合成路线1

合成路线2

2) By reaction of 4-methoxybenzylamine (I) with diethyl iminocarbonate (A) in water to give diethyl N-(4-methoxybenzyl)iminocarbonate (II), followed by treatment with methylamine in water - ethanol - H2SO4.

合成路线3

The condensation of 4-[2-(acetylamino)ethyl]benzenesulfonyl chloride (I) with 1-cyclohexyl-2-iminoimidazolidine (III) by means of NaOH in refluxing acetone gives 1-[[4-(2-acetamidoethyl)phenyl]sulfonyl]-3-cyclohexyl-2-iminoimidazolidine (III), which is hydrolyzed with refluxing 2N HCl yielding 1-[[4-(2-aminoethyl)phenyl]sulfonyl]-3-cyclohexyl-2-iminoimidazolidine (IV). Finally, this compound is acylated with crotonic anhydride (V) in dioxane. The starting products (I) and (II) are obtained as follows: 1) The acetylation of 2-phenylethylamine (VI) with acetic anhydride gives N-(2-phenylethyl)acetamide (VII), which is sulfonated with chlorosulfonic acid yielding compound (I). 2) The reductocondensation of cyclohexanone (IX) with ethylenediamine (VIII) gives N-cyclohexylethylenediamine (X), which is then cyclized with cyanogen chloride to compound (II).

合成路线4

This compound can be obtained by two related ways: 1) The Wittig condensation of 2-benzoylpyridine (I) with diethyl cyanomethylphosphonate (II) by means of sodium ethoxide in hot ethanol gives 3-phenyl-3-(2-pyridyl)acrylonitrite (III), which is reduced with NaBH4 in refluxing ethanol to yield 3-phenyl-3-(2-pyridyl)propionitrite (IV). Finally, this compound is cyclized with ethylenediamine (V) at reflux temperature. 2) The cyctization of 3-phenyl-3-(2-pyridyl)acrylonitrite (III) with ethylenediamine (V) at reflux temperature gives 2-[2-phenyl-2-(2-pyridyl)viny]-2-imidazoline (VI), which is then reduced with H2 over Pd/C in ethanol.

合成路线5

By condensation of ethylenediamine (I) with 1,2-dichloroethane (II).

合成路线6

The condensation of 2-glycidyloxy-1-chlorobenzene (I) with ethylenediamine (II) in refluxing ethanol gives N-[3-(2-chlorophenoxy)-2-hydroxy propyl]ethylenediamine (III), which is then condensed with 4,5-dichloropyridazinone (IV) in refluxing ethanol.

合成路线7

By condensation of 1,4,5,8-tetrahydroxyanthraquinone (I) with ethylenediamine (II) in hot tetramethylethylenediamine.

合成路线8

The cyclization of catechol (I) with 2-chloroacrylonitrile (II) by means of K2CO3 in acetone gives 2-cyanobenzo-1,4-dioxane (III), which is hydrolyzed with ethanol and HCl to the corresponding iminoether (IV) Finally, this compound is cyclized with ethylenediamine (V) in cool ethanol.

合成路线9

The reaction of N-(2-chloro-4-methyl-3-thienyl)thiourea (I) with methyl iodide in methanol gives S-methyl-N-(2-chloro-4-methyl-3-thienyl)isothiouronium iodide (II), m.p. 113-5 C, which is then condensed with ethylenediamine (A) in methanol at 100 C.

合成路线10

6) The reaction of amine (I) with phenyl chloroformate (XI) in pyridine gives N-(5-bromoquinoxalin-6-yl)carbamic acid phenyl ester (XII), which is then treated with ethylenediamine (XIII) to afford N-(2-aminoethyl)-N'-(5-bromoquinoxalin-6-yl)urea (AGN-192170)).

