Synthetic Studies on Sialoglycoconjugates 7: Synthesis of N-Acetylneuraminic Acid Derivatives and Analogs

ABSTRACT

Various types of the O-protected derivatives and the 9-bromo analogs of methyl [2-(trimethylsilyl)ethyl 5-acetamido-3, 5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosid]onate were synthesized from methyl [2-(trimetnyl-silyl)ethyl 5-acetamido-4, 7-di-O-acetyl-3, 5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosid]onate (1) or methyl [2-(trimethylsilyl)ethyl 5-acetamido-8, 9-di-O-isopropylidene-D-glycero-α-D-galacto-2-nonulopyranosidlonate (3).     

Synthesis and some transformations of methyl [4-(oxoacetyl)phenyl]carbamate

The oxidation of methyl (4-acetylphenyl)carbamate with selenium dioxide in dioxane–water (30: 1) gave methyl [4-(oxoacetyl)phenyl]carbamate whose condensation with ethyl acetoacetate or diethyl malonate and hydrazine hydrate afforded ethyl 3-methyl-6-[4-(methoxycarbonylamino)phenyl]pyridazine-4-carboxylate and methyl {4-[5-(hydrazinecarbonyl)-6-oxo-1,6-dihydropyridazin-3-yl]phenyl}carbamate, respectively. The reaction of methyl [4-(oxoacetyl)phenyl]carbamate with o-phenylenediamine in dimethylformamide–ethanol on heating led to the formation of methyl [4-(quinoxalin-2-yl)phenyl]carbamate. Methyl {4-(5,7-dioxo- 4,4a,5,6,7,8-hexahydropyrimido[4,5-c]pyridazin-3-yl)phenyl}carbamate and methyl {4-(5-oxo-7-sulfanylidene- 4,4a,5,6,7,8-hexahydropyrimido[4,5-c]pyridazin-3-yl)phenyl}carbamate were synthesized by reactions of methyl [4-(oxoacetyl)phenyl]carbamate with barbituric and thiobarbituric acids, respectively, and hydrazine hydrate in the presence of zirconyl chloride octahydrate at room temperature.     

Synthesis of pyrazolo[3,4-c][1,2]thiazin-4(3H)-one 2,2-dioxides,new heterocycles

The reaction of substituted ethyl 5-aminopyrazole-4-carboxylates with two equivalents of methanesul-fonyl chloride gave the substituted ethyl 5-[bis(methylsufonyl)amino]-1H.-pyrazole-4-carboxylates II . Removal of one of the methanesulfonyl groups, followed by alkylation of the ethyl 5-[(methylsulfonyl)amino]-1H-pyrazole-4-carboxylates III with methyl iodide produced the substituted ethyl 5-[methyl(methylsulfonyl)amino]-1H-pyrazole-4-carboxylates IV . Treatment of IV with sodium hydride gave the 7-substituted 1,7-dihydro-1-methylpyrazolo[3,4-c][1,2]thiazin-4(3H)-one 2,2-dioxides V .     

Synthesis of azoles from 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides

Condensation of 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides with 2,4-pentanedione, phenyl isocyanate or phenyl isothiocyanate (with subsequent work up of the semicarbazides obtained by base), and carbon disulfide gave respectively: 1-(3,5-dimethyl-1H-1-pyrazolyl)-3-[3-(3,5-dimethyl-1H-1-pyrazolyl)-3-oxopropylanilino]-1-propanone, 3-(2-{[2-(5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]anilino}ethyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-one and its thio analog, and 5-(2-{[2-(2-thioxo-2,3-dihydro-1,3,4-oxadiazol-5-yl)ethyl]anilino}ethyl)-2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione plus their methyl derivatives. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1353–1358, September, 2007.     

Synthesis of 3-pyrrol-3′-yloxindoles with a carbamate function

By the reaction of methyl {4(3)-[2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetyl]phenyl} carbamates with ethyl 3-aminocrotonate at boiling in the mixture toluene-anhydrous ethanol, 2: 1, ethyl 5-{3(4)-[(methoxycarbonyl)amino]phenyl}-2-methyl-4-(2-oxo-2,3-dihydro-1H-indol-3-yl)-1H-pyrrole-3-carboxylates were obtained. The condensation of methyl {3(4)-[2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetyl] phenyl}carbamates with ethyl acetoacetate in the presence of ammonium acetate and 20 mol% of 1-methyl-3-butylimidazolium chloride or 1-methyl-3-octylimidazolium tetrafluoroborate at boiling in anhydrous ethanol led to the formation of the corresponding 3-pyrrol-3′-yloxindoles with a carbamate function.     

