A facile preparation of ammonium [<Superscript>14</Superscript>C]thiocyanate

Summary An attractive and simple method has been developed for the preparation of ammonium [¹⁴C]thiocyanate from [¹⁴C]thiourea which eliminates the necessity of handling highly hazardous potassium [¹⁴C] cyanide. [¹⁴C]thiourea was isomerized to ammonium [¹⁴C]thiocyanate by heating the aqueous solution of thiourea (12%) in a sealed tube at 160 °C for 24 hours. The product formed was purified by silica-gel column chromatography. A radiochemical yield of 92.7% was obtained based on [¹⁴C]thiourea. The specific activity of the product obtained was 53.3 mCi/mmol (1.97 GBq/mmol) and the radiochemical purity was greater than 99%. This method has not been reported so far for the production of this labeled compound.     

14C-labeling of bromobutide, 2-bromo-3,3-dimethyl-N-(alpha, alpha-dimethylbenzyl)butyramide

Bromobutide, a novel herbicide, was labeled with carbon-14 independently at the carbonyl group and the phenyl ring for use in metabolic studies. 14C-Carbonation of neopentylmagnesium chloride (3) gave 3,3-dimethyl[1-14C]butyric acid (4a) quantitatively. Chlorination of 4a with thionyl chloride followed by alpha-bromination with bromine yielded 2-bromo-3,3-dimethyl[1-14C]-butyryl halide (5a), which was subsequently condensed with alpha, alpha-dimethylbenzylamine (6a) to afford [carbonyl-14C]bromobutide (1a). The overall yield of 1a was 76% from barium [14C]-carbonate (2). Similarly, condensation of alpha, alpha-dimethyl[phenyl-14C]benzylamine (6b), which was prepared from alpha-methyl[phenyl-U-14C]styrene (7) in three steps, with 2-bromo-3,3-dimethylbutyryl halide (5b) gave [phenyl-14C]bromobutide (1b) in 67% yield after purification. The specific activities of 1a and 1b were 1.38 and 0.781 GBq/mmol (37.2 and 21.1 mCi/mmol), respectively.     

An improved method for 14C-labelling of farnesylacetic acid and its geranyl ester

Farnesylacetic acid was efficiently labelled with 14C at the 5-position and gefarnate, a potent ulcer inhibitor, was prepared from it in radioactive form for use in metabolic studies. Condensation of [carbonyl-14C]acetyl chloride (5) with t-butyl 2-ethoxymagnesiomalonate (6) followed by acid-catalyzed deprotection and decarboxylation gave ethyl 3-oxo[3-14C]butanoate (8). Alkylation of the keto ester (8) with geranyl bromide (9) afforded the unsaturated keto ester (10), which was hydrolyzed and decarboxylated to give geranyl[2-14C]acetone (11). Grignard reaction of 11 with cyclopropylmagnesium bromide followed by treatment with hydrobromic acid yielded [4-14C]homofarnesyl bromide (13). Cyanation of 13 with potassium cyanide and subsequent hydrolysis gave [5-14C]farnesylacetic acid (1) in 6.1% yield from barium [14C]carbonate (3). Chlorination of 1 followed by esterification with geraniol afforded [5-14C]gefarnate (2) in 88% yield.     

Synthesis of ammonium [14C]thiocyanate

Ammonium [¹⁴C]thiocyanate was prepared from potassium [¹⁴C]cyanide with a radiochemical yield of 90%. [¹⁴C]hydrocyanic acid, generated from potassium [¹⁴C]cyanide by sulphuric acid, reacts with aqueous ammonia and elemental sulphur in the presence of trace amounts of ammonium sulphide to yield ammonium [¹⁴C]thiocyanate.     

Syntheses of [prolyl-U-14C]alacepril and its related compounds

In order to study the metabolic fate of alacepril, an anti-hypertensive agent, the 14C-labeled compound of alacepril and its related compounds were synthesized. [Prolyl-U-14C]alacepril was synthesized in over-all yield of 32.7-38.0% by the mixed anhydride condensation of L-phenylalanine with [prolyl-U-14C]DU-1163, which had been prepared from L-[U-14C]proline and N-(S-3-acetylthio-2-methylpropanoyloxy)succinimide. [Prolyl-U-14C]captopril and [prolyl-U-14C]DU-1227 were prepared in high yields by hydrolysis of [prolyl-U-14C]DU-1163 and [prolyl-U-14C]alacepril, respectively. [Prolyl-U-14C]captopril-cysteine was synthesized by condensation of [prolyl-U-14C]captopril with cystine S-monoxide in 55.0% yield.     