合成路线11

4-Amino-5-chloro-2,1,3-benzothiadiazole (I) is reacted with CSCl2 to 5-chloro-4-isothiocyano-2,1,3-benzothiadiazole (II), which gives 4-[3-(2-aminoethyl)-2-thioureido]-5-chloro-2,1,3-benzothiadiazole (IV) with 1,2-diaminoethane (III). Cyclization in methanol in the presence of KOH/Pb(OAc)2 leads after 1 h at reflux to DS 103-282.

合成路线12

The reaction of 5-isoquinolinesulfonyl chloride (I) with ethyldiamine (II) in methylene chloride gives N-(2-aminoethyl)isoquinoline-5-sulfonamide (III), which is then condensed with S-methylisothiourea sulfate (IV) by means of NaOH at 80 C.

合成路线13

Compound can be prepared in two different ways: 1) The condensation of 2,6-dichlorophenol (I) with alpha-bromopropionitrile (II) by means of K2CO3 in refluxing butanone gives alpha-(2,6-dichlorophenoxy)propionitrile (III), which by hydrolysis with ethanol and HCl affords ethyl ester hydrochloride (IV). Finally, this compound is cyclized with ethylenediamine (A) in ethanol at 70 C. 2) By condensation of sodium 2,6-dichlorophenolate (V) with 2-(alpha-chloroethyl)-2-imidazoline (VI) in refluxing dioxane.

合成路线14

The cyclization of ethyl 2-(2-thienyl)glyoxylate (I) with ethylenediamine (II) in refluxing ethanol gives 3-(2-thienyl)-1,2,5,6-tetrahydropyrazin-2-one (III), which is reduced with H2 over Raney Nickel (RaNi) in hot ethanol at 50 bar.

合成路线15

The reaction of 2-chloro-5-tritluoromethylaniline (I) with ammonium thiocyanate (II) in hot chlorobenzene gives N-(2-chloro-5-trifluoromethylphenyl)isothiourea (III), whith is cyclized with ethylenediamine (IV) in refluxing methanol.

合成路线16

The cyclization of diphenyldiazomethane (I) with acrylonitrile (II) in CHCl3 gives cyano-2,2-diphenylcyclopropane (III), which is then cyclized with ethylenediamine tosylate (IV) by heating at 200 C.

合成路线17

The cyclization of 2-amino-4'-bromobenzophenone (I) with ethyl 2-(methylthio)acetate (II) by means of tert-butyl hypochlorite in dichloromethane at 70 C gives 7-(4-bromobenzoyl)-3-(methylthio)-2,3-dihydro-1H-indol-2-one (III), which is desulfurized by a treatment with Raney Nickel in THF yielding 7-(4-bromobenzoyl)-2,3-dihydro-1H-indol-2-one (IV). Finally, this compound is hydrolyzed with refluxing 3N NaOH and acidified with concentrated HCl.

合成路线18

The condensation of 2-hydroxybenzaldehyde (I) with ethyl 2-bromobutyrate (II) by means of K2CO3 and NaI in DMF gives ethyl-2-(2-formylphenoxy) butyrate (III), which is reduced with NaBH4 and NaOEt in ethanol yielding the hydroxymethyl derivative (IV). The reaction of (IV) with SOCl2 affords the corresponding chloromethyl compound (V), which is cyclized by means of NaH in N-methylpyrrolidone to give 2-ethyl-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester (VI). The hydrolysis of the ethyl ester of (VI) with NaOH in methanol yields the expected carboxylic acid (VII), which is treated with SOCl2 and then with NH3 to afford the amide (VIII). This compound can also be obtained directly from ester (VI) by reaction with NH3. The dehydration of (VIII) by means of P2O5 or POCl3 gives the nitrile (IX), which is treated with HCl in ethanol yielding the carboxyimidate (X). Finally, this compound is cyclized with ethylenediamine (XI) in ethanol.

