Abstract:
2-Amino-6-alkoxypurine is an important intermediate of nucleotide.From guanine,through acylation,chloridization and hydrolysis,2-amino-6-chloropurine(Ⅱ,75.8% yield) was obtained Reaction of Ⅱ with a series of so dium alkoxides gave 2-amino-6-methoxypurine(Ⅲa,96.5% yield),2-amino6-ethoxypurine(Ⅲb,79.6% yield),2-amino-6-isopropoxypurine(Ⅲc,73.2% yield) and 2-amino-6-triflouroethoxypurine(Ⅲd,49.8% yield).The products were characterized by elementary analysis,~1HNMR,MS and IR.Ⅲd was studied emphatically,and the best reaction conditions were:n(Ⅱ)∶n(NaOCH_2CF_3)=1∶5,DMSO as solvent,m(DMSO)∶m(Ⅱ)=13∶1,CuI as catalyst,n(CuI)∶n(Ⅱ)=2∶1 and reaction temperature 160 ℃.Cite
The p fluorophenyl propyl ketone was synthesized with fluobenzene (Ⅰ) and butyryl chloride (Ⅱ).Effects of catalyst (Ⅲ,AlCl 3) amount,the solvent (Ⅳ,CS 2) amount,the reaction time,the reaction temperature and the ratio of reactants were investigated.The optimum conditions are follows:a molar ratios of Ⅱ/Ⅰ=1.4/1,Ⅲ/Ⅰ=2.5/1,and a ratio of Ⅳ/Ⅰ=250 ml/molⅠ,reaction temperature is 45℃ and reaction time is 6 hours.The yield under the optimum conditions was up to 68.1%.The product was characterized by IR and elementary analysis.
Molar ratio
Reaction conditions
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7-Amino-6-nitrobenzodifuroxan(ANBDF) was prepared through a four-step reaction process using 3,5-dichloroaniline as starting material.3,5-dichloro-N-chloroacetaniline(Ⅰ) was prepared in 97.7% yield by the reaction of chloro-acetic chloride with 3,5-dichloroaniline in the media of THF.Nitration of the compound(Ⅰ) with a mixture of fuming nitric acid(98%) and concentrated sulphuric acid(98%) at room temperature for 2 h gave 3,5-dichloro-2,4,6-trinitro-N-chloroacetaniline (Ⅱ) in 92.3% yield.7-Chloroacetamide-6-nitrobenzodifuroxan(Ⅲ) was obtanined in(82.5%) yield from (Ⅱ) and sodium azide in acetic acid through denitrogenization at 110 °C.The title compound(Ⅳ) was prepared by hydrolyzing of(Ⅲ) in basic media with a yield of 66%.The melting point of Ⅳ is 204～205 °C.The factors affecting the key reactions were discussed.The structures of 7-amino-6-nitrobenzodifuroxan and its three intermediates have all been determined by IR,~1H NMR,MS and elemental analysis.
Sodium azide
Nitric acid
Proton NMR
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6-(3-methyl-4-p-toluenesufonyl-2-butenyl)-2,3,4,5-tetramethoxytoluene(Ⅵ),an intermediate of coenzyme Q10,was synthesized from p-cresol(Ⅰ) via four step procedure in overall yield of 49.6%.Bromination of Ⅰ in the presence of Fe powder gave 2,3,6-tribromo-4-methyphenol (Ⅱ) in 78% yield.Ⅱ reacted with CH3ONa in the presence of CuI,and then with (CH3)2SO4 to give 2,3,4,5-tetramethoxytoluene (Ⅲ) in 92.5% yield.Compound Ⅲ was brominated to give 6-bromo-2,3,4,5-tetramethoxytoluene (Ⅳ) in 85% yield,Ⅳ reacted with Mg,followed by reaction with (E)-4-cholro-2-methyl-p-toluenesufonyl-2-butene (Ⅴ),to give compound Ⅵ in 81% yield.The double bond of compound Ⅵ was confirmed to be E-isomer by 1HNMR.
