合成路线1

合成路线2

The reaction of 3-(chloromethyl)-7-(phenylacetamido)-3-cephem-4-carboxylic acid 4-methoxybenzyl ester (I) with triphenylphosphine and NaI in acetone gives the corresponding phosphonium salt (II), which is condensed with 4-methylthiazole-5-carboxaldehyde (III) by means of NaHCO3 in dichloromethane affording 3-[2(Z)-(4-methylthiazol-5-yl)vinyl]-7-(phenylacetamido)-3-cephem-4-carboxylic acid 4-methoxybenzyl ester (IV). The cleavage of the amido group of (IV) with PCl5 and pyridine yields the 7-amino compound (V), which is condensed with 2-(methoxyimino)-2-[2-(tritylamino)thiazol-4-yl]acetic acid (VI) by means of POCl3 in dichloromethane giving 3-[2(Z)-(4-methylthiazol-5-yl)vinyl]-7-[2(Z)-methoxyimino)-2-(2-tritylamino)thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid 4-methoxybenzyl ester (VII). The deprotection of (VII) with trifluoroacetic acid and anisole yields the free amino acid (VIII), which is finally esterified with iodomethyl pivalate (IX) in DMF.

合成路线3

Coupling of ethyl glyoxylate derivative (I) with Boc-L-Alanine (II) by means of EDC and DMAP in DMF provides compound (III), whose ethyl ester is subjected to saponification by treatment with NaOH in EtOH to furnish carboxylic acid (IV). Condensation of (IV) with methoxyamine (NH2OMe) in THF/H2O yields methoxyimino acetic acid derivative (V), which is then coupled to pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) in CH2Cl2 by means of phosphorus oxychloride (POCl3) in DMF/EtOAc and N-trimethylsilylacetamide to give compound (VII). Finally, the desired compound is obtained after treatment of (VII) with TFA and anisole in CH2Cl2 for Boc removal . Alternatively, methoxyimino acetic acid derivative (V) can be converted into intermediate (VII) by coupling with 7-amino-3-cephem-4-carboxylic acid (VIII) by means of POCl3 in DMF/EtOAc and N-trimethylsilylacetamide in CH2Cl2 to provide derivative (IX), followed by condensation with iodomethyl pivalate (X) by means of potassium acetate in DMF.

合成路线4

Coupling of pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) and methoxyimino acetic acid derivative (XI) by means of POCl3 and pyridine in CH2Cl2 gives compound (XII) (alternatively (XII) can be obtained by condensation of ceftizoxime (CZX) (XIII) with iodomethyl pivalate (X) in N,N-dimethylacetamide (DMAc) in the presence of dicyclohexylamine). Coupling of (XII) with Boc-L-alanine (II) by means of EDC and DMAP in CH2Cl2 gives intermediate (VII), whose Boc protecting group is removed by treatment with either HCl/isopropanol in formic acid or TFA and anisole in CH2Cl2. Yet another strategy can be followed, involving the coupling of pivaloyloxymethyl 7-amino-3-cephem-4-carboxylate (VI) with derivative (XIV) by means of Et3N in N,N-dimethylacetamide.

合成路线5

Adefovir dipivoxil can be obtained by two similar ways: 1) The reaction of adenine (I) with 2-(diisopropoxyphosphorylmethoxy)ethyl methanesulfonate (II) by means of cesium carbonate in DMF gives the expected condensation product (III), which is converted into the phosphonic acid (IV) by treatment with trimethylsilyl bromide in acetonitrile (1). Finally, this compound is condensed with chloromethyl pivalate (V) by means of N,N'-dicyclohexylmorpholine-4-carboxamidine in DMF. 2) The final condensation of the phosphonic acid (IV) can also be performed with iodomethyl pivalate (VI) in pyridine.

合成路线6

Finally, the target compound has been obtained as follows: The selective esterification of the phosphono group of intermediate (IX) with iodomethyl pivalate (XVIII) by means of triethylamine in DMF gives the sulfonic acid (XIX), which was purified through its calcium salt. Finally, this compound is treated with tert-butylamine in methanol to afford the target salt.

合成路线7

1) The mesylation of 4(S)-hydroxypyrrolidin-2-one (I) with mesyl chloride and triethylamine in pyridine gives the corresponding ester (II), which is treated with potassium thioacetate (III) in refluxing acetonitrile yielding 4(R)-(acetylsulfanyl)pyrrolidin-2-one (IV). The hydrolysis of (IV) with sodium methoxide in methanol followed by acidification with aqueous HCl affords 4(R)-sulfanylpyrrolidin-2-one (V), which is condensed with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VI) by means of ethyldiisopropylamine in acetonitrile to give (1R,5S,6S)-6-[1(R)-hydroxyethyl]-1-methyl-2-[5-oxopyrrolidin-3(R)-ylsulfanyl]-1-carba-2-penem-3-carboxylic acid p-nitrobenzyl ester (VII). The hydrogenolysis of (VII) with H2 over Pd/C in THF/aqueous phosphate buffer yields the sodium salt (VIII), which is finally esterified with pivaloyloxymethyl iodide (IX) in dimethylacetamide.

