合成路线1

The condensation of 2-nitroimidazole (I) with methyl chloroacetate (II) by means of sodium methoxide in hot DMF gives methyl (2-nitro-1-imidazolyl)acetate (III), which is then treated with ethanolamine (IV) in methanol.

合成路线2

In a further process, the racemic trans glycidic ester (XII), prepared by Darzen's condensation between anisaldehyde (X) and methyl chloroacetate (XI), was resolved by enantioselective enzymatic hydrolysis, using several different enzymes and reaction conditions to produce the undesired (2S,3R) acid (XIII), while leaving intact the required (2R,3S)-glycidic ester (XIV) (4-7). Opening of the chiral epoxide (XIV) with 2-aminobenzenethiol (VII) proceeded with retention of the configuration, producing methyl (2S,3S)-2-hydroxy-3-(2-aminophenylsulfanyl)-3-(4-methoxyphenyl)propionate (XV) (8). Alternatively, the (S,S)-amino ester (XV) was obtained by resolution with tartaric acid of the racemic three-adduct resulting from epoxide (XII) and 2-aminobenzenethiol (VII) (9). Cyclization of amino ester (XV) in refluxing xylene in the presence of p-toluenesulfonic acid afforded the target lactam (VIII) (9). The cyclization of (XV) to lactam (VIII) was also accomplished by means of trichloroacetic acid or under basic conditions

合成路线3

Several related procedures utilize racemic intermediates that are resolved in more advanced synthetic steps. The racemic trans-glycidic ester (IX) was prepared by Darzen's condensation between anisaldehyde (VII) and methyl chloroacetate (VIII). Opening of the epoxide group of (IX) with 2-aminothiophenol (X) in hot chlorobenzene in the presence of FeCl3 gave rise to the racemic threo adduct (XI) which, without isolation, was cyclized to the cis-lactam (XII) by addition of methanesulfonic acid and then heating to reflux. Alkylation of the lactam N of (XII) with 2-(dimethylamino)ethyl chloride (II) led to the racemic precursor (XIII). Resolution of (XIII) to provide the (S,S)-isomer (VII) was then accomplished by preferential crystallization of supersaturated solutions of several sulfonate salts of (XIII) upon seeding with the desired enantiomer. Racemic diltiazem (XIV), obtained by acetylation of (XIII), has been resolved via formation of the corresponding diastereoisomeric salts with (S)-naproxen

合成路线4

Several novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), a key intermediate in the synthesis of losartan, have been described: 1) Treatment of glycine methyl ester hydrochloride (I) with NaOH in methanol, followed by reaction with methyl pentanimidate (II), gives 2-butyl-4,5-dihydro-1H-imidazol-5-one (III), which is treated with POCl3 to give the 2-butyl-5-chloro-1H-imidazole (IV). Reaction of (IV) with POCl3 and DMF yields the enamine (V), which is finally hydrolyzed with water to 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), the desired intemediate in the synthesis of losartan. 2) Imidazolinone (III) can also be obtained by cyclization of chloroacetic acid methyl ester (VI), chloroacetyl chloride (VII) or bromoacetyl bromide (VIII) with pentanamidine (IX) by means of NaOH in methanol. 3) Alternatively, imidazolinone (III) can be treated with dimethylformamide dimethylacetal in dichloromethane yielding the enamine (X), which is finally treated with POCl3 and hydrolyzed with water. 4) The reaction of glycine (XI) with methyl pentanimidate (II) in NaOH/MeOH gives amidine (XII), which, without isolation, is treated with POCl3 and DMF at 100 C for 2 h, and then hydrolyzed with water to give the desired 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde. Methyl pentanimidate (II) is obtained treating a solution of valeronitrile in MeOH with HCl gas followed by neutralization with aqueous KOH and extraction with Et2O.

