合成路线1

By alkylation of sisomicin (I) with acetaldehyde (II) and sodium cyanoborohydride in water with some sulfuric acid.

合成路线2

The reaction of 2-chloro-4-fluorosulfonylbenzyl bromide (I) with triphenylphosphine (II) in refluxing benzene gives the corresponding triphenylphosphonium bromide (III), which is submitted to a Wittig condensation with 2-chloro-4-nitrocinnamaldehyde (IV) [prepared by an aldol condensation of 2-chloro-4-nitrobenzaldehyde (V) and acetaldehyde (VI)] yielding 1-(4-fluorosulfonyl-2-chlorophenyl)-4-(2-chloro-4-nitrophenyl)butadiene (VII). The reduction of (VII) with H2 over PtO2 in methoxyethanol affords 1-(4-fluorosulfonyl-2-chlorophenyl)-4-(2-chloro-4-aminophenyl)butane (VIII), which is finally cyclized with cyanoguanidine (IX) and acetone and treated with ethanesultonic acid.

合成路线3

The reaction of 7-chloro-5-phenyl-2-hydrazino-1,3-dihydro-3H-1,4-benzodiazepine (X) with refluxing acetaldehyde (C) gives 7-chloro-5-phenyl-2-ethylydenhydrazino-1,3-dihydro-3H-1,4-benzodiazepine (XI), which is cyclized by refluxing in chloroform (10.5 h) or by heating at 160-72 C (10 min).

合成路线4

The condensation of 2-pyrrolidinone (I) with 2-oxoacetic acid (II) in ethyl ether gives 2-hydroxy-2-(2-oxopyrrolidin-1-yl)acetic acid (III), which is fully methylated with methanol and conc. sulfuric acid to yield 2-methoxy-2-(2-oxopyrrolidin-1-yl)acetic acid methyl ester (IV). The reaction of (IV) with PCl3 in hot toluene affords 2-chloro-2-(2-oxopyrrolidin-1-yl)acetic acid methyl ester (V), which is condensed with triethyl phosphite (VI), also in hot toluene, to provide the dimethyl phosphonate (VII). The condensation of (VII) with acetaldehyde (VIII) in THF by means of tetramethylguanidine gives 2-(2-oxopyrrolidin-1-yl)-2-butenoic acid methyl ester (IX), which is reduced with H2 and a chiral Rhodium catalyst in THF to yield 2(S)-(2-oxopyrrolidin-1-yl)butyric acid methyl ester (X). Finally, this ester is treated with ammonia in methanol to afford the target chiral amide.

合成路线5

The reaction between acetaldehyde (I), ethyl 3-aminocrotonate (II) and acetoacetate (III) in ethanolic medium yields the corresponding 1,4-dihydropyridine.

合成路线6

Reaction of quinuclidin-3-one (I) with trimethylsulfoxonium iodide and NaH in DMSO gives epoxide (II), which is opened with SH2 in NaOH/water, yielding 3-hydroxy-3-(sulfanylmethyl)quinuclidine (III). The cyclization of compound (III) with acetaldehyde (IV) catalyzed by boron trifluoride ethearate or by SnCl4, POCl3, H3PO4 or p-toluenesulfonic acid affords a mixture of two diastereomeric spiroracemates, the (±)-trans (V) and (±)-cis (cevimeline). This mixture is separated by fractional recrystallization in acetone or by TLC chromatography, and treated with hydrochloric acid. The (±)-trans-compound (V) can be isomerized to cevimeline by treatment with an acidic catalyst such as an organic sulfonic acid (trifluoromethanesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid), a Lewis acid (SnCl4, FeCl3, BF3 or AlCl3) or sulfuric acid in refluxing toluene, hexane or CHCl3. Cevimeline hydrochloride hemihydrate is obtained from the above mentioned hydrochloride by a complex work-up using water, isopropanol and n-hexane.