合成路线19

The condensation of 2-fluorobenzylmagnesium bromide (XII) with 2-oxobutyric acid ethyl ester (XIII) in ethyl ether gives 2-(2-fluorobenzyl)-2-hydroxybutyric acid ethyl ester (XIV), which is cyclized by means of NaH in toluene/DMF yielding he ester (VI). The hydrolysis of (VI) with NaOH affords the acid (VII), which is treated with SOCl2 to give the acyl chloride (XV). Then this compound is cyclized with ethylenediamine (XI) by means of AlMe3 in refluxing toluene. The reaction of 2-fluorobenzaldehyde (XVI) with ethyl 2-bromobutyrate (II) by means of potassium tert-butoxide in dioxane gives the epoxide (XVII), which is opened by hydrogenation with H2 over Pd/C in ethanol to afford the previously reported hydroxybutyric ester (XIV). The condensation of 2-fluorophenyllithium (XVIII) or 2-fluorophenylmagnesium bromide (XIX) with 2-(benzyloxymethyl)-2-ethyloxirane (XX) gives 1-(benzyloxy)-2-ethyl-3-(2-fluorophenyl)-2-propanol (XXI), which is cyclized by means of NaH yielding 2-(benzyloxymethyl)-2-ethyl-2,3-dihydrobenzofuran (XXII). Finally, this compound is debenzylated with H2 over Pd/C and oxidized with CrO3 and sulfuric acid to afford the previously reported carboxylic acid (VII). The alkylation of 2,3-dihydrobenzofuran-2-carboxylic acid (XXIII) with ethyl iodide by means of lithium diisopropylamide gives the previously reported carboxylic acid (VII).

合成路线20

The condensation of pyridoxal 5-phosphate (I) with ethylenediamine (II) in methanol by means of NaOH gives the corresponding diimine (III), which is reduced with hydrogen over Pt/C in methanol/water yielding the expected diamine (IV). The reaction of (IV) with bromoacetic acid (V) by means of NaOH in methanol/water affords the N,N'-diacetic acid derivative (VI), which is finally treated with MnCl2 in water containing NaOH.

合成路线21

Morpholine (VI) was treated with carbonyl diimidazole (VII), and the resulting imidazolide (VIII) was further condensed with ethylenediamine (IX) to give urea (X). Reaction of epoxide (V) with amine (X) furnished the title compound.

合成路线22

The condensation of tert-butoxycarbonyl-D-alanine (I) with ethylenediamine (II) gives the corresponding protected diamide (III), which is deprotected in acidic medium to the diamide (IV). The reduction of (IV) with diborane in THF yields the (R,R)-4,7-diazadecane-2,9-diamine (V), which is finally condensed with 3-nitronaphthalene-1,8-dicarboxylic acid anhydride (VI) in refluxing ethanol and salified with methanesulfonic acid.

合成路线23

3,4-Pyridinedicarboxylic acid (I) was converted to the cyclic anhydride (II) upon heating with acetic anhydride. Friedel-Crafts condensation of anhydride (II) with p-difluorobenzene (III) in the presence of AlCl3 gave rise to a mixture of two regioisomeric keto acids, (IV) and (V). Cyclization of this mixture in fuming sulfuric acid at 140 C generated the benzoisoquinoline (VI) (1,2). Subsequent displacement of the fluorine atoms of (VI) with ethylenediamine (VII) in pyridine provided the target bis(2-aminoethylamino) derivative, which was finally converted to the stable dimaleate salt. Alternatively, ethylenediamine (VII) was protected as the mono-N-Boc derivative (VIII) by treatment with Boc2O. Condensation of the difluoro compound (VI) with the protected ethylenediamine (VIII) furnished (IX). The Boc groups of (IX) were then removed by treatment with trifluoroacetic acid. After adjustment of the pH to 4.2 with KOH, treatment with maleic acid provided BBR-2778.

合成路线24

Friedel-Crafts bis-acylation of p-dimethoxybenzene (X) with anhydride (II) in molten aluminum chloride/sodium chloride afforded the benzoisoquinoline (XI). This compound was reduced with sodium dithionite to generate an intermediate leuco form (XII). Subsequent addition of Boc-ethylenediamine (VIII) to (XII) produced, after air oxidation during the work-up, the protected tetraamino compound (IX). Alternatively, addition of ethylenediamine (VII) to the intermediate (XII) led to the free base of BBR-2778, which was converted to the maleate.