Novel approach to the synthesis of 3-acyl substituted indolizines. The synthesis of 3-(indolizinyl-2)alanine and 4-(indolizinyl-3) homoalanine derivatives

A novel approach to the synthesis of 3-acylindolizines and the transformations of some acids into tryptophane analogues are described. Reaction of ethyl 2-pyridinylacetate and methyl 2-quinolinylacetate with N-trifluoroacetyl-5-bromo-4-oxonorvaline methylester led to N-trifluoroacetyl-3-(1-ethoxycarbonylindolizinyl-2) alanine methyl ester and N-trifluoroacetyl-3-(3-methoxycarbonylpyrrolo [1,2-a]quinolinyl-2) alanine methyl ester, respectively. Treatment of ethyl 2-pyridinylacetate and 2-pyridinylacetonitrile, first with N,N-dimethylformamide dimethyl acetal (DMFDMA), followed by reaction with phenacyl bromide, gave the corresponding 3-benzoylindolizines, while the reaction of ethyl 2-pyridinylacetate and 2-pyridinylacetonitrile with DMFDMA, followed by treatment with (S)-N-trifluoroacetyl-5-bromo-4-oxonorvaline methyl ester, gave the corresponding N-trifluoroacetyl-4-oxo-4-(indolizinyl-3)homoalanine methyl esters.     

达比加群酯中间体3-【【【2-{[(4-氰基苯基)氨基]甲基}-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯的合成

以对氨基苯腈为起始原料,经胺化反应制得N-(4-氰基苯基)甘氨酸(4);4与N-[3-氨基-4-(甲基氨基)苯甲酰基]-N-2-吡啶-β-丙氨酸乙酯(5)经酰胺化后经闭环反应,合成了达比加群酯的关键中间体——3-【【【2-{[(4-氰基苯基)氨基]甲基}-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯,总收率79.6%,其结构经~1H NMR和ESI-MS确证。     

Stereospecific substitution of enantiomerically pure 1-(2-pyridinyl)ethyl methanesulfonate with beta-dicarbony compounds

The alkylation of the sodium salt of the malonic acid diester with (R)-1-(2-pyridinyl)ethyl methanesulfonate (2) gave the dimethyl (R)-[1-(2-pyridinyl)ethyl]malonate (3a), stereospecifically. The alkylation reaction of methyl acetoacetate gave the methyl (2'S,2R/2S)-3-oxo-2-[1-(2-pyridinyl)ethyl]butanoate (3d) along with the methyl (S)-3-[1-(2-pyridinyl)ethoxy]-2-butenoate (4d). The acid hydrolysis and decarboxylation of 3d under acidic conditions gave (R)-4-(2-pyridinyl)pentan-2-one (6), and the alkylation of methyl (R)-[1-(2-pyridinyl)ethyl]acetoacetate with benzyl bromide gave a mixture of C-benzylated and O-benzylated products 7 and 8.     

Family of mixed-valence oxovanadium(IV/V) dinuclear entities incorporating N4O3-coordinating heptadentate ligands: synthesis, structure, and EPR spectra