合成路线7

The condensation of the amine intermediate (VIII) with iodo-L-phenylalanine intermediate (XVII), 4-methoxyphenyl isocyanide (XVIII) and acetaldehyde (XIX) in refluxing methanol gives the adduct (XX), which is desilylated with TBAF in THF and acylated with Ac2O and pyridine to yield the acetoxy derivative (XXI). Elimination of the Mom and Boc protecting groups of (XXI) by means of TFA in dichloromethane affords the aminophenol (XXII), which is submitted to cyclization in refluxing ethyl acetate to provide the piperazinedione derivative (XXIII). The reaction of the OH group of (XXIII) with MsCl and pyridine in dichloromethane and the piperazine NH with Boc2O and DMAP in acetonitrile gives the fully protected compound (XXIV), which is reduced with NaBH4 in EtOH/dichloromethane and dehydrated by means of CSA and quinoline in refluxing toluene to yield the tetrahydropyrazinone (XXV). The cyclization of (XXV) by means of Pd2(dba)3, P(o-tol)3 and TEA in refluxing acetonitrile affords the tricyclic compound (XXVI).

合成路线8

The intermediate (XXX) has been obtained as follows: The condensation of benzylated hydroxypentanone (XXII) with acetaldehyde (XXIII) by means of DCHBCl gives the hydroxyhexanone (XXIV), which is reduced with LiBH4, yielding the diol (XXV). The silylation of (XXV) with Tbdms-OTf affords the disilyl ether (XXVI), which is regioselectively monodesilylated with CSA, providing the alcohol (XXVII). The hydrogenolysis of (XXVII) with H2 over Pd/C gives the primary alcohol (XXVIII), which is treated with (COCl)2 and NaClO2 in order to oxidize the primary alcohol to carboxylic acid and the secondary alcohol to ketone to furnish the ketoacid (XXIX). Finally, this compound is esterified with diazomethane to afford the desired ester intermediate (XXX).

合成路线9

The selective acetylation of erythromycin B (I) with acetic anhydride in methylene chloride gives the 2'-O-acetyl derivative (II), which is treated with thiocarbonyldiimidazole (CSDI) and DMAP in dichloromethane to yield the 4''-O-thiocarbonyl derivative (III). The reduction of (III) with Bu3SnH in refluxing toluene affords 2'-O-acetyl-4''-deoxyerythromycin B (IV), which is deacetylated in refluxing methanol giving 4''-deoxyerythromycin B (V). The reaction of (V) with AcOH and NaHCO3 yields the hemiketal (VI), which is demethylated at the NMe2 group by means of I2, NaOAc and Na2S2O3 affording the methylamino compound (VII). Finally, this compound is submitted to a reductive alkylation with acetaldehyde (VII) and H2 over Pd/C in methanol.

合成路线10

The omega iodoalkyl thiazole intermediate (XII) is obtained as follows: The cyclization of 2-hydroxypropionaldehyde dimethyl acetal (I) with acetaldehyde (II) by means of warm Dowex (H+) and catalyzed by 2-deoxyribose-5-phosphate aldolase (DERA) gives the chiral tetrahydrofuran derivative (III), which is acylated with Ac-Cl and pyridine to yield the acetoxy compound (IV). The reaction of (IV) with BF3/Et2O, propane-1,3-dithiol (V) and TiCl4 affords the protected dithiane (VI), which is oxidized with oxalyl chloride in DMSO to provide the ketone (VII). The Wittig condensation of (VII) with phosphine oxide (VIII) by means of BuLi in THF provides the protected alkyl thiazole (IX), which is treated with HgClO4 to cleave the dithiane ring and yield carbaldehyde (X). Finally, this aldehyde is coupled with iodomethylenephosphorane (XI) by means of NaHMDS in THF/HMPA to afford the target omega iodoalkyl thiazole intermediate (XII).