合成路线25

The cyclization of 9-fluoro-6-(tosyloxy)-5,10-dihydrobenzo[g]isoquinoline-5,10-dione (I) with 2-(dimethylamino)ethylhydrazine (II) gives 2-[2-(dimethylamino)ethyl]-5-(tosyloxy)indazolo[4,3-gh]isoquinolin-6(2H)-one (III), which is finally condensed with ethylene-1,2-diamine (IV) to afford the title compound.

合成路线26

Condensation of N,N'-dibenzylethylenediamine (I) with ethyl 2,3-dibromopropionate (II) in the presence of Et3N in toluene at 80 C gave, after acidification, piperazine (III). Then, hydrogenolytic N-debenzylation in the presence of Pd/C provided ethyl piperazine-2-carboxylate (IV), which was selectively alkylated at position 4 with 1 equivalent of triphenylmethyl chloride in the presence of Et3N at -10 C to give (V). Subsequent alkylation with 2,4-dichlorobenzyl chloride (VI) in the presence of K2CO3 and a catalytic amount of KI provided (VII). Removal of the N-trityl group by treatment with HCl in either acetone or ethanol afforded piperarine (VIII), which was N-methylated by reaction with formaldehyde and formic acid in refluxing MeOH. Finally, the resulting compound (IX) was converted into the imidazoline on treatment with ethylenediamine and trimethylaluminum in refluxing toluene.

合成路线27

The amidation of L-serine methyl ester (I) with ethylenediamine (II) gives the amide (III), which is reduced with borane/THF to 2(R)-(hydroxymethyl)diethylenetriamine (IV). The reaction of (IV) with bromoacetic acid tert-butyl ester (V) by means of DIEA in DMF affords the penta tert-butyl acetate (VI), which is condensed with the chlorophosphoramidite (VII) by means of DIEA in dichloromethane giving the phosphoramidite intermediate (VIII). The condensation of (VIII) with 4,4-diphenylcyclohexanol (IX) (see scheme 23537901b) by means of tetrazole in acetonitile, with simultaneous oxidation with tert-butyl hydroperoxide yields the phosphate (X), which is selectively hydrolyzed at the 2-cyanoethyl ester group with ammonia in methanol affording the ammonium phosphate (XI). Finally, the hydrolysis of (XI) with HCl in ether/water eliminates the tert-butyl groups affording the desired chelating ligand (XII)

合成路线28

Alkylation of ethyl piperazine-2-carboxylate (I) with two equivalents of isopropyl iodide (II) afforded disubstituted piperazine (III). The title imidazoline was then obtained by reaction of the ester function of (III) with ethylenediamine (IV) in the presence of trimethylaluminum.

合成路线29

The reaction of ethylenediamine (I) with Boc2O in dioxane gives the monocarbamate (II), which is condensed with O-methylisourea (III) to yield the aminoguanidine carbamate (IV). The cleavage of the carbamate group of (IV) by means of HCl in methanol affords the aminoguanidine (V), which is condensed with 1-methyl-4-nitropyrrole-2-carbonyl chloride (VI) by means of NaHCO3 in dioxane/water to provide the amide (VII). The reduction of the nitro group of (VII) by means of H2 over Pd/C in 1N HCl affords the 4-aminopyrrole-2-carboxamide (VIII), which is condensed with the acid chloride (VI) as before to give the diamide (IX). Reduction of the nitro group of (IX) under the same conditions described above yields the amino diamide (X), which is condensed with the 14-labeled acid chloride (XI) as described above to afford the triamide (XII). Further reduction of the nitro group of (XII) gives the amino triamide (XIII), which is finally condensed with 4-(2-bromopropenamido)-1-methylpyrrole-2-carbonyl chloride (XIV) by means of NaHCO3 in dioxane/water to yield the target 14C labeled pentaamide compound.