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The synthesis of a novel explosive-N,N′-bis(3,5-dichloro-2,4,6-trinitrophenyl)-3,4-diaminofurazan(BCNDAF) is described in detail.The condensation of dichloroglyoxime(Ⅰ) with 3,5-chloroaniline in basic media gives N,N′-bis(3,5-dichlorophenyl)diaminoglyxime(Ⅱ) with a yield of 66%.(Ⅱ) can then be converted to N,N′-bis(3,5-dichlorophenyl)-3,4-diaminofurazan(Ⅲ) with a yield of 64% via dehydration in a NaOH/HOCH_2CH_2OH solution at high temperature.The title compound(Ⅳ) is obtained in 82.7% yield by the nitration of(Ⅲ) with nitric acid(w(HNO_3)=85%)at 70?℃ for 3?h.The melting point of(Ⅳ)is 124～125?℃.The structures of N,N′-bis(3,5-dichloro-2,4,6-trinitrophenyl)-3,4-diaminofurazan and its two intermediates have been determined by IR,()~1HNMR,MS and elemental analysis.
Nitric acid
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2-Benzylthio-5,7-dimethoxy-1,2,4-triazole[1,5-a]pyrimidine(Ⅲ) is the most important intermediate of metosulam and 1,2,4-triazolopyrimidine-2-ether derivatives.2-Benzylthio-5,7-dichloro-1,2,4-triazolepyrimidine(Ⅱ) was synthesized from 5-amino-3-benzylthio-1,2,4-triazole(Ⅰ) by ring closure and chlorination;based on the optimized test of time 、temperature and the molar ratio between malonic acid and(Ⅰ),(Ⅱ) had a yield above 85% with 20 h 、the molar ratio above 1.1∶1 at 90 ℃ in one step.(Ⅲ) was prepared from(Ⅱ) with sodium methylate by metathetical reactions;after the optimized test of temperature and the molar ratio between sodium methylate and(Ⅱ),(Ⅲ) had a yield above 90% with the molar ratio above 5∶1 at 25 ℃.(Ⅱ)、(Ⅲ) were identified by 1H NMR、MS、IR.This route is simple,the reaction conditions are mild,the raw materials are cheap and easy to obtain.
Molar ratio
Proton NMR
1,2,4-Triazole
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8-Iodo-9-benzyl-9H-purine was synthesized using 9-benzyl-9H-purine(Ⅰ) and N-iodosuccinimide(Ⅱ) as starting materials and tetrahydrofuran as solvent.Under the optimum reaction conditions of reaction temperature 70 ℃,n(Ⅰ)∶n(Ⅱ)=1.0∶2.5 and reaction time 48 h,yield of the product was over 87%.The product was characterized by~1HNMR,~(13)CNMR,MS,Heteronuclear correlation(HETCOR) and long range HETCOR.
Heteronuclear molecule
Tetrahydrofuran
Reaction conditions
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A full account is given of the synthesis and glycosidic hydrolysis of 7-alkyladenosines (4), which established an alternative synthesis of 7-alkyladenines (11). Methylation of N6-methoxyadenosine(5)with MeI in AcNMe2 at 30°C for 8h gave N6-methoxy-7-methyladenosine, which was isolated in the form of the sulfate [7a (X=1/2SO4)] in 55% yield. N6-Methoxy-N6-methyladenosine (9a) was a by-product in this methylation. Demethoxylation of 7a (X=1/2SO4)by catalytic hydrogenolysis using hydrogen and Raney Ni catalyst produced, after replacement of the anion with perchlorate ion, 7-methyladenosine perchlorate [4a (X=ClO4)] in a pure and crystalline form. 7-Ethyladenosine perchlorate [4b (X=ClO4)] was also synthesized from N6-benzyloxyadenosine (6) through a parallel route via N6-benzyloxy-7-ethyladenosine sulfate [8b (X=1/2SO4)]. On treatment with H2O at 98-100°C for 40 min, 4a (X=ClO4) and 4b (X=ClO4) furnished 7-methyladenine (11a) and 7-ethyladenine (11b) in 84% and 55% yields, respectively. Similar hydrolyses of 7a (X=ClO4) and 8b (X=1/2SO4) gave N6-methoxy-7-methyladenine (12a) and N6-benzyloxy-7-ethyladenine (12b), respectively. Catalytic hydrogenolysis of 12b using hydrogen and Raney Ni catalyst afforded 11b in 82% yield. In 0.1 N aqueous HCl at 25°C, 4a (X=ClO4) and 4b (X=ClO4) were found to undergo glycosidic hydrolysis at rates of 2.22×10-3 min-1 (half-life 5.2h) and 1.69×10-3 min-1 (half-life 6.8h), respectively. Comparison of these rate constants with those of the other three NX-methyladenosines (1-3) has revealed that the ease with which depurinylation occurs decreased in going through the series 3-(2)>7-(4a)»N6-(3)≥1-methyladenosine (1). On treatment with 1 N aqueous NaOH at 60°C for 3h, 4a (X=ClO4) was hydrolyzed to give 11a in 44% yield.
