合成路线1

By cyclization of 5-methyl-3-phenylindazole (I) with 1,3-dibromopropane (II) by means of NaH in DMF or triethylbenzylammonium chloride NaOH in toluene - water.

合成路线2

The reaction of 2-amino-3'-chlorobenzophenone (I) with dichloroacetyl chloride (II) in acetone gives o-(m'-chlorobenzoyl)-2,2-dichloroacetanilide (III), which is cyclized with potassium cyanide in water yielding 2-amino-3-(m-chlorophenyl-3H-indol-3-ol (IV). Finally, this compound is condensed with 1,3-dibromopropane (A) in refluxing ethanol.

合成路线3

1) The condensation of 1,3-dibromopropane (II) with diethyl phosphonate (III) gives diethyl 3-bromopropylphosphonate (IV), which by reaction with butyraldehyde oxime (V) by means of sodium ethoxide in ethanol is converted to diethyl 3-(butylideneamino)propylphosphonate-N-oxide (VI). Finally, this compound is hydrolyzed with HCl in refluxing acetic acid to obtain compound (I). 2) The condensation of (IV) with N-(p-methoxybenzyloxy)-p-toluenesulfonamide (VII) by means of sodium ethoxide in ethanol gives diethyl 3-[N-methoxybenzyloxy)-N-tosylamino]propyl phosphonate (VIII), which is hydrolyzed with HCl in acetic acid to obtain compound (I). 3) The condensation of (IV) with methyl N-(benzyloxy)carbamate (IX) by means of sodium ethoxide in ethanol yields diethyl 3-(N-benzyloxy-N-methoxycarbonylamino)propylphosphonate (X), which is hydrolyzed with HCl in acetic acid to obtain compound (I). 4) The condensation of (IV) with hydroxylamine by means of NaOH in MeOH-H2O gives diethyl 3-(N-hydroxylamino)propylphosphonate (XI), which is hydrolyzed with HCl in acetic acid to obtain compound (I).

合成路线4

This compound has been obtained by two similar ways: 1) The alkylation of 4-hydroxyphenyl(2-isopropylindolizin-1-yl)sulfone (I) 1,3-dibromopropane (II) by means of K2CO3 in DMF gives 4-(3-bromopropoxy)phenyl(2-isopropylindolizin-1-yl)sulfone (III), which is finally condensed with N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine. 2) By direct condensation of sulfone (I) with the tertiary amine N-(3-chloropropyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine.

合成路线5

Reaction of the sodium salt of p-hydroxyphenylacetic acid methyl ester (I) with phthalide (II) gives 2-(4-carboxymethylphenoxymethyl)benzoic acid methyl ester (III), which is cyclized with trifluoroacetic anhydride followed by borontrifluoride etherate to yield 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid methyl ester (IV). Wittig reaction of compound (IV) with 3-(dimethylaminopropyl)triphenylphosphonium bromide hydrobromide (V) yields (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid methyl ester (VIII), which is hydrolyzed with NaOH and treated with p-toluenesulfonic acid in isopropanol to afford the p-toluenesulfonate salt (IX), from which the free base is finally liberated. Compound (V) is obtained from (3-bromopropyl)triphenylphosphonium bromide hydrobromide (VI), previously prepared from 1,3-dibromopropane (VII) and triphenylphosphine in toluene.

合成路线6

Reaction of theophylline (I) with 1,3-dibromopropane (II) in DMF in the presence of triethylamine afforded the bromo intermediate (III)) in 77% yield. Reaction of (III) with 4-hydroxypiperidine (IV) in DMF in the presence of sodium bicarbonate afforded the unsubstituted hydroxypiperidinyl intermediate (V) in 31% yield which was subsequently alkylated with diphenylmethylbromide (VI) to afford Wy-49,051 in 29% yield.