Dinuclear (V(IV)V(V)) oxophenoxovanadates of general formula [V2O3L] have been synthesized in excellent yields by reacting bis(acetylacetonato)oxovanadium(IV) with H3L in a 2:1 ratio in acetone under an N2 atmosphere. Here L3- is the deprotonated form of 2,6-bis[{{(2-hydroxybenzyl)(N',N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol (H3L1), 2,6-bis[{{(5-methyl-2-hydroxybenzyl)(N',N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol (H3L2), 2,6-bis[{{(5-tert-butyl-2-hydroxybenzyl)(N',N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol (H3L3), 2,6-bis[{{(5-chloro-2-hydroxybenzyl)(N',N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol(H3L4), 2,6-bis[{{(5-bromo-2-hydroxybenzyl)(N'N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol (H3L5), or 2,6-bis[{{(5-methoxy-2-hydroxybenzyl)(N'N'-(dimethylamino)ethyl)}methyl]-4-methylphenol (H3L6). In [V2O3L1], both the metal atoms have distorted octahedral geometry. The relative disposition of two terminal V=O groups in the complex is essentially cis. The O=V...V=O torsion angle is 24.6(2) degrees . The V-O(oxo)-V and V-O(phenoxo)-V angles are 117.5(4) and 93.4(3) degrees , respectively. The V...V bond distance is 3.173(5) A. X-ray crystallography, IR, UV-vis, and 1H and 51V NMR measurements show that the mixed-valence complexes contain two indistinguishable vanadium atoms (type III). The thermal ellipsoids of O2, O4, C10, C14, and C15 also suggests a type III complex in the solid state. EPR spectra of solid complexes at 77 K display a single line indicating the localization of the odd electron (3d(xy)1). Valence localization at 77 K is also consistent with the 51V hyperfine structure of the axial EPR spectra (3d(xy)1 ground state) of the complexes in frozen (77 K) dichloromethane solution: S = 1/2, g(parallel) approximately 1.94, g(perpendicular) approximately 1.98, A(parallel) approximately 166 x 10(-4) cm(-1), and A(perpendicular) approximately 68 x 10(-4) cm(-1). In contrast isotropic room-temperature solution spectra of the family have 15 hyperfine lines (g(iso) approximately 1.974 and A(iso) approximately 50 x 10(-4) cm(-1)) revealing that the unpaired electron is delocalized between the metal centers. Crystal data for the [V2O3L1].CH2Cl2 complex are as follows: chemical formula, C32H43O6N4Cl2V2; crystal system, monoclinic; space group, C2/c; a = 18.461(4), b = 17.230(3), c = 13.700(3) A; beta = 117.88(3) degrees ; Z = 8.     

Synthesis of 2H-Thiopirano[3,4-c]pyrazol-7-one Derivatives as the First Example a New Heterocyclic System

Russian Journal of General Chemistry - A series of ethyl 4-[(Z)-(4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl]-1-aryl-1H-pyrazole-3-carboxylates was obtained as a result of the reaction of ethyl...     

Synthesis and Bioactivity of 5-Aryl-4-acyl-3-hydroxy-1-[2-(imidazolyl-3-yl)ethyl]3-pyrroline-2-ones

Russian Journal of General Chemistry - 5-Aryl-4-acyl-3-hydroxy-1-[2-(imidazolyl-3-yl)ethyl]-3-pyrroline-2-ones were synthesized by three-component reaction of methyl dioxobutanoates with aromatic...     

Synthesis of 3-arylsulfonylmethyl-1,2,4-oxadiazole-5-carboxylic acid derivatives

Several new 3-arylsulfonylmethyl-1,2,4-oxadiazole-5-carboxylic acid derivatives have been synthesized. A typical example, 3-[(4-chlorophenylsulfonyl)methyl]-1,2,4-oxadiazole-5-carboxylic acid ethyl ester ( 2c ), was prepared from the reaction of 2-(4-chlorophenylsulfonyl)acetamide oxime ( 1c ) with ethyl oxalyl chloride. The hydrazide derivative ( 3f ) showed antihypertensive activity in rats. Various structural modifications to improve activity are discussed.     

Reaction of ethyl 4-aryl-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates with N-methylmorpholinium 3-cyano-1,4-dihydro- and 3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates

Alkylation of N-methylmorpholinium 4-Ar¹-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates using ethyl 4-Ar-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (10 % KOH, DMF) gives mixtures of diastereomers of ethyl 4-Ar-6-[(4-Ar¹-3-cyano-1,4,5,6-tetrahydropyridin-2-ylthio)methyl]-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates in overall 30-58 % yield. Under these conditions the N-methylmorpholinium 4-Ar1-5-(N-Ar²-carbamoyl)-3-cyano-6-methyl-1,4-dihydropyridine-2-thiolates undergo aromatization of the dihydropyridine ring to give ethyl 4-Ar-6-[4-Ar¹-5-(N-Ar²-carbamoyl)-3-cyano-6-methylpyridin-2-ylthio)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (37-51 %). In the absence of KOH, only the substituted pyridine-2(1 H)-thione is formed as a product of oxidation of the dihydropyridine ring in the starting substrate. Some of the alkylation products obtained possess weak or moderate antibacterial activity towards the specific strains of Escherichia coli and Bacillus subtilis but are inactive towards Candida albicans and Staphylococcus aureus.     