Analogs of alicyclic alpha-amino acids--effect of ring size and side chain on tumor accumulation

We studied the tumor-localizing characteristics of alicyclic alpha-amino acid analogs (a-j) without alpha-hydrogen, because of the selective affinity of synthetic nonmetabolizing amino acids such as 1-aminocyclopentanecarboxylic acid (ACPC) and alpha-aminoisobutyric acid alpha-AIB) to tumor tissues. Ten different alicyclic alpha-amino acids (a-j) were labeled with 14C using a modified Bücherer synthesis for amino acids. The tissue distributions and whole-body autoradiographic study of these 14C-labeled alicyclic alpha-amino acid analogs (a-j) were investigated in mice bearing Ehrlich tumor. These results showed that the tumor uptakes and tumor to tissue concentration ratios increased with decreasing ringsize in homologous series (8- through 4-membered ring systems) and alicyclic alpha-amino acid analogs containing 3- or 4-methyl group had the higher tumor to tissue concentration ratios. On the other hand, alicyclic alpha-amino acid analogs containing 2-methyl group and 4-phenyl group showed the lower tumor uptakes and the lower tumor to tissue concentration ratios. These results suggest that the small ringsize alicyclic alpha-amino acid analogs containing 3-methyl group such as 3-methyl-1-aminocyclopentanecarboxylic acid (3-MeACPC) may be effective for the early detection of tumors.     

无溶剂条件下煤基活性炭负载硫酸作为固体酸催化合成 14-烷基(芳基)-14H-二苯并[a,j]氧杂蒽类化合物

以自制的煤基活性炭负载硫酸为催化剂, β-萘酚、醛和脂肪醛为原料, 用一锅法成功合成了11个14-烷基(芳基)-14H-二苯并[a,j]氧杂蒽类化合物, 反应时间0.1～1 h, 收率71%～96%. 该方法不仅反应时间短, 产率高, 而且催化剂价廉易得, 对环境友好, 可重复利用5次, 活性没有明显降低, 并测得催化剂的酸值为3.06 mmol/g.     

Facile conversion of [1-<Superscript>14</Superscript>C]lauronitrile to [1-<Superscript>14</Superscript>C]lauric acid under microwave irradiation

Summary A highly efficient and an optimized synthesis of [1-¹⁴C]lauric acid with high specific activity (50 mCi/mmol) is described. [1-¹⁴C]lauric acid was prepared from [1-¹⁴C]lauronitrile, in 2 minutes with a mixture of concentrated hydrochloric acid: propionic acid (1: 2 v/v) under microwave irradiation, in quantitative yield.     

S-烃基-1-烃基-3-[4-(苯并咪唑-2-巯基)苯基]异硫脲的合成及其iNOS抑制活性

以2-巯基苯并咪唑(1)为原料,经缩合和还原得到2-(4-氨基苯硫基)苯并咪唑(3),再与异硫氰酸苯甲酰酯或异硫氰酸烃基酯反应得到取代硫脲(5和7),最后与卤代烃反应得到20个新的S-烃基-1-烃基-3-[4-(苯并咪唑-2-巯基)苯基]异硫脲化合物(6和8),其结构经IR,¹HNMR,MS及元素分析确证.初步的药理试验表明,20个目标化合物均有不同程度的iNOS抑制活性,其中化合物6b,8d和8f的iNOS抑制活性与阳性对照药氨基胍相当.     

A rapid microwave induced synthesis of [carboxyl-14C]-nicotinic acid (vitamin B3) and [carbonyl-14C]-nicotinamide using K14CN

Microwave assisted direct aromatic substitution of 3-bromopyridine with K¹⁴CN as the cyanide source and catalytic amount of tetrabutylammonium bromide afforded [3-¹⁴C]-cyanopyridine 3 in 90% yield. Microwave assisted hydrolysis of 3 with a mixture of concentrated hydrochloric acid and propionic acid afforded [carboxyl-¹⁴C]-nicotinic acid in 95% yield whereas microwave assisted hydrolysis of 3 with a mixture of concentrated sulfuric acid and propionic acid afforded [carbonyl-¹⁴C]-nicotinamide in 85% yield.     