合成路线7

1) The reaction of 3-(2,5,5-trimethyl-1,3-dioxan-2-yl)thiophene (I) with butyllithium, SO2 and hydroxylamine-O-sulfonic acid in hexane/THF gives the corresponding sulfonamide (II), which is hydrolyzed with HCl yielding 3-acetylthiophene-2-sulfonamide (III). The cyclization of (III) with pyridinium bromide perbromide (IV) and NaBH4 affords 4-hydroxy-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine 1,1-dioxide (V), which is treated with 1,3-dibromopropane (VI) and NaH in DMF giving the corresponding 3-bromopropyl derivative (VII). The protection of the hydroxy group of (VII) with ethyl vinyl ether (VIII) in p-toluenesulfonic acid yields the ethoxyethyl ether (IX), which by reaction with sodium methoxide in refluxing methanol affords the 3-methoxypropyl derivative (X). The sulfonation of (X) with butyllithium, SO2 and hydroxylamine-O-sulfonic acid in hexane/THF gives the sulfonamide (XI), which is oxidized with CrO3/H2SO4 to yield 2-(3-methoxypropyl)-4-oxo-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 1,1-dioxide (XII). The stereocontrolled reduction of (XII) with (+)-beta-chlorodiisopinocamphenylborane [(+)-CDPB] in THF affords the 4(S)-hydroxy derivative (XIII), which is finally treated first with p-toluenesulfonyl chloride/triethylamine and then with ethylamine in THF.

合成路线8

Reaction of 2-(3,4-dimethoxyphenyl)-3-methylbutyronitrile (I) with 1,3-dibromopropane (II) in the presence of n-butyllithium at -78 C provided bromonitrile (III). Alkylation of potassium phthalimide (V) with 9-(chloromethyl)anthracene (IV) yielded the N-alkylated phthalimide (VI), and subsequent hydrazinolysis gave the aminomethyl compound (VIII). Finally, amine (VIII) was alkylated with bromide (III) in Et3N at 60 C to produce the title compound, which was isolated as the corresponding hydrochloride salt.

合成路线9

Salicylaldehyde (I) was alkylated with 1,3-dibromopropane (II) to provide bromopropyl ether (III). Furter displacement of the bromine of (III) with the potassium salt of 2-mercaptoimidazole (IV) gave thioether (V). Condensation of methyl cyanoacetate (VI) with 3-chlorobenzylamine (VII) at 120 C afforded cyanoacetamide (VIII). Finally, Knoevenagel reaction of (VIII) with benzaldehyde (V) in the presence of beta-alanine furnished the title compound.

合成路线10

The title compound was originally isolated from the fermentation broths of Streptomyces rubellomurinus. The chemical synthesis of this compound was further described. Treatment of O-benzyl hydroxylamine (I) with TsCl in pyridine afforded N-(benzyloxy)-p-toluenesulfonamide (II). A closely related procedure used O-(p-methoxy-benzyl)hydroxylamine. Diethyl (3-bromopropyl)phosphonate (V) was obtained by alkylation of the sodium salt of diethyl phosphonate (III) with 1,3-dibromopropane (IV). Related procedures used dibutyl phosphonate or 1-bromo-3-chloropropane instead of (III) or (IV). The condensation of protected hydroxylamine (II) with bromide (V) in the presence of NaH furnished adduct (VI). Alternatively, intermediate (VI) was prepared by first alkylation of N-(benzyloxy)-p-toluenesulfonamide (II) with 1,3-dibromopropane (IV) to give (VII), and then condensation of bromide (VII) with the sodium salt of diethyl phosphonate (III). Hydrolysis of (VI) with HCl in HOAc gave rise to 3-(N-hydroxyamino)propylphosphonic acid (VIII). This was finally acetylated with Ac2O in NaOH.

合成路线11

Isobutyl N-hydroxycarbamate (IX) was O-alkylated with 4-methoxybenzyl bromide (X) using NaOEt to give (XI). Subsequent N-alkylation with 1,3-dibromopropane (IV) produced bromide (XII), which was condensed with the sodium salt of dibutyl phosphonate (XIII) to furnish adduct (XIV). Acid hydrolysis of (XIV) then gave intermediate (VIII).