合成路线5

The condensation of 5(S)-(trityloxymethyl)-2-pyrrolidinone (I) with benzyl chloroformate (II) and BuLi in THF gives the carbamate (III), which is alkylated with tert-butyl 2-chloroacetate (IV) and LHMDS in THF to yield 2-[1-(benzyloxycarbonyl)-2-oxo-5(S)-(trityloxymethyl)pyrrolidin-2(S)-yl]acetic acid tert-butyl ester (V). The hydrogenation of (V) with H2 over Pd/C in hot tert-butanol affords 2-[5(S)-(hydroxymethyl)-2-oxopyrrolidin-2(S)-yl]acetic acid tert-butyl ester (VI), which is treated with MsCl and TEA in dichloromethane to provide the methanesulfonate (VII). The condensation of (VII) with 4'-hydroxybiphenyl-4-carbonitrile (VIII) by means of potassium tert-butoxide in DMF gives the adduct (IX), which by treatment with HCl in methanol, and with ammonia in the same solvent yields 2-[5(S)-(4'-amidinobiphenyl-4-yloxymethyl)-2-oxopyrrolidin-3(S)-yl]acetic acid methyl ester (X). Finally, this compound is condensed with methyl chloroformate (XI) by means of NaOH in dichloromethane to afford the target compound.

合成路线6

The Darzen's condensation of 4-iodoacetophenone (I) with methyl chloroacetate (II) in the presence of NaOMe afforded the glycidic ester (III), which was further hydrolyzed to the corresponding glycidic acid (IV) with NaOH in aqueous ethanol. Subsequent decarboxylation of (IV) under acidic conditions furnished 2-(4-iodophenyl)propionaldehyde (V). After oxidation of aldehyde (V) with sodium chlorite, the resultant carboxylic acid was converted to the corresponding zinc salt (VI) upon treatment with ZnCl2 and NaOH. Coupling of aryl iodide (VI) with the Grignard reagent (VIII) (prepared from 2-bromo-3-methylthiophene (VII)) in the presence of PdCl2 gave rise to the racemic biarylpropionic acid (IX)). The title (R)-enantiomer was then resolved via formation of the diastereoisomeric salts with D-phenylglycine methyl ester (X)

合成路线7

Preparation of the racemic arylpropionic acid (IX) has been reported through a number of different procedures. 4-Aminoacetophenone (XI) was diazotized to (XII) employing isoamyl nitrite and either acetic or fluoboric acid. Then, the Gomberg-Bachmann coupling of diazonium salt (XII) with 3-methylthiophene (XIII) furnished 4-(3-methyl-2-thienyl)acetophenone (XIV). Subsequent Darzen's condensation of acetophenone (XIV) with methyl chloroacetate (II) afforded the glycidic ester (XV), which was further hydrolyzed to acid (XVI), and then decarboxylated to aldehyde (XVII). Oxidation of (XVII) to the key carboxylic acid was performed by treatment with potassium permanganate

合成路线8

The reaction of ethyl chloroacetate (I) with ethyl formate (II) by means of potassium tert-butoxide in diisopropyl ether gives the 2-formylchloroacetate (III), which is cyclized with 6-methylpyridine-2-amine (IV) by means of conc. H2SO4, yielding 5-methylimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (V). The chlorination of (V) with NCS in THF affords the chloromethyl derivative (VI), which is condensed with the monoprotected diamine (VII) by means of TEA to provide the adduct (VIII). The cyclization of (VIII) by means of NaOMe, TEA and NaI in DMF gives 4-[4-(benzyloxycarbonylamino)butyl]-4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one (IX), which is deprotected with H2 over Pd/C in MeOH, yielding the butylamine derivative (X). Finally, this compound is sulfonated with N-phenyltrifluoromethylsulfonimide (XI) and TEA in DMF.

合成路线9

Alkylation of 7-hydroxyindole (I) with methyl chloroacetate (II) provided indolyl ether (III). Conjugate addition of 2-nitropropene (IV) to indole (III) in refluxing benzene, afforded the 3-(2-nitropropyl)indole (V), which was further reduced to the corresponding amine (VI) by catalytic hydrogenation over Raney nickel. Ring opening of the chiral epoxide (VII) with the racemic amine (VI) gave rise to a diastereomeric mixture of amino alcohols (VIII). After isolation of the desired (R,R)-isomer by column chromatography, basic hydrolysis of the methyl ester function yielded the title carboxylic acid.

合成路线10

A pilot plant process was further developed for the (S)-enantiomer. Darzens condensation of benzophenone (VIII) with methyl chloroacetate gave the glycidic ester (X). Epoxide opening in (X) with trimethylaluminum furnished methyl 2-hydroxy-3,3-diphenylbutyrate (XI), which was hydrolyzed to the corresponding acid (VI) by using KOH in isopropanol. Treatment of the racemic acid (VI) with (S)-1-(4-chlorophenyl)ethylamine (XII) provided the desired (S)-acid salt (XIII). This was finally condensed with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (XIV) in the presence of lithium amide to yield the title compound.