Synthesis of <Superscript>14</Superscript>C analogue of 1,2-diaryl-[2-<Superscript>14</Superscript>C]-pyrroles

Three 1,2-diaryl pyrroles selective COX-2 inhibitors, 2-(4-fluorophenyl)-5-methyl-1-(4-methylsulfonyl-phenyl)-1H pyrrole, 2-(4-fluorophenyl)-1-[4-(methylsulfonyl) phenyl]-1H-pyrrole and 4-[2-(4-fluorophenyl)-1H-pyrrol-1-yl]benzenesulfon-amide, all three labeled with ¹⁴C in the 2-position were prepared from para-fluoro-benzaldehyde-[carbonyl-¹⁴C].     

Use of Dibutyl[14C]formamide as a Formylating Reagent in the Vilsmeier–Haack Reaction and Synthesis of a 14C‐Labeled Novel Phosphodiesterase‐4 (PDE‐4) Inhibitor

A simple, high‐yielding synthesis of dibutyl[¹⁴C]formamide ([¹⁴C]DBF; 1 ) from ¹⁴CO₂ was developed (Scheme 1): reaction of LiBEt₃H and ¹⁴CO₂ followed by aqueous workup gave H¹⁴CO₂H in high yield. Conversion of the [¹⁴C]formic acid to 1 was effected by a standard carbodiimide coupling procedure. The utility of 1 as an alternative to dimethyl[¹⁴C]formamide ([¹⁴C]DMF) in alkylation reactions and in the [¹⁴C]Vilsmeier–Haack reaction was demonstrated for several substrates (Table 2). A ¹⁴C‐labeled phosphodiesterase‐4 (PDE‐4) inhibitor, [¹⁴C]‐ 2 , was synthesized by application of this technology (Scheme 2).     

新型除草剂丙酯草醚A环14C均标记合成和鉴定

以U-¹⁴C-对氨基苯甲酸为前体, 通过酯化、缩合、还原和取代四步反应获得了A环¹⁴C均标记的丙酯草醚, 用PHPLC对其进行纯化. 采用HPLC-MS(ESI), MS(EI)和¹H NMR验证了其结构, 通过HPLC(外标法)确定其化学纯度大于98%; HPLC-LSC和TLC-IIA两种方法分析表明, 其放射化学纯度大于98%, 其比活度为1.089±0.011 mCi/mmol. 合成的化学收率和放化收率均为53%.     

Furopyridines. XI. 13C NMR Spectra of 2- or 3-Substituted Furo[2,3-b]-, Furo[3,2-b]-, Furo[2,3-c]- and Furo[3,2-c]pyridine

The ¹³C nmr spectra of 2- or 3-monosubstituted furo[2,3-b]- 1a-1j , furo[3,2-b]- 2a-2j , furo[2,3-c]- 3a-3j and furo[3,2-c]pyridine derivatives 4a-4j are reported. Effects by change in annelation and substituent effects on ¹³C chemical shifts and carbon-proton coupling constants are discussed. The spectra of benzo[b]furan derivatives 5a-5j having the corresponding substituent are also reported for comparison.     

Preparation of some carbon-14-labeled amino acids by radiophotosynthesis using sugar beet plant

Radiophotosynthesis has been applied as a means for preparing a number of carbon-14-labeled amino acids using sugar beet plants grown under controlled environmental conditions. The apparatus used, conditions of operation, isolation of products, and their analysis and radiometry have been discussed in detail. From the results obtained, it can be inferred that a number of labeled amino acids could be separated from the leaves of sugar beet including [¹⁴C]alanine, γ-[¹⁴C]aminobutyric acid, [¹⁴C]glutamic acid, [¹⁴C]aspartic acid, [¹⁴C]serine, [¹⁴C]valine, and [¹⁴C]aspargine with specific activities of several microcuries per millimole. The specific activities of the products could be significantly increased by increasing the specific activity of the radioactive carbonate initially used.     

Assignment of the relative configuration of spiro[4.5]decanes by 13C, 15N and 17O NMR

The relative configuration of 11 1,4-diazaspiro[4.5]decanes (1a-1j and 1m), 15 1,4-oxazaspiro[4.5]decanes (2a-2o) and 10 1,4-dioxaspiro[4.5]decanes (3a-3n) substituted at the 2-, 6-, 7- or 8-position by a methyl group or using the tert-butyl group as a model for the ananchomeric structure is reported. The relative stereochemistry was analyzed by 1H, 13C, 15N and 17O NMR and all isomers present were characterized spectroscopically. Compounds with a methyl group in the six-membered ring show a chair conformation preference with the methyl group in the equatorial position. Compounds with one or two nitrogens exhibit a tautomeric equilibrium between the imine-diazolidine forms, as demonstrated by IR and 13C NMR.     