合成路线30

The reaction of deuterium labeled ethylenediamine (I) with Boc2O in dioxane gives the monocarbamate (II), which is condensed with O-methylisourea (III) to yield the labeled aminoguanidine carbamate (IV). The cleavage of the carbamate group of (IV) by means of HCl in methanol affords the aminoguanidine (V), which is condensed with 1-methyl-4-nitropyrrole-2-carbonyl chloride (VI) by means of NaHCO3 in dioxane/water to provide the amide (VII). The reduction of the nitro group of (VII) by means of H2 over Pd/C in 1N HCl affords the 4-aminopyrrole-2-carboxamide (VIII), which is condensed with the acid chloride (VI) as before to give the diamide (IX). Reduction of the nitro group of (IX) under the same conditions described above yields the amino diamide (X), which is condensed with acid chloride (VI) as described above to afford the triamide (XI). Further reduction of the nitro group of (XI) gives the amino triamide (XII), which is finally condensed with 4-(2-bromopropenamido)-1-methylpyrrole-2-carbonyl chloride (XIII) by means of NaHCO3 in dioxane/water to yield the target deuterium labeled pentaamide compound.

合成路线31

3,4,5-Trimethoxyphenylacetic acid (IX) was alkylated with ethyl iodide in the presence of two equivalents of sodium bis(trimethylsilyl)amide to afford racemic trimethoxyphenylbutyric acid (X). After conversion to the corresponding acid chloride with SOCl2, condensation with (R)-4-benzyl-2-oxazolidinone (XI) in the presence of n-butyllithium gave N-acyloxazolidinone (XII) as a diastereomeric mixture that was separated by column chromatography. The required diastereoisomer was then hydrolyzed with lithium peroxide to provide (S)-2-(3,4,5-trimethoxyphenyl)butyric acid (XIII). Subsequent coupling of (XIII) with methyl (S)-pipecolate (XIV) employing 2-chloro-1-methylpyridinium iodide, followed by ester hydrolysis with LiOH, provided amide (XV). Further DCC-promoted coupling of (XV) to alcohol (VIII) provided (XVI). After acid cleavage of the tert-butyl ester, the resulting carboxylic acid was finally coupled to etylenediamine (XVII) in the presence of 1-benzotriazolyloxy tris(dimethylamino)phosphonium hexafluorophosphate to yield the title compound.

合成路线32

The reaction of 3,4-difluorobenzaldehyde (I) with methyl 4-methoxyacetoacetate (II) by means of piperidinium acetate in benzene gives the 3-benzylidene derivative (III), which is cyclized with O-methylisourea (IV) yielding dihydropyrimidine (V). The optical resolution of dihydropyrimidine (V) can also be performed as follows: Dihydropyrimidine (V) is condensed with 4-nitrophenyl chloroformate (VI) by means of DMAP giving the 4-nitrophenyl ester (VII), which is treated with (R)-(+)-alpha-methylbenzylamine [(R)-MBA] yielding amide (VIII) as mixture of diastereomers that is separated by column chromatography. The (+) isomer was then treated with DBU in hot toluene to provide the dihydropyrimidine (+)(IX), already reported. The intermediate 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) has been obtained by reductocondensation of 4-cyano-4-phenylcyclohexanone (XIII) with ethylenediamine (XIV) by means of p-toluenesulfonic acid and NaBH4 and separation of the isomers by careful chromatography.

合成路线33

The reaction of 3,4-difluorobenzaldehyde (I) with methyl 4-methoxyacetoacetate (II) by means of piperidinium acetate in benzene gives the 3-benzylidene derivative (III), which is cyclized with O-methylisourea (IV) yielding dihydropyrimidine (V). The optical resolution of (V) by chiral chromatography affords the (+)(IX) isomer, which is condensed with 4-nitrophenyl chloroformate (VI) by means of DMAP in dichloromethane giving the active 4-nitrophenyl ester (+)(X). The hydrolysis of the enol methyl ether of (X) with HCl in ether/dichloromethane yields the pyrimidinone (+)(XI), which is finally condensed with 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) in dichloromethane. The intermediate 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) has been obtained by reductocondensation of 4-cyano-4-phenylcyclohexanone (XIII) with ethylenediamine (XIV) by means of p-toluenesulfonic acid and NaBH4 and separation of the isomers by careful chromatography.