合成路线12

Diphenylacetonitrile (I) was alkylated with 1,3-dibromopropane (II) in the presence of NaH in DMF to afford the bromopropyl derivative (III). Subsequent condensation of bromide (III) with 4-(4-chlorophenyl)-4-hydroxypiperidine (IV) gave the tertiary amine (V). This was then quaternized with methyl iodide to furnish the corresponding piperidinium salt.

合成路线13

The reaction of 2,4,5-trichlorophenol (I) with 1,3-dibromopropane (II) by means of refluxing 25% aqueous NaOH gives 3-(2,4,5-trichlorophenoxy)propyl bromide (III), which is condensed with benzhydroxamic acid (IV) by means of NaOH in refluxing methanol yielding 3-(2,4,5-trichlorophenoxy)propyl benzhydroxamate (V). The hydrolysis of (V) with HCl in refluxing methanol affords 3-(2,4,5-trichlorophenoxy)propyloxyamine (VI), which is then condensed with dicyandiamide (VII) in refluxing ethanol to give 3'-(2,4,5-trichlorophenoxy)propyloxydiguanide (VIII). Finally, this compound is cyclized with acetone (IX) by means of HCl.

合成路线14

Treatment of N,N'-bis(2-hydroxyethyl)ethylenediamine (I) with p-toluenesulfonyl chloride in pyridine afforded the tretratosyl derivative (II). The disodium salt (IV) prepared from tritosyl diethylenetriamine (III) was then condensed with (II) in hot DMF to produce the macrocyclic compound (V). Cleavage of the N-tosyl groups of (V) to afford (VI) was effected by treatment with H2SO4 at 110 C. Quaternization of triethylamine with 1,3-dibromopropane (VII) gave rise to ammonium salt (VIII). Macrocycle (VI) was then alkylated with bromide (VIII) to furnish (IX). Then, complexation of (IX) with 99TcO2 was carried out by treatment with radiolabeled sodium pertechnetate in the presence of SnCl2.

合成路线15

The reaction of 1,3-dibromopropane (I) with triethyl phosphite (II) at 160 C gives triethyl 3-bromopropylphosphonate (III), which is treated with Tms-Br and water to yield the corresponding phosphonic acid (IV). The reaction of (IV) with PCl3 in refluxing chloroform affords the acyl chloride (V), which is treated with 4-methoxyphenol (VI) and pyridine to provide the expected 4-methoxyphenyl diester (VII). The reaction of (VII) with N,O-bis(tert-butoxycarbonyl)hydroxylamine (VIII) by means of NaH in DMF gives the fully protected hydroxyamino derivative (IX), which by treatment with TFA in dichloromethane yields 3-(hydroxyamino)propylphosphonic acid 4-methoxyphenyl diester (X). Finally, this compound is acylated with Ac-Cl and TEA in ethyl ether to afford the target N-acetylhydroxyamino compound.

合成路线16

Lithiation of 1,3-bis(O-methoxymethyl)resorcinol (I) by means of n-butyllithium, followed by acylation with acetyl chloride, gave the protected acetophenone (II). Subsequent acid hydrolysis of the methoxymethyl protecting groups furnished diol (III). The 4-hydroxybenzofuran derivative (VI) was prepared by monoalkylation of (III) with ethyl bromoacetate (IV), followed by base-catalyzed cyclization of the resulting keto ester (V). Alkylation of the hydroxybenzofuran (VI) with 1,3-dibromopropane (VII) gave the bromopropyl ether (VIII). This was finally condensed with 3-picolylamine (IX) to produce the title compound.

合成路线17

Alkylation of the lithium salt of 2-(3,4-dimethoxyphenyl)isobutyronitrile (I) with 1,3-dibromopropane (II) gave the bromo nitrile (III). Conversion of bromide (III) into the desired primary amine (VI) was achieved through a Gabriel synthesis by condensation with potassium phthalimide (IV), followed by hydrazinolysis of the resultant N-substituted phthalimide (V). A two-step procedure was finally employed for the reductive alkylation of amine (VI), consisting of condensation between amine (VI) and the bromo fluorenone (VII) in the presence of titanium isopropoxide and then reduction of the intermediate (VIII) with NaBH3CN.