抗丙肝药物维拉帕维的合成

以7-羟甲基-1-四氢萘酮和1-溴-4-氯-苯甲醛为起始原料,经14步反应合成了抗丙肝新药维拉帕维--甲基（2S）-1-【(2S,5S)-2-【9{2［（2S,4S）-1-（2R)-2-［（甲氧基羰基）氨基］-2-苯乙酰基-4-（甲氧基甲基）吡咯烷-2-基］-1H-咪唑 5 基} 1,11-二氢异色烯［4′,3′ :6,7］萘并［1,2-d］咪唑-2-基-5-甲基吡咯烷-1-基】-3-甲基-1-氧丁烷-2-基】氨基甲酸酯,总产率10.14%,其结构经¹H NMR和ESI-MS确证。     

Radical-mediated carboxylation of alkyl iodides with [11C]carbon monoxide in solvent mixtures

[reaction: see text] [carboxyl-(11)C]Carboxylic acids were prepared from alkyl iodides via photoinitiated radical reactions using 10(-)(8) mol of [(11)C]carbon monoxide in binary and ternary homogeneous solvent mixtures. Short- (isobutyric), medium-, and long-chain saturated fatty acids (heptadecanoic) were labeled with isolated decay-corrected radiochemical yields ranging from 55% to 70% in 5-7-min reactions. The conversion of [(11)C]carbon monoxide to products reached 80-90%. To obtain good yields in the reactions performed in water-acetonitrile and water-THF mixtures, the addition of tetrabutylammonium hydroxide or potassium hydroxide was essential. The carboxylation was efficient for primary and secondary alkyl iodides. The carboxylation of tertiary iodides was feasible for 1-iodoadamantane but not for tert-butyl iodide. The dependence of the radiochemical yields on reaction time, photoirradiation conditions, and organic and inorganic additives was studied. The method provides a one-step route to [carboxyl-(11)C]carboxylic acids; traditional methods, in contrast, would require several steps. For example, using the devised reaction conditions, 3.19 GBq of purified [1-(11)C]1,10-decanedicarboxylic acid (specific radioactivity 188 GBq/mumol) was obtained within 35 min of the end of 10 muAh bombardment. (1-(13)C)4-Phenylbutyric acid was synthesized using ((13)C)carbon monoxide for identifying the labeling position with (1)H and (13)C NMR.     

Facile syntheses of isotope-labeled chiral octahydroindole-2-carboxylic acid and its <Emphasis Type="Italic">N</Emphasis>-methyl analog

We have synthesized deuterium and carbon-14 labeled enantiomerically pure octahydroindole-2-carboxylic acid (PD0140417), N-methyl octahydroindole-2-carboxylic acid (PD0348183) and their racemic analogs (PD0108405 and PD0338055). [ring-U-¹⁴C]PD0140417 was prepared from [ring-U-¹⁴C]benzoic acid in a seven-step synthesis in 6.2% overall radiochemical yield. [¹⁴C]PD0348183 was prepared from [¹⁴C]BaCO₃ in a five-step synthesis in 16% radiochemical yield. Additionally, [D]PD0108405 and [D]PD0338055 were synthesized by direct platinum-catalyzed hydrogenation with deuterium gas.     

Synthesis of 1-(4-methylsulfone-phenyl)-5-(4-fluoro-phenyl)-5-[14C]-1,2,3-triazole and 1-(4-sulfonamide-phenyl)-5-(4-fluoro-phenyl)-5-[14C]-1,2,3-triazole as novel carbon-14 anticonvulsant

Summary Two 1,2,3-triazole anticonvulsants, 1-(4-methylsulfone-phenyl)-5-(4-fluoro-phenyl)-5-[¹⁴C]-1,2,3-triazole and 1-(4-sulfonamide-phenyl)-5-(4-fluoro-phenyl)-5-[¹⁴C]-1,2,3-triazole, both labeled with carbon-14 in the 5-position were prepared from para-fluoro-benzonitrile-[cyano-¹⁴C].