合成路线34

Alkylation of ethyl piperazine-2-carboxylate (I) with two equivalents of isobutyl bromide (II) under catalysis of KI afforded disubstituted piperazine (III). The title imidazoline was then obtained by reaction of the ester function of (III) with ethylenediamine (IV) in the presence of trimethylaluminum.

合成路线35

The condensation of protected L-proline (I) with RINK RESIN (II) by means of TBTU, HOBT and DIEA in DMF gives the protected, rein bounded proline (III), which is deprotected by means of piperidine in DMF to yield the resin bounded proline (IV). The condensation of (IV) with 2-bromoacetic acid (V) by means of DIC in the same solvent affords the acyl proline (VI), which is treated with ethylene-1,2-diamine (VII) to provide the aminoacetyl proline (VIII). The condensation of (VIII) with 2-acetyldimedone (IX) gives the regioselectively monoprotected diaminoproline compound (X), which is treated with Boc2O and DIEA in dioxane to protect the secondary amino group of (X) and yield (XI). The selective elimination of the dimedone protecting group with hydrazine in DMF affords compound (XII) selectively monoprotected at the secondary amino group, which is condensed with 6-chloropyridine-3-carbonitrile (XIII) by means of DIEA in NMP to provide the resin adduct (XIV). The cleavage of the resin group of (XIV) by means of TFA and TFAA in dichloromethane takes place with simultaneous dehydration of the carboxamide group and removal of the Boc protecting group affording the trifluoroacetamido derivative (XV). Finally, the trifluoroacetyl group is removed by means of NH3 in aqueous methanol to give rise to the target pyridine carbonitrile derivative.

合成路线36

The precursor bromoether (III) was prepared by condensation of 4,4’-difluorobenzhydrol (I) with 2-bromoethanol (II) under acidic conditions. Treatment of 4-bromocinnamic acid (IV) with thionyl chloride afforded acid chloride (V), which was coupled with ethylenediamine (VI) to furnish mono amide (VII). The title compound was finally obtained by alkylation of amine (VII) with bromide (III) in the presence of K2CO3.

合成路线37

The acetylation of clarithromycin (I) with acetic anhydride gives the diacetate (II), which is acylated with CDI yielding the 12-O-(imidazolylcarbonyl compound (III). The cyclization of (III) with ethylenediamine (IV) affords the cyclic carbamate (V), which is alkylated by reductocondensation with pyridine-3-carbaldehyde (VI) and NaBH(OAc)3 to give the secondary amine (VII). The methylation of this amine with formaldehyde and NaBH(OAc)3 yields the corresponding tertiary amine (VIII), which is treated with aqueous HCl to provide the descladinosyl compound (IX). Finally, this compound is acylated with 2-(2-pyridyl)acetic acid (X) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC), and deacetylated with methanol to afford the target compound.

合成路线38

The selective hydrolysis of clarithromycin (I) with aqueous HCl, followed by acylation with acetic anhydride gives the monoacetylated descladinosyl compound (XI), which by reaction with trichloromethyl chloroformate (TCF) yields the cyclic carbonate (XII). The reaction of (XII) with 1,1,3,3-tetramethylguanidine (TMG) affords intermediate (XIII), which is selecti-ely acylated with 2-(2-pyridyl)acetic acid (X) and WSC giving the 3-O-acylated compound (XIV). The activation of (XIV) with CDI affords the 12-O-imidazolylcarbonyl derivative (XV), which is cyclized with ethylenediamine (IV) providing the carbamate (XVI). The alkylation of the primary amine of (XVI) by reductocondensation with pyridine-3-carbaldehyde (VI) and NaBH(OAc)3 gives the secondary amine (XVII).

