合成路线1

Eplerenone was prepared by several related ways. Microbiological hydroxylation of canrenone (I) provided the 11-a hydroxy derivative (II). This was converted to enamino compound (IV) by double addition of cyanide, followed by cyclization, on treatment with acetone cyanohydrin (III) in the presence of triethylamine and lithium chloride in DMF or, alternatively, by treatment with sodium cyanide and sulfuric acid. Hydrolysis of enamine (IV) with HCl in a methanol-water solution gave diketone (V), and further reaction with sodium methoxide in refluxing methanol gave hydroxyester (VI). After mesylation of the 11-a hydroxyl group with with mesyl chloride and triethylamine in cold dichloromethane, elimination of the resulting sulfonate (VII) to give olefin (VIII) was achieved on treatment with potassium formate in a mixture of formic acid and acetic anhydride at 100 C. Other conditions used for the elimination were potassium acetate in trifluoroacetic acid-trifluoroacetic anhydride, isopropenyl acetate and p-TsOH, or thermoelimination in DMSO at 80 C. Alternatively, hydroxyester (VI) was reacted with sulfuryl chloride at -70 C, and then treated with imidazole at room temperature to afford olefin (VIII). Finally, epoxidation was performed by reaction with hydrogen peroxide in the presence of trichloroacetamide or trichloroacetonitrile and PO4HK2 to give eplerenone.

合成路线2

In a related way, canrenone (I) was converted to mexrenone (XI) by an analogous sequence including cyanide addition to give enamine (IX), hydrolysis to diketone (X), and ring opening with NaOMe. The microbiological oxidation of mexrenone (XI) yielded either the 9-a (XII) or the 11-b (XIII) hydroxylated compounds, which were dehydrated to the olefin (VIII), whose epoxidation, as before, afforded eplerenone.

合成路线3

The intermediate 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (VIII) has been obtained by three different ways: 1) The cyclization of 2-hdroxybenzaldehyde (I) with ethyl 2-bromoacetate (II) by means of K2CO3 in DMF gives ethyl benzofuran-2-carboxylate (III), which is reduced with LiAlH4 in refluxing THF to the carbinol (IV). The reaction of (IV) with acetone cyanohydrin (V), PPh3 and DEAD yields the acetonitrile (VI), which is reduced with H2 over Raney-Ni to afford the ethylamine (VII). Finally, this compound is cyclized with formaldehyde in refluxing water to provide the desired intermediate (VIII). 2) The intermediate ethyl benzofuran-2-carboxylate (III), is hydrolyzed with NaOH to the corresponding free acid (IX), which is decarboxylated with Cu at 240 C in quinoline to yield benzofuran (X). The reaction of (X) with oxirane (XI) by means of n-BuLi in ethyl ether affords 2-(2-benzofuryl)ethanol (XII), which is treated first with MsCl and TEA, and then with NaI in refluxing acetone to provide the 2-(2-iodoethyl)benzofuran (XIII). The reaction of (XIII) with hexamethylenetetramine (HMT) gives the adduct (XIV), which is finally cyclized to the target intermediate (VIII) by means of HCl in refluxing ethanol. 3) The target intermediate (VIII) can also be obtained by cyclization of O-phenylhydroxylamine (XV) with 4-piperidone (XVI) in refluxing isopropanol. Finally, intermediate (VIII) is condensed with 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidine (XVII) by means of Na2CO3 and KI in a refluxing organic solvent such as 4-methyl-2-pentanone.

合成路线4

Racemic allylglycine (I) was protected as the N-Boc derivative (II) and then converted to the Weinreb amide (III) by treatment with N,O-dimethylhydroxylamine and BOP. Reduction of (III) with LiAlH4 afforded aldehyde (IV), which, upon treatment with acetone cyanohydrin (V), furnished the corresponding hydroxy nitrile (VI). Acid hydrolysis of the nitrile (VI) with concomitant Boc group deprotection provided hydroxy acid (VII), which was further reprotected as the N-Boc derivative (VIII). Coupling of hydroxy acid (VIII) with allylamine (IX) yielded amide (X). After Boc group cleavage with HCl in dioxan, the resulting amine (XI) was coupled with pentapeptide (XII) (obtained using a peptide synthesizer under standard conditions), to give the alpha-hydroxyamide (XIII).

合成路线5

合成路线6

Oxidation of 2-fluoro-4-nitrotoluene (I) by means of periodic acid and CrO3 affords 2-fluoro-4-nitrobenzoic acid (II), which by chlorination with SOCl2 in DMF at –5 °C, followed by condensation with methylamine, yields 2-fluoro-N-methyl-4-nitrobenzamide (III). Reduction of the nitro group in compound (III) with Fe in refluxing AcOH/EtOAc gives amine (IV), which is then condensed with pure acetone cyanohydrin (V) in the presence of anhydrous MgSO4 at 80 °C to provide 4-(1-cyano-1-methylethylamino)-2-fluoro-Nmethylbenzamide (VI). Finally, compound (VI) is condensed with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (VII) (prepared by reaction of 4-amino-2-(trifluoromethyl)benzonitrile (VIII) with thiophosgene in H2O) in DMF heated to 100 °C under microwave irradiation, and then cyclized by means of HCl in refluxing MeOH .

合成路线7

N-Protection of 2-methylalanine with Boc2O, optionally in the presence of NaHCO3, in THF/H2O yields N-Boc-2-methylalanine (II) , which is then methylated with Me3SiCHN2 in MeOH/THF or with MeI using KHCO3 in DMF to give the methyl ester (III) . Reduction of the ester (III) by means of LiBH4 in THF /EtOH affords the primary alcohol (IV) , which can also be prepared from 2-amino-2-methyl-1-propanol (V) by N-protection with Boc2O in CH2Cl2 . After conversion of alcohol (IV) to the corresponding mesylate (VI) with MsCl and Et3N in CH2Cl2, N-deprotection with HCl in dioxane provides amine (VII), which by reaction with Na2SO3 in H2O yields the aminosulfonic acid (VIII) . Finally, compound (VIII) is N-chlorinated using trichloroisocyanuric acid , Cl2 , HOCl or NaOCl/HCl .
The aminosulfonic acid (VIII) can also be prepared by the following two strategies: Condensation of acetone (IX) with t-BuSONH2 by means of Ti(OEt)4 gives the N-sulfinylimine (X), which is then coupled with ethyl methanesulfonate (XI) in the presence of BuLi and HMPA in THF to produce the propanesulfonate derivative (XII). Finally, hydrolysis of the sulfonate ester (XII) with LiOH in THF/MeOH/H2O, followed by removal of the sulfinyl protecting group with HCl in MeOH furnishes aminosulfonic acid (VIII) .
Reduction of 2-hydroxy-2-methylpropanenitrile (XIII) by means of LiAlH4 yields 1-amino-2-methylpropan-2-ol (XIV), which is then Nprotected with Boc2O to give N-Boc-1-amino-2-methylpropan-2-ol (XV). Mesylation of the alcohol (XV) with MsCl using Et3N in CH2Cl2 and subsequent N-deprotection of the resulting mesylate (XVI) with HCl in dioxane affords the amino mesylate (XVII). Finally, substitution of the tertiary mesylate (XVII) with Na2SO3 occurs with rearrangement of the primary amino group generating aminosulfonic acid (VIII) .