Novel 1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive activity of 3-[4-(substituted amino)phenylalkyl]ester derivatives

Novel 1,4-dihydropyridine derivatives bearing 3-[4-(substituted amino)phenylalkyl]ester side chains were prepared and tested for their antihypertensive activity in spontaneously hypertensive rats. Most compounds showed a more potent antihypertensive effect and a longer duration of action than nicardipine. The derivatives with a benzhydrylpiperazinyl and a benzhydrylpiperidinyl group were distinctive. 2-[4-(4-Benzhydryl-1-piperazinyl)phenyl]ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (4e), its 4-(4-cyano-2-pyridyl) analogue (4f), its 3-[4-(4-benzhydryl-1-piperazinyl)phenyl]propyl ester analogue (4h), its 2-[4-(4-benzhydryl-1-piperidinyl)phenyl]ethyl ester analogue (4j), and its 2-[4-(1-benzhydryl-4-piperidinyl)phenyl]ethyl ester analogue (4k) were selected as candidates for further pharmacological investigations.     

Synthesis and antimicrobial activity of some derivatives of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide

(7-Hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide (2) was prepared from (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid ethyl ester (1) and 100% hydrazine hydrate. Compound 2, is the key intermediate for the synthesis of several series of new compounds such as Schiff's bases 3a-l, formic acid N'-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)acetyl] hydrazide (4), acetic acid N'-[2-(7-hydroxy-2-oxo-2H-chromen-4- yl)-acetyl] hydrazide (5), (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid N'-[2-(4- hydroxy-2-oxo-2H-chromen-3-yl)-2-oxoethyl] hydrazide (6), 4-phenyl-1-(7-hydroxy-2- oxo-2H-chromen- 4-acetyl) thiosemicarbazide (7), ethyl 3-{2-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)-acetyl]hydrazono}butanoate (8), (7-hydroxy-2-oxo-2H-chromen-4-yl)- acetic acid N'-[(4-trifluoromethylphenylimino)methyl] hydrazide (9) and (7-hydroxy-2- oxo-2H-chromen-4-yl)acetic acid N'-[(2,3,4-trifluorophenylimino)-methyl] hydrazide (10). Cyclo- condensation of compound 2 with pentane-2,4-dione gave 4-[2-(3,5- dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-7-hydroxy-2H-chromen-2-one (11), while with carbon disulfide it afforded 7-hydroxy-4-[(5-mercapto-1,3,4-oxadiazol-2-yl)methyl]-2H- chromen-2-one (12) and with potassium isothiocyanate it gave 7-hydroxy-4-[(5- mercapto-4H-1,2,4-triazol-3-yl)methyl]-2H-chromen-2-one (14). Compound 7 was cyclized to afford 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)-N -(4-oxo-2-phenylimino- thiazolidin-3-yl) acetamide (15).     

甲磺酸达比加群酯杂质的合成

根据甲磺酸达比加群酯工艺,合成了甲磺酸达比加群酯的7个杂质：3-【【【2-｛［(4-氰基苯基)氨基］甲基｝-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸（A）, 3-【【【2-【｛［4-(乙氧基)叔胺基］苯基｝氨基】甲基】-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯盐酸盐(B), 3-【【【2-【｛［(4-甲脒基)苯基］氨基｝甲基】-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯盐酸盐(C), 3-【【【2-【【【4-｛［(己氧基)羰基］氨基亚甲胺基｝苯基】氨基】甲基】-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸甲酯盐酸盐(D), 3-【【【2-【【【4-【｛［(己氧基)羰基］氨基｝羰基】苯基】氨基】甲基】-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯(E), 3-【【【2-【【【4-【｛［(己氧基)羰基］氨基｝亚氨甲基】苯基】氨基】甲基】-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸(F), (Z)-3-【【【2-【【【4-【｛［(N,N′-二己氧基)羰基］脒基｝亚氨甲基】苯基】氨基】甲基】-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯(G),其结构经¹H NMR和ESI-MS确证。     

Synthesis of Some New Benzopyranopyrimidin-2-Thiol Derivatives

Reaction of 2-mercapto-4-hydroxy-5H-[1]-benzopyrano-[4,3- d ]-pyrimidin-5-one ( 3 ) with phenyl isothiocyanate and methyl acrylate yielded the corresponding 2-(substituted)thio-4-hydroxy-5H-[1]-benzopyrano-[4,3- d ]-pyrimidin-5-ones ( 4 , 5 ). Hydrolysis and hydrazinolysis of 5 gave acid derivative 6 , and hydrazone 7 . Treatment of hydrazone 7 with ethyl acetoacetate, diethyl malonate, and phenyl isothiocyanate yielded the corresponding 2-(substituted)thio-4-hydroxy-5H-[1]-benzopyrano- [4,3- d ]-pyrimidin-5-ones ( 8 , 9 , and 11 ). Cyclization of 11 with 2 N NaOH led to 12 .     