合成路线11

The reductocondensation of ethanolamine (I) with 3-methylbenzaldehyde (II) by means of NaBH4 gives N-(3-methylbenzyl)ethanolamine (III), which is treated with SOCl2 to yield the 2-chloroethyl derivative (IV). The reaction of (IV) with methylamine (V) affords N-methyl-N'-(3-methylbenzyl)ethane-1,2-diamine (VI), which is condensed with the pyrazole-carboxamide derivative (VII) to provide the unstable compound (VIII)?? (IX). The reduction of (IX) with NaBH4 gives the racemic amide (X), which is submitted to optical resolution by preferential crystallization to yield the (R)-isomer (XI) (1,2). The hydrogenation of (XI) with H2 over Pd/C in ethanol affords the debenzylated compound (XII), which is alkylated by reductocondensation with acetaldehyde (XIII) and NaBH4 in methanol to provide the chiral N-(1-ethyl-4'-methylperhydro-1,4-diazepin-6-(R)-yl)-1H-pyrazole-3-carboxamide (XIV). Finally, this compound is treated with refluxing aqueous HCl to give the corresponding 6(R)-amino derivative (XV).

合成路线12

The condensation of 6-chloro-5-methoxy-1H-indole (I) with Meldrum's acid (II) and acetaldehyde (III) catalyzed by L-proline in acetonitrile gives the adduct (IV), which is treated with Cu and ethanol in refluxing pyridine to yield 3-(6-chloro-5-methoxy-1H-indol-3-yl)butyric acid ethyl ester (V). The reaction of (V) with hydrazine at 140 C affords the hydrazide (VI), which is treated with NaNO2 and Ac-OH to provide the corresponding azide that, without isolation, is thermolyzed and rearranged in toluene at 80?C to give 7-chloro-6-methoxy-4-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-1-one (VII). The cleavage of the lactam ring of (VII) with KOH in refluxing ethanol/water yields 3-(2-amino-1-methylethyl)-6-chloro-5-methoxy-1H-indole-2-carboxylic acid (VIII). The decarboxylation of (VIII) by means of refluxing aq. 3M HCl affords 3-(2-amino-1-methylethyl)-6-chloro-5-methoxy-1H-indole (IX), which is finally acylated with acetic anhydride and pyridine in toluene to provide the target 6-chloromelatonin as a racemic compound.

合成路线13

The asymetric Michael addition of malonic ester (II) to 2-cyclohexenone (I) catalyzed by (R)-ALB and t-BuOK in THF gives the (R)-enantiomer (III), which is cyclized with phenylhydrazine (IV) in hot acetic acid yielding the tetrahydrocarbazole (V). The protection of (V) with Boc2O, TEA and DMAP in dichloromethane gives protected (VI), which is condensed with acetaldehyde (VII) by means of LDA in THF affording crotonate (VIII). The reduction of the ester group of (VIII) with DIBAL, followed by oxidation with MnO2 gives the corresponding aldehyde (IX), which is reductocondensed with 2-aminoacetaldehyde dimethylacetal (XI) by means of titanium tetraisopropoxide and NaBH4 in toluene/methanol providing adduct (XI). The deprotection of (XI) with TFA and anisole gives the free tetrahydrocarbazole (XII), which is cyclized by means of DDQ in THF yielding the tetracyclic compound (XIII). The reduction of the exocyclic double bond of (XIII) with RhCl(PPh3)3 in benzene/isopropanol affords the (S)-ethyl derivative (XIV), which is treated with Et-SH and BF3/Et2O in dichloromethane to give the thioacetal (XV). Finally, this compound is cyclized with DMTSF, LiAlH4 and Raney-Ni in refluxing ethanol.