Hydrogenolysis
Perchlorate
Raney nickel
Glycosidic bond
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To increase the yield of(R)-α-lipoic acid(Ⅱ) and reduce its cost,an one-step synthesis of Ⅱ by using(R)-6,8-dichlorooctanoic acid(Ⅰ) as starting material was described.The synthesis steps involved chiral resolution of 6,8-dichlorooctanoic acid by(R)-α-phenylethylamine and substitution reaction in water phase.The optimized parameters were as follow.In the chiral resolution,n(6,8-dichlorooctanic acid)∶n((R)-α-phenylethylamine)=1∶0.48,and reaction temperature is 35 ℃;in the substitution reaction,n(Ⅰ)∶n(Na2S2)=1∶1.2,the reaction temperature is 75 ℃,and the dropping time keeps 3.0 h.Under the optimal conditions,the total yield of Ⅱ was 30.0%.When starting material 6,8-dichlorooctanic acid was expanded to 600 g and Ⅰ was increased to 222.0 g,the total yield of Ⅱ was up to 34.3%.
Reaction conditions
Chiral resolution
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2-Amino-6-chloropurine as the starting material was treated with 2-bromoethyl acetate to produce 9-acetoxyethyl-2-amino-6-chloropurine( Ⅰ,65. 6% yield). Compound Ⅰ was diazotized and reacted with disulfides to afford 9-acetoxyethyl-2-alkythio-6-chloropurine( Ⅱ,58. 3% ~ 72. 1% yield).NaN3 reacted with Ⅱ to acquire 9-acetoxyethyl-2-alkythio-6-triazo purine( Ⅲ,86. 4% ~ 92. 0%yield). The results of NMR test( Ⅲ) show that there were azido tautomer( A) and tetrazolyl tautomer( T) in the solution,and the ratio of azido tautomer was 61.5% ~67.2%. PPh3-HCl-DMSO was used as the reaction solvent to reduce triazo to amino and to hydrolyze the ester completely to afford the 2-alkylthio-6-amino-9-( 2-hydroxylethyl) purines( Ⅳ) in a good yield( ~ 90%) in one pot. All the compounds synthesized were confirmed through IR,1HNMR,13 CNMR,and HRMS.
Purine metabolism
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Ethyl 4-chlorophenoxyacetate(Ⅰ) was prepared in 85.7% yield by reaction of 4-chlorophenol with ethyl chloroacetate in the presence of anhydrous potassium carbonate,acetone and potassium iodide.Ⅰ reacted with 80% hydrazine hydrate for 8 h in anhydrous ethanol to give 4-chlorophenoxyacetylhydrazine(Ⅱ) in 78.2% yield.Then with Na_2CO_3 as acid acceptor at 40 ℃,Ⅱ reacted with(a) benzoyl chloride,(b)4-methoxybenzoyl chloride,(c)3,5-dimethylbenzoyl chloride,(d)4-methylbenzoyl chloride and (e)4-chlorobenzoyl chloride to give N,N′-diacylhydrazines (Ⅲa～e),respectively in 90.2%,89.3%,85.1%,91.4% and 86.1%.Finally,cyclodehydration of Ⅲa～e with POCl_3 afforded 2-(4-chlorophenoxy)-5-aryl-1,3,4-oxadiazoles (Ⅳa～e) in 87.2%,89.6%,86.1%,88.4% and 84.3% yield respectively.Structures of Ⅳa～e were confirmed by elementary analysis,IR,~1HNMR and MS spectroscopy.
Anhydrous
Potassium carbonate
Hydrazine (antidepressant)
Ethyl chloroacetate
Ethyl iodide
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