合成路线39

The acetylation of clarithromycin (I) with acetic anhydride gives the diacetate (II), which is acylated with CDI yielding the 12-O-(imidazolylcarbonyl) compound (III). The cyclization of (III) with ethylenediamine (IV) affords the cyclic carbamate (V), which is alkylated by reductocondensation with quinoline-3-carbaldehyde (VI) and NaBH(OAc)3 to give the secondary amine (VII). The methylation of this amine with formaldehyde and NaBH(OAc)3 yields the corresponding tertiary amine (VIII), which is treated with aqueous HCl to provide the descladinosyl compound (IX). Finally, this compound is acylated with 2-(2-pyridyl)acetic acid (X) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) and deacetylated with methanol to afford the target compound.

合成路线40

The selective hydrolysis of clarithromycin (I) with aqueous HCl, followed by acylation with acetic anhydride gives the monoacetylated descladinosyl compound (XI), which by reaction with trichloromethyl chloroformate (TCF) yields the cyclic carbonate (XII). The reaction of (XII) with 1,1,3,3-tetramethylguanidine (TMG) affords intermediate (XIII), which is selectively acylated with 2-(2-pyridyl)acetic acid (X) and WSC giving the 3-O-acylated compound (XIV). The activation of (XIV) with CDI affords the 12-O-imidazolylcarbonyl derivative (XV), which is cyclized with ethylenediamine (IV) providing the carbamate (XVI). The alkylation of the primary amine of (XVI) by reductocondensation with quinoline-3-carbaldehyde (VI) and NaBH(OAc)3 gives the secondary amine (XVII).

合成路线41

Condensation of the salicylaldehyde derivative (I) with ethylenediamine (II) affords the bis-imine (III). The title manganese complex is then obtained by treatment of (III) with manganese diacetate in ethanol.

合成路线42

Reaction of 2-chloropyrazine (I) with 3,4-dichlorophenylmagnesium bromide (II) in the presence of [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride produced the 2-arylpyrazine (III), which was reduced to the corresponding piperazine (IV) by means of DIBAL in THF. In a different procedure, bromination of methyl 3,4-dichlorophenylacetate (V) using N-bromosuccinimide, followed by reaction of the resulting bromo ester (VI) with ethylenediamine (VII) afforded the piperazinone (VIII), which was further reduced to (IV) by using LiAlH4 in Et2O.

合成路线43

The condensation of 1-(2-cyanophenoxy)-2,3-epoxypropane (I) with ethylenediamine (II) gives 1-(2-cyanophenoxy)-3-(2-aminoethylamino)-2-propanol (III), which is finally treated with phenyl isocyanate (IV) in acetonitrile.

合成路线44

The peroxidation of 1,4-diphenyl-1-cyclopentadiene (I) with O2, white light and activated by tetraphenylporphyrin in dichloromethane gives the peroxide (II), which is condensed with cyclohexane-1,4-dione (III) by means of trimethylsilyl trifluoromethanesulfonate in dichloromethane, yielding the adduct (IV). The reductocondensation of (IV) with N-(7-chloroquinolin-4-yl)ethylenediamine (V) by means of NaBH(OAc)3 in dichloromethane affords the tricyclic trioxane (VI), which is finally treated with citric acid in acetone to provide the target citrate. The intermediate N-(7-chloroquinolin-4-yl)ethylenediamine (V) has been obtained by reaction of 4,7-dichloroquinoline (VIII) with ethylenediamine by means of NaOH at 85 C.

合成路线45

The title imidazoline was synthesized by heating a solution of 2-fluoro-5-methylbenzonitrile (I) in ethylenediamine (II) in the presence of a catalytic amount of phosphorus pentasulfide.