合成路线18

The reaction of 3,4-dichlorophenol (I) with 1,3-dibromopropane (II) by means of NaOH and tetrabutylammonium hydrogensulfate gives the corresponding phenol ether (III), which is condensed with N-acetylhydroxylamine (IV) by means of NaOH or KOH in an alcoholic solvent to yield the O-substituted acetylhydroxylamine (V). The hydrolysis of (V) with HCl in methanol affords the free O-substituted hydroxylamine (VI), which is finally condensed with N1-cyano-N3-isopropylguanidine (VII) in hot ethyl acetate. The intermediate N1-cyano-N3-isopropylguanidine (VII) has been obtained by reaction of sodium dicyanamide (VIII) with isopropylamine (IX) and HCl in a hot alcoholic solvent.

合成路线19

Alkylation of ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (I) with 1,3-dibromopropane (II) in the presence of K2CO3 produced the bromopropyl ether (III). Subsequent displacement of the remaining bromine of (III) with 3-picolylamine (IV) furnished the secondary amine (V). The ester group of (V) was then reduced to alcohol (VI) with LiAlH4. Finally, Mitsunobu coupling of alcohol (VI) with 2,4-difluorophenol (VII) in the presence of 1,1'-(azodicarbonyl)dipiperidine and tributylphosphine gave rise to the target difluorophenyl ether.

合成路线20

Condensation of ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (I) with 1,3-dibromopropane (II) affords the benzofuran bromopropyl ether (III). Subsequent displacement of bromide (III) with 3-picolylamine (IV) yields amine (V). The ester group of (V) is then reduced with LiAlH4 to furnish alcohol (VI). Finally, Mitsunobu coupling between alcohol (VI) and 2,3,4-trifluorophenol (VII) in the presence of 1,1'-(azodicarbonyl)dipiperidine (ADDP) and tributylphosphine provides the title compound

合成路线21

It can be prepared in several different way (Scheme 31229302a): 1) The nitrosation of 2-[3-(dimethylamino)propylamino]-5-methylbenzophenone (I) with NaNO2 and HCl in chloroform gives the corresponding N-nitroso compound (II), which is cyclized by reaction with Zn in acetic acid. 2) By reaction of 1-(3-methylaminopropyl)-5-methyl-3-phenyl-1H-indazole (III) with formaldehyde and NaBH4 in methanol. 3) The reaction of 3-phenyl-5-methyl-1H-indazole (IV) with 1,3-dibromopropane (V) by means of NaH in DMF gives 1-(3-bromopropyl)-5-methyl-3-phenyl-1H-indazole (VI), which is then condensed with dimethylamine (VII). 4) By reaction of (IV) with 1-(dimethylamino)-3-bromopropane (VIII) by means of NaOH in a mixture of toluene and water.

合成路线22

In an alternative method, the title dimer compound is obtained by condensation of two equivalents of N-[2-(7-hydroxynaphth-1-yl)ethyl]acetamide (I) with 1,3-dibromopropane (II) in the presence of K2CO3 in acetonitrile

合成路线23

A different protection strategy involves masking the ring nitrogens as amide groups. Methyl acrylate (XVII) is reacted with neat ethylenediamine (XVIII) to yield the aminopropionamide derivative (XIX), which is then cyclized with dimethyl malonate (XX), producing the trioxocyclam (XXI). After condensation of (XXI) with p-dibromoxylene (IIIa), the resulting hexaoxo bis-cyclam (XXII) is reduced to the title compound employing borane-dimethyl sulfide complex in refluxing THF (10). Alternatively, protection of the linear tetraamine (XXIII) with pyruvic aldehyde (XXIV) generates the tricyclic bisaminal (XXV) along with its minor isomer (XXVI). The crude mixture of bis-aminals (XXV) and (XXVI) is then cyclized to (XXVIII) with 1,3-dibromopropane (XXVII) and K2CO3. After condensation of (XXVIII) with dibromide (IIIa), the resulting bis-ammonium dimer (XXIX) is hydrolyzed to the title compound upon heating with 3M NaOH (11). Scheme 3.

合成路线24