2,2'-联吡啶参与的分子梭合成与1H NMR研究

2-{2-[4-苯基-二(4-特丁基苯基)甲基]苯氧基}乙氧乙醇磺酸酯(1)与4,4'-联吡啶在乙腈中回流36 h, 随后通过阴离子交换得到N-{2-{2-[4-苯基-二(4-特丁基苯基)甲基]苯氧基}乙氧乙基}-4,4'-联吡啶六氟磷酸盐(3), 产率为93.4%. 3与4,4'-二(溴甲基)-2,2'-联吡啶在乙腈中、70 ℃下反应72 h, 生成哑铃型化合物5, 产率为45%. 5与冠醚BPP34C10在55 ℃下搅拌5 d, 得到分子梭6和7, 产率分别为42.3%和27.3%. ¹H NMR数据表明, 富电子冠醚BPP34C10与哑铃型组分上贫电子4,4'-联吡啶的非键作用使4,4'-联吡啶上氢的化学位移向高场有较大移动.     

Synthesis of 4‐(1‐phenyl‐1H‐pyrazol‐3‐yl)‐[1,2,4]triazolo[4,3‐a]quinoxalines and their 4‐halogenopyrazolyl analogs

Synthesis of {3‐[1‐(ethoxycarbonyl)‐[1,2,4]triazolo[4,3‐a]quinoxalin‐4‐yl]‐1‐phenyl‐1H‐pyrazol‐5‐yl}methyl ethyl oxalate ( 2 ), ethyl 4‐[5‐(acetoxymethyl)‐1‐phenyl‐1H‐pyrazol‐3‐yl]‐[1,2,4]triazolo[4,3‐a]quioxaline‐1‐carboxylate ( 4 ), [4‐halo‐1‐phenyl‐3‐(1‐phenyl‐[1,2,4]triazolo[4,3‐a]quioxalin‐4‐yl)‐1H‐pyrazol‐5‐yl]methyl acetate ( 11 ), {4‐halo‐3‐[1‐methyl‐[1,2,4]triazolo[4,3‐a]quinoxalin‐4‐yl]‐1‐phenyl‐1H‐pyraz‐ol‐5‐yl}methyl acetate ( 13 ), and [3‐([1,2,4]triazolo‐[4,3‐a]quinoxalin‐4‐yl)‐4‐halo‐1‐phenyl‐1H‐pyrazol‐5‐yl] methyl formate ( 15 ) was accomplished. The structural investigation of the new compounds is based on chemical and spectroscopic evidences. J. Heterocyclic Chem., (2011)     

新型哌嗪化合物的合成及其晶体结构

以2-［1,2-二(2-羟基苯甲氨基)-2-(吡啶基)乙基］苯酚和2-［1,2-二(2-羟基苯甲氨基)-4-(吡啶基)乙基］苯酚为原料,分别与乙二醛经缩合反应,合成了两个新型的哌嗪化合物--2-【{12-(2-吡啶基)-3,20-二氧-11,21-二氮杂五环［11.7.1.O^2,11.O^4,9.O^14,19］二十一-4,6,8,14,16,18-六环-21-基}甲基】苯酚(2a)和2-【{12-(4-吡啶基)-3,20-二氧-11,21-二氮杂五环［11.7.1.O^2,11.O^4,9.O^14,19］二十一-4,6,8,14,16,18-六环-21-基}甲基】苯酚(2b),其结构经¹H NMR, ¹³C NMR, FT-IR, ESI-MS和X-射线单晶衍射表征。2a(CCDC: 1 439 422)属单斜晶系,空间群P2₁/n,晶胞参数a=12.250 2(16) , b=10.299 6(13) , c=18.296(2) , β=95.798(2)°, V=2 296.6(5) ³, Dc=1.341 mg·cm^-3,Z=4, F(000)=976, μ=0.088 mm^-1。