合成路线14

The acetylenic ester intermediate (XVI) has been obtained as follows. The reaction of acetaldehyde (I) with acetyl bromide (II) by means of a chiral Al catalyst gives lactone (III), which is condensed with N,O-dimethylhydroxylamine (IV) to yield the Weinreb amide (V). The reduction of (V) with iBu2AlH affords the chiral butyraldehyde (VI), which is condensed with acetyl bromide (II) and DIEA to provide the lactone (VII). The reaction of (VII) with methylmagnesium bromide gives the chiral pentanoic acid (VIII), which is reduced with BH3/Me2S and reoxidated with PCC to yield the aldehyde (IX). The condensation of (IX) with acetyl bromide (II) and DIEA affords the lactone (X), which is treated with the lithium salt (XI) to provide the dihydropyranone (XII). The reduction of (XII) with NaBH4 and CeCl3, followed by reaction with Ac2O and TEA gives the acetoxy derivative (XIII), which is desilylated with TBAF and oxidized with PDC to yield the methyl ketone (XIV). Finally, the condensation of (XIV) with the allenic tributyl tin derivative (XV) by means of Bu3Sn-OTf in dichloromethane affords the target acetylenic ester intermediate (XVI).

合成路线15

Condensation of 4-chloroacetophenone (I) with ethyl diethoxyacetate (II) in the presence of lithium hexamethyldisilazide afforded diketoacetal (III). Formation of pyrazole (V) was accomplished by treatment of (III) with 4-methoxy-phenylhydrazine (IV). Subsequent acid hydrolysis of the diethyl acetal gave aldehyde (VI), which was condensed with carbon tetrabromide using triphenyl phosphine to furnish dibromoethylene compound (VII). Elimination of HBr in (VII) by treatment with tetrabutylammonium fluoride produced bromoacetylene (VIII). After lithium-bromine exchange, addition of acetaldehyde yielded the propargyl alcohol (IX). Further Mitsunobu coupling of (IX) with N,O-bis(tert-butoxycarbonyl)hydroxylamine (X) gave the N,O-bis-protected N-alkyl hydroxylamine (XI). After Boc deprotection of (XI) by means of trifluoroacetic acid, coupling with acetyl chloride provided the O-acetyl hydroxamic acid (XII). Finally, cleavage of the O-acyl group of (XII) with methanolic NaOH furnished the title compound.

合成路线16

Treatment of allomaltol (I) with acetaldehyde (II) and NaOH in H2O affords pyranone derivative (III), which is benzylated by means of benzyl bromide (IV) and NaOH in refluxing H2O/MeOH to provide compound (V). O-Methylation of (V) by reaction with NaH and MeI in DMF furnishes methoxyethyl derivative (VI), which is then heated with methylamine and NaOH in EtOH/H2O to yield pyridinone derivative (VII). Finally, the benzyl group of (VII) is removed by hydrogenation over Pd/C in MeOH to give the desired product.

合成路线17

The omega iodoalkyl thiazole intermediate (XII) is obtained as follows: The cyclization of 2-hydroxypropionaldehyde dimethyl acetal (I) with acetaldehyde (II) by means of warm Dowex (H+) and catalyzed by 2-deoxyribose-5-phosphate aldolase (DERA) gives the chiral tetrahydrofuran derivative (III), which is acylated with Ac-Cl and pyridine to yield the acetoxy compound (IV). The reaction of (IV) with BF3/Et2O, propane-1,3-dithiol (V) and TiCl4 affords the protected dithiane (VI), which is oxidized with oxalyl chloride in DMSO to provide the ketone (VII). The Wittig condensation of (VII) with phosphine oxide (VIII) by means of BuLi in THF provides the protected alkyl thiazole (IX), which is treated with HgClO4 to cleave the dithiane ring and yield carbaldehyde (X). Finally, this aldehyde is coupled with iodomethylenephosphorane (XI) by means of NaHMDS in THF/HMPA to afford the target omega iodoalkyl thiazole intermediate (XII).

合成路线18

By basic selfcondensation of acetaldehyde (I) to give acetaldol (II), which is reduced with H2 over Cu, Pt or Raney-Ni.

合成路线19

合成路线20