合成路线11

The condensation of benzophenone (I) with methyl 2-chloroacetate (II) by means of NaOMe in THF gives 3,3-diphenyloxirane-2-carboxylic acid methyl ester (III), which by treatment with BF3/Et2O and methanol, followed by optical resolution, yielded the pure enantiomer 2(S)-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (IV). The condensation of (IV) with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (V) by means of K2CO3 in DMF affords 2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester (VI), which is finally hydrolyzed with KOH in hot dioxane to afford the target propionic acid as a racemic mixture.

合成路线12

Treatment of salicylaldehyde (I) with methyl chloroacetate (II) in DMF in the presence of potassium carbonate provides methyl o-formylphenoxyacetate (III), which is converted into methyl 2-benzofuranecarboxylate (IV) by reaction with DBU in toluene. Reduction of (IV) by means of LiAlH4 in ether yields hydroxy derivative (V), which then reacts with SOCl2 in ether/DMF to furnish chloro derivative (VI). Treatment of (VI) with NaCN in DMSO affords cyano derivative (VII), which is converted into 2-benzofuraneacetic acid (VIII) by treatment with NaOH in boiling water. Esterification of (VIII) by treatment with HCl in refluxing MeOH affords methyl acetate derivative (IX), which is condensed with p-anisoyl chloride (X) by means of SnCl4 in 1,2-dichloroethane to yield compound (XI). Treatment of (XI) with aluminum powder and iodine crystals (to generate AlI3) in refluxing benzene gives acetic acid derivative (XII), which is iodinated with iodine and K2CO3 in H2O to give derivative (XIII). Esterification of (XIII) by means of iPrOH and H2SO4 provides isopropyl acetate derivative (XIV), which is finally converted into the desired product by reaction with diethylaminoethyl chloride (XV) in NaOH and CH2Cl2 in the presence of benzyltriethylammonium chloride.

合成路线13

The condensation of 2-nitroimidazole (I) with methyl chloroacetate (II) by means of sodium methoxide in methanol - DMF at 150 C gives methyl 2-nitro-1-imidazolylacetate (III), which is then condensed with benzylamine (IV) in methanol.

合成路线14

Treatment of deoxybenzoin (I) with hydroxylamine hydrochloride produces the corresponding oxime (II). Condensation of the dilithium derivative of (II) with methyl chloroacetate (III) generates the dihydroisoxazole (IV). Subsequent chlorosulfonation of (IV), followed by treatment with ammonia, furnishes sulfonamide (V). Then, displacement of the chloro group of (V) with silver nitrate gives rise to the target nitrate ester. Alternatively, chloride (V) is converted to alcohol (VI) by displacement with formic acid, followed by alkaline hydrolysis. Then, reaction of alcohol (VI) with in situ generated acetyl nitrate yields the corresponding nitrate.

合成路线15

合成路线16

合成路线17

Cyclization of 4-cyclopropyl-1-naphthyl isothiocyanate (I) with aminoguanidine hydrochloride (II) using DIEA in DMF yields the naphthyl-1,2,4-triazole-3-thiol (III), which is then alkylated with methyl chloroacetate (IV) by means of K2CO3 in DMF to give the (triazolylsulfanyl)acetate (V). Diazotization of the amine (V) with NaNO2 and Cl2CHCOOH in the presence of BnEt3NBr or BnEt3NCl in CHBr3 gives rise to the 5-bromotriazole derivative (VI), which is hydrolyzed with LiOH in THF/EtOH/H2O to produce lesinurad (VII) , and is finally treated with NaOH in EtOH .
Also, coupling of the thiol (III) with the 2-chloroacetamide derivative (VIII) by means of K2CO3 in DMF yields the amide (IX), which is then brominated with CHBr3 in the presence of NaNO2, Cl2CHCOOH and BnEt3NBr or BnEt3NCl to give the 5-bromotriazole derivative (X) .Finally, hydrolysis of amide (X) with NaOH in refluxing EtOH affords lesinurad (VII) .

合成路线18