合成路线1

2-Methylimidazole (I) is converted into the bisulfate salt, and then nitrated by means of a sulfonitric mixture in Ac2O to produce 2-methyl-4-nitroimidazole (II) . In a variant of this procedure, 2-methylimidazole (I) is nitrated by using a ferric nitrate-tonsyl adduct in several solvents. Imidazole (II) is then regioselectively alkylated with boiling 2-chloroethanol to produce the title compound. Alternatively, the alkylation of (II) has been reported by treatment with ethylene oxide (III) under acidic conditions.

合成路线2

The title compound can be obtained by reaction of 1-(acetoxymethyl)-2-methyl-4-nitroimidazole (I) with ethylene oxide (II) in the presence of sulfur trioxide, followed by hydrolysis in aqueous H2SO4

合成路线3

Alternatively, 2-methyl-4-nitroimidazole (I) is protected by acylation in hot acetic anhydride to give (II). Addition of ethylene oxide (III) to the N-acetyl imidazole (II) in the presence of SO3, followed by acidic hydrolysis furnishes the title compound

合成路线4

Compound can be prepared in three different ways all starting from p-trifluoromethyl-5-methoxy-valerophenone (I): 1) By condensation of (I) with 2-aminooxyethylamine dihydrochloride in refluxing pyridine ethanol (C). 2) The reaction of (I) with hydroxylamine as usual yields the corresponding oxime (II), which is then condensed with 2-chloroethylamine (B) by means of KOH in DMF. 3) The reaction of the oxime (II) with Li and ethylene oxide (A) in absolute ethanol affords the O-(2-hydroxyethyl)oxime (III), which is esterified with mesyl chloride by means of triethylamine in methylene chloride giving the O-(2-mesyloxyethyl)oxime (IV). Finally, this compound is treated with NH3 in methanol at 100 C in a pressure vessel.

合成路线5

In a different method, reaction of styrene oxide (XV) with methylamine provided amino alcohol (XVI), which was further condensed with ethylene oxide (XVII) to afford amino diol (XVIII). Alternatively, diol (XVIII) was prepared by a more direct procedure by condensation of epoxide (XV) with 2-(methylamino)ethanol (XIX). Chlorination of (XVIII) employing SOCl2 yielded the dichloro derivative (XX), which was subsequently condensed with 2-aminobenzyl alcohol (X) leading to piperazine (XXI). Cyclization of (XXI) to the title compound was accomplished by treatment with hot polyphosphoric acid. Optionally, alcohol (XXI) was converted to chloride (XXII), which was then cyclized in the presence of AlCl3. In a related method, alcohol (XXI) was esterified with AcOH, and the resultant acetate ester (XXIII) was then cyclized in the presence of polyphosphoric acid

合成路线6

Delmopinol can be obtained by three different ways: 1) The reaction of 2-(benzylamino)-6-propylnonan-1-ol (I) with ethylene oxide (II) in ethanol at 100 C yields the corresponding N-(2-hydroxyethyl)derivative (III), which is cyclized with H2SO4 at 140-150 C to 4-benzyl-3-(4-propylheptyl)morpholine (IV). The debenzylation of (IV) by hydrogenolysis with H2 over Pd/C affords the free morpholine (V), which is finally condensed with 2-chloroethanol (VI) by means of KI and KOH in refluxing ethanol. 2) The Grignard condensation of 4-heptanone (VII) with allyl bromide (VIII) in ethyl ether gives 4-propyl-1-hepten-4-ol (IX), which is cyclocondensed with morpholine (X) by means of H2O2 and Na2WO4 in methanol to yield 4-(perhydroisoxazol[3,2-c][1,4]oxazin-2-ylmethyl)-4-heptanol (XI). Reductive ring opening of (XI) by hydrogenation with H2 over Pd/C and p-toluenesulfonic acid in isopropanol affords a mixture of the morpholine (V) and the hydroxymorpholine (XII). This mixture, without separation, is treated first with SOCl2 in chloroform to perform Cl-OH interchange, then with NaOH to obtain the corresponding double bond, and finally, the mixture is hydrogenated with H2 over Ra-nickel and triethylamine in dioxane in order to obtain pure (V), already obtained. 3) The acylation of the alkylmorpholine (V) with oxalic acid monomethyl ester (XIII) by means of triethylamine in refluxing benzene gives the corresponding condensation compound (XIV), which is then reduced with LiAlH4 in refluxing ethyl ester.

合成路线7

The condensation of 2-methoxyphenol (I) with ethylene oxide (II) gives 2-(2-methoxyphenoxy)ethanol (III), which is treated with SOCl2 to yield 2-(2-methoxyphenoxy)ethyl chloride (IV). The reaction of (IV) with benzylamine (A) gives N-[2-(2-methoxyphenoxy)ethyl]benzylamine (V), which is condensed with 2-methyl-5-bromoacetylbenzenesulfonamide (VI) affording N-[2-(2-methoxyphenoxy)ethyl]-N-[(4-methyl-3-aminosulfonylbenzoyl)methyl]benzylamine (VII). The reduction of (VII) with NaBH4 affords the corresponding protected carbinol (VIII), which is finally debenzylated by hydrogenation with H2 over Pd/C.