合成路线46

Condensation of 2-chloro-5-cyanopyridine (V) with ethylenediamine (VI) yields the N-pyridyl ethylenediamine (VII). Subsequent reaction of amine (VII) with pyrazole-1-carboxyamidine (VIII) in refluxing acetonitrile affords guanidine (IX). Finally, condensation between guanidine (IX) and enaminone (IV) in the presence of NaOEt produces the title pyrimidine derivative

合成路线47

4-Amiomoindan (I) is reacted with benzoylisothiocyanate (II) to give the benzoylthiourea (III), which after hydrolysis of 4-indanyltiourea (IV) is methylated with iodomethane to (V). The free base (VI) is cyclized with ethyldiamine (A) and p-toluenesulfonic acid to indanazoline

合成路线48

By reaction of 2-chloro-p-toluidine (I) with ammonium thiocyanide to give N-(2-chloro-p-tolyl)thiourea (II), which is then treated with methyl iodide in methanol to yield N-(2-chloro-p-tolyl)-S-methylisothiouronium iodide (III), which, without purification is condensed with ethylenediamine (IV) at 150-50 C.

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The reaction of 2,6-dichloro-4-methoxybenzyl chloride (I) with tetraethylammonium cyanide in refluxing dichloromethane gives 2-(2,6-dichloro-4-methoxyphenyl)acetonitrile (II), which is condensed with ethyl acetate (III) by means of sodium ethoxide in refluxing ethanol to yield the 3-oxobutyronitrile (IV). The cyclization of (IV) with hydrazine (V) by means of HOAc in refluxing benzene affords the aminopyrazole (VI), which is further cyclized with ethyl acetoacetate (VII) in refluxing acetic acid to provide 3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-ol (VIII). The reaction of (VIII) with refluxing POCl3 furnishes the corresponding chloro derivative (IX), which is allowed to react with ethylenediamine (X) in hot acetonitrile to give 7-(2-aminoethylamino)-3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine (XI). Finally, this compound is reductocondensed with tetrahydropyran-4-one (XII) by means of sodium cyanoborohydride in methanol/HOAc to yield the target CP-671906-01.

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The title compound is prepared starting from the known (S) methyl 2-(biphenyl-2-yloxy)propionate (I). Treatment of ester (I) with ethylenediamine (II) in the presence of AlMe3 gives rise to the corresponding imidazoline (II) with some loss of optical purity. Enantiomeric enrichment of (II) is accomplished by fractional crystallization with (-)-di-O,O'-p-toluoyl-L-tartaric acid. The optically pure imidazoline is finally isolated as the corresponding oxalate salt.

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Reaction of methyl 6-nitroindole-2-carboxylate (I) with ethylenediamine (II) in hot DMF gives amino amide (III). After protection of (III) as the N-Boc derivative (IV), catalytic hydrogenation of its nitro group affords amine (V). Indole-2,5-dicarboxylic (VI) is activated as the bis-pentafluorophenyl ester (VII) by treatment with pentafluorophenyl trifluoroacetate. Subsequent coupling between the bis-pentafluorophenyl ester (VII) and amino indole (V) furnishes diamide (VIII). Removal of the N-Boc groups using trifluoroacetic acid in the presence of anisole produces diamine (IX).

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Condensation of 1,8-naphthalic anhydride (I) with ethylenediamine (II) provides the N-aminoethyl naphthalimide (III). Amine (III) is subsequently condensed with 2-chloroethyl isocyanate (IV) to afford urea (V). Finally, nitrosation of (V) by means of NaNO2 and formic acid leads to the title N-nitrosourea.

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Addition of benzylmagnesium bromide to 4-chlorobutyronitrile (II) gives rise to the chloro ketone adduct (III). Subsequent chloride displacement with ethylenediamine (IV) furnishes the target diamino ketone.

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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.

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In an adapted method, complete solution-phase synthesis of SQ-109 is achieved by the substitution of (2E)-1-bromo-3,7-dimethylocta-2,6-diene (VIII) by ethylene diamine (IX) at –78 °C in dry DCM to give (E)-N’-(3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (X) (4, 5). Finally, amine (X) is made to undergo reductive amination with 2-adamantanone (XI) in MeOH using NaBH4 under an N2 atmosphere overnight to give SQ-109, which can be extracted with ethyl acetate or converted to a hydrochloride salt using HCl and MeOH. Scheme 2.

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