroquinoline (XV). The cyclization of (XV) with hydrazine in refluxing methanol affords 5-cyano-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline (XVI), which by a reductive cleavage with Zn and acetic acid gives 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline (XVII). Finally, this compound is alkylated with propionaldehyde (B) and sodium cyanoborohydride in methanol.

合成路线7

The intermediate, the furanone derivative (VIII) has been obtained as follows: The reaction of propargyl alcohol (XIII) with dihydropyran and Ts-OH gives the tetrahydropyranyl ether (XIV), which is treated with ethylmagnesium bromide to yield the corresponding magnesium derivative (XV). The reaction of (XV) with propionaldehyde (XVI) in THF affords the secondary alcohol (XVII), which is benzoylated with benzoyl chloride and triethylamine affording the benzoate (XVIII). The deprotection of (XVIII) with Ts-OH gives the primary alcohol (XIX), which is oxidized with pyridinium chlorochromate (PCC) to the corresponding aldehyde (XX). The Diels-Alder reaction of (XX) with 5-ethoxy-4-methyloxazole (XXI) in refluxing toluene yields 4-(1-benzoyloxypropyl)-2-ethoxyfuran-3-carbaldehyde (XXII), which is reduced with NaBH4 in methanol to the carbinol (XXIII). The controlled oxidation of (XXIII) with MnO2/HCl affords 4-(1-benzoyloxypropyl)-5-hydroxy-3-(hydroxymethyl)furan-2(5H)-one (XXIV), which is finally treated with SOCl2 and DMF in chloroform to afford the target intermediate (VIII).

合成路线8

6) Mass labeled saprisartan has been obtained as follows: The Wittig condensation of cyclopropylcarbonyl chloride (XXVII) with ethoxycarbonylmethylene triphenylphosphorane (XXVIII) by means of bis(trimethylsilyl)acetamide in dichloromethane gives 3-cyclopropyl-3-oxo-2-(triphenylphosphoranylidene)propionic acid ethyl ester (XXIX), which is oxidized with potassium peroxymonosulfate to the dicarbonyl compound (XXX). The cyclization of (XXX) with [all-13C]-propionaldehyde (XXXI) (obtained by hydrogenation of the corresponding acyl chloride (XXXII) with H2 over Pd/C in THF containing 2,6-lutidine) and [15N]-ammonium acetate by means of triethylamine in THF yields 4-cyclopropyl-2-[1,2-13C]-ethyl-[1,3-15N,2-13C]imidazole-5-carboxylic acid ethyl ester (XXXIII). The condensation of (XXXIII) with the benzofuran (XXI) (already described in Scheme 2) by means of K2CO3 in dimethylacetamide affords 1-[3-bromo-2-(2-nitrophenyl)benzofuran-5-ylmethyl]-4-cyclopropyl-2-[1,2-13C]-ethyl-[1,3-15N,2-13C]imidazole-5-carboxylic acid ethyl ester (XXXIV), which is finally treated sequentially with Fe and acetic acid to reduce the nitro group, with trifluoromethanesulfonic anhydride to acylate the amino group, with NaOH to hydrolyze the ester group, and with carbonyldiimidazole and ammonia to generate the amide group, thus obtaining mass labeled saprisartan. This sequence has already been described in Scheme 19090802a for the unlabeled compound.

合成路线9

The condensation of 3-(methylsulfonyl)bromobenzene (I) with diethyl(3-pyridyl)borane (II) by means of Pd(PPh3)4, KOH and tetrabutylammonium iodide (TBAI) gives 3-[3-(methylsulfonyl)phenyl]pyridine (III), which is hydrogenated with H2 over PtO2 in methanol, yielding the racemic piperidine (IV). The optical resolution of (IV) with (+)-tartaric acid affords the (S)-enantiomer (V), which is alkylated by reductocondensation with propionic aldehyde and NaBH(O-tBu)3 in dichloroethane and HOAc.

合成路线10

C1-C6 fragment.- The reaction of 3-methyl-2-butenylmagnesium chloride (I) with propanal (II) gives racemic 4,4-dimethyl-5-hexen-3-ol (III), which was submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme yielding the (R) enantiomer (IV). The esterification of (IV) with bromoacetyl bromide (V) and dimethylaniline yields the corresponding ester (VI), which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to afford chiral tetrahydropyran-2-one (VII). The reduction of (VII) with Red-Al, followed by cyclization with 2-methoxypropene (VIII) and PPTS yields the acetonide (IX), which is finally oxidized with N-methylmorpholine-N-oxide and PPTS in dichloromethane giving the target intermediate (X).

合成路线11

Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiovalerate (V). Ethyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.

合成路线12

Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with propanethiol (IV), followed by decarboxylation provided S-propyl 3-oxothiovalerate (V). Propyl 3-amino-3-(m-chlorophenyl)-2-propenoate (VII) was prepared by reaction of (3-chlorobenzoyl)acetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.

合成路线13

Acylation of Meldrum's acid (I) with butyryl chloride (II) in the presence of pyridine gave butyryl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiocaproate (V). Ethyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), b-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.

合成路线14

The reaction of phenylhydrazine (I) with propionaldehyde (II) gives the corresponding hydrazone (III), which is condensed with phenyldiazoninum chloride (IV) to yield the formazan (V). The cyclization of (V) by means of BF3 in hot acetic acid affords 3-ethyl-1,2,4-benzotriazine (VI), which is finally oxidized to the target dioxide by means of H2O2 and trifluoroacetic anhydride in dichloromethane.

合成路线15

The reaction of 3-methyl-2-butenylmagnesium bromide (XVI) with propanal (XVII) gives racemic hexenol (XVIII), which is submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme, yielding the R-enantiomer (XIX). The esterification of (XIX) with bromoacetyl bromide (XX) and dimethylaniline (DMA) affords the corresponding ester (XXI), which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to provide the chiral tetrahydropyranone (XXII). The reduction of (XXII) with Red-Al, followed by cyclization with 2-methoxypropene (XXIII) and PPTS, gives the acetonide (XXIV), which is oxidized with PPTS and NMO to provide the protected dihydroxyketone (XXV). The condensation of the ketone (XXV) with 2(S)-methyl-6-heptenal (XXVI) by means of LDA in THF gives the hydroxyundecenone (XXVII), which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (XXVIII). The silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (XXIX), which is selectively monodesilylated with CSA to provide the primary alcohol (XXX). Finally, this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the target tridecenoic acid intermediate (XII).

合成路线16

Pyridine (V) was prepared by Hantsch synthesis upon condensation of ketothioester (I), aldehyde (II) and enamino ester (III), followed by oxidative aromatization of the resulting dihydropyridine (IV) with chloranil, according to a reported method. N-Alkylation of pyridine (V) with iodomethane in hot nitromethane in a sealed tube under pressure furnished the title pyridinium salt.

合成路线17