合成路线8

By cleavage of the 7-methoxy-9-oxoxanthene-2-carboxylic acid (I) with AlCl3 in xylene to give 7-hydroxy-9-oxoxanthene-2-carboxylic acid (II), which is then esterified with ethanol and anhydrous HCl to the corresponding ethyl ester (III). This product is treated first with ethylene oxide (A) in DMF, and finally hydrolyzed with NaOH in ethanol-water. The condensation of 2-chloro-5-nitrobenzoic acid (IV) with 4-methoxyphenol (V) by means of K2CO3, Cu and Cu2I2 in n-pentanol gives 2-(4-methoxyphenoxy)-5-nitrobenzoic acid (VI), which is cyclized with concentrated H2SO4 to 7-methoxy-2-nitroxanthone (VII). The reduction of the nitro group of (VII) with SnCl2 in concentrated HCl yields 7-methoxy-2-aminoxanthone (VIII). Finally, this product is treated first with NaNO2 - HCl, then with NaCN and finally hydrolyzed with H2SO4 to afford 7-methoxy-9-oxoxanthene-2-carboxylic acid.

合成路线9

In a related method, the intermediate tetrahydroxy amine (I) is acylated by chloroacetyl chloride (II) to produce the penta(chloroacetyl) derivative (III). The chloroacetate ester groups are then hydrolyzed under basic conditions to afford the tetra-hydroxy chloroacetamide (IV). Conversion of (IV) to the hydroxy acetamide (V) is accomplished by treatment with sodium acetate and NaOH. Amide (V) is finally alkylated with either chloroetanol (VI) or with ethylene oxide (VII) to furnish the title N-(hydroxyethyl) amide.

合成路线10

The condensation of 3,5-dimethylisoxazole (I) with ethylene oxide (II) by means of butyllithium in THF gives 3-(3-methylisoxazol-5-yl)-1-propanol (III), which by reaction with refluxing SOCl2 yields the corresponding propyl chloride (IV). The condensation of (IV) with 4-hydroxy-3,5-dimethylbenzonitrile (V) [obtained by reaction of 4-bromo-2,6-dimethylphenol (VI) with Cu2CN2 in refluxing DMF] by means of K2CO3 and KI in hot N-methylpyrrolidone affords 3,5-dimethyl-4-[3-(3-methylisoxazol-5-yl)propoxy]benzonitrile (VII). The reaction of (VII) with hydroxylamine (VIII) and K2CO3 in refluxing ethanol gives the corresponding benzohydroxamic acid (IX), which is finally cyclized with refluxing trifluoroacetic anhydride and pyridine.

合成路线11

Intermediate (XVI) is treated with BuLi and diisopropylamine in THF giving the chiral acetylenic tetrahydrofuran (XVII). The addition of ethylene oxide (XVIII) to the terminal acetylene of (XVII) by means of BF3/Et2O in THF gives the 3-butyl-1-ol derivative (XIX), which is condensed with N,O-bis(phenoxy- carbonyl)hydroxylamine (XX) by means of PPh3 and diisopropylazodicarboxylate (DIAD) in THF yielding the final intermediate (XXI). Finally, this compound is treated with ammonia in methanol to obtain the target urea derivative.

合成路线12

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13

Protection of 2-bromoethanol (I) upon treatment with 2-methoxypropene (II) gave a mixture of ketals (III) and (IV). This mixture was used for N-alkylation of 5-bromoindole (V) in the presence of KOH to afford, after ketal hydrolysis, 1-(2-hydroxyethyl)-5-bromoindole (VI) (1). Alternatively, compound (VI) was obtained by alkylation of 5-bromoindole (V) with ethylene oxide (VII) in the presence of NaOH in DMSO (2). The hydroxyl group of (VI) was then protected as the silyl ether (VII) by treatment with tert-butyldimethylsilyl chloride. Subsequent lithium-halogen exchange in (VIII) with tert-butyllithium, followed by reaction with bismuth trichloride provided the triindolyl bismuthane (IX) (1, 2). This was oxidized with either benzoyl peroxide (1) or peracetic acid (2) to produce the corresponding di(acyloxy) pentavalent bismuthanes (X).

合成路线14

By reaction of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (I) with ethylene oxide (II) by means of AlCl3 in benzene

合成路线15

Coupling of tyramine (I) with p-nitrophenyl isocyanate (II) affords urea (III). Subsequent nitro group reduction with H2 and Pd/C gives amine (IV). Condensation of amine (IV) with ethylene oxide (V) leads to the bis-hydroxyethyl amine (VI). This is finally chlorinated employing SOCl2 in pyridine. Alternatively, amine (IV) is subjected to reductive alkylation with chloroacetaldehyde and NaBH3CN to furnish the target bis-chloroethyl amine. (1,2)

合成路线16

In an alternative method, p-nitroaniline (I) is reacted with ethylene oxide (II) to afford diol (III). This compound can also be prepared by condensation of 1-fluoro-4-nitrobenzene (IV) with diethanolamine (V). Chlorination of diol (III) to provide (VI) is accomplished with either mesyl chloride or SOCl2 in the presence of pyridine. Then, nitro group reduction in (VI) by means of iron and HCl affords aniline (VII).

合成路线17