合成路线8

A short-step synthesis of CS-834 has been described: The condensation of azetidinone (I) with pyrrolidinone (II) by means of CDI gives the thioester (III), which is desilylated with BF3/Et2O to the alcohol (IV). In order to have a more labile protecting group, alcohol (IV) is resilylated with TMS-Cl (or TES-Cl) and triethylamine affording the silyl ether (V), which is protected again at the pyrrolidine nitrogen with TES-Cl, affording the disilylated azetidinone (VI). The condensation of (VI) with the oxalyl chloride (VII) by means of triethylamine in dichloromethane gives the expected oxalylazetidinone (VIII), which is treated with diethyl ethylphosphonite in toluene yielding the ylide (IX). This compound, without isolation, is cyclized in refluxing mesitylene to afford the protected carbapenem intermediate (X), which is finally desilylated with HCl in acetonitrile. The cyclization of azetidinone (VIII) to carbapenem (X) can also be performed with triethyl phosphite instead of diethyl ethylphosphonite. The oxalyl chloride (VII) is obtained by monoesterification of oxalic acid (XI) with pivaloyloxymethyl iodide (XII) by means of triethylamine yielding monoester (XIII), which is finally converted to intermediate (VII) by treatment with oxalyl chloride in dichloromethane.

合成路线9

Condensation of (phosphoryloxy)carbapenem (XVI) with 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (XI) gave thioether (XVII). The p-nitrobenzyl ester group of (XVII) was then deprotected with Zn powder to afford carboxylic acid. Finally, treatment of (XVIII) with either iodo or chloromethyl pivalate (XIX) produced the target compound.

合成路线10

Protection of alcohol (I) with TBDMSCl and imidazole gives silyl compound (II) which is N-methylated by means of NaH and MeI and then deprotected with HCl to yield derivative (III). Mesylation of (III) with MsCl in presence of Et3N followed by thioacetylation with AcSK (A) affords thioacetate (IV) which is then hydrolyzed with NaOMe to yield (V). Treatment of (VI) with diphenylphosphoryl chloride (B) and DIEA in acetonitrile yields (VII), which is then condensed with mercaptan (V) by means of DIEA in the same solvent to provide carbapenem (VIII). Deprotection of the carboxyl moiety of (VIII) by hydrogenation with H2 over Pd/C affords carboxylate (IX), which is finally esterified with pivaloyloxymethyl iodide (X) in N,N-dimethylacetamide or DMF.

合成路线11

Alcohol (I) is protected with TBDMSCl and imidazole to give silyl compound (II), which is N-methylated by means of NaH and MeI and then deprotected with HCl to yield derivative (III). Mitsunobu reaction of (III) with 4-nitrobenzoic acid in presence of PPh3 and DEAD, followed by ester hydrolysis with K2CO3, provides alcohol (IV). Mesylation of (IV) with MsCl in presence of Et3N, followed by thioacetylation with AcSK (A), affords thioacetate (V), which is then hydrolyzed with NaOMe to yield (VI). Treatment of (VII) with diphenylphosphoryl chloride (B) in CH3CN and DIEA in CH3CN yields (VIII), which is then condensed with mercaptan (VI) by means of DIEA in the same solvent to provide carbapenem (IX). Deprotection of the carboxyl moiety of (IX) by hydrogenation with H2 over Pd/C affords carboxylate (X), which is finally esterified with pivaloyloxymethyl iodide (XI) in N,N-dimethylacetamide or DMF.

合成路线12

Alkylation of 4,5,6,7-tetrahydro-1,2-benzisoxazol-3-ol (I) with ethyl bromide in the presence of K2CO3 afforded the ethoxy derivative (II). Subsequent oxidation of (II) with sodium dichromate and H2SO4 provided the desired ketone (III) along with minor amounts of the isomeric 7-oxo compound (IV) that were separated by column chromatography. Conversion of (III) to the corresponding oxime (V), followed by reduction with aluminum amalgam yielded amine (VI). Resolution was achieved via formation of the diastereomeric amides with (R)-alpha-methoxyphenylacetyl chloride (VII) and isolation of the desired isomer (VIII) by preparative HPLC. Cleavage of amide and ether groups of (VIII) by means of HBr furnished (R)-4-amino-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole (IX). Protection as the corresponding tert-butyl carbamate, followed by N-methylation with CH3I and NaH provided intermediate (X). An alternative procedure for the preparation of intermediate (X) consisted in the reductive amination of ketone (III) with methylamine and NaBH3CN, followed by condensation of the resulting amine (XI) with the chiral acid chloride (VII) and chromatographic isolation of the desired diastereoisomer (XII). The alpha-methoxyphenylacetyl group of (XII) was then removed by an alternative method consisting in the treatment with lithium triethylborohydride to give the chiral amine (XIII). Cleavage of the ethyl ether group of (XIII) was effected by means of HBr in AcOH, and the resulting compound (XIV) was condensed with di-tert-butyl dicarbonate to produce carbamate (X). Subsequent reaction of (X) with pivaloyloxymethyl iodide (XV) in the presence of potassium tert-butoxide yielded the target O-alkylated compound (XVI) along with some N-alkylated regioisomer. The Boc protecting group of (XVI) was finally removed by treatment with trifluoroacetic acid.