Ethylene Chlorohydrin Research Articles

Synthesis and antitumor activity of 5-methylbenzofuryl-substituted 1,2,4-triazoles and triazoline-5-thiones

3-(5-Methylbenzofuryl)-4-phenyl(benzyl, allyl)-5-mercapto-1,2,4-triazoles were synthesized by cyclization of the corresponding substituted thiosemicarbazides. S-alkylation, N-aminomethylation, and N-hydroxymethylation of the 5-mercaptotriazoles by ethylene chlorohydrin, chloroacetamide, and chloroacetic acid produced N-aminomethylene- and N-hydroxymethylenetriazoline-5-thiones. The antitumor activity of the synthesized compounds was studied.

Concentration effects in the nucleophilic reactions of tertiary amines in aqueous solutions. Alkylation of amines with ethylene chlorohydrin

During the alkylation of tertiary amines with ethylene chlorohydrin in aqueous solutions, the initial rates and degrees of conversion attained within control periods of time showed nonstandard dependences on the initial concentrations of reagents. The character of the concentration dependences depended on the structure of the hydrocarbon fragments and the available sets of functional groups in amines. On the basis of our results and viscosimetric data for the model systems, we assumed that these effects were due to pre-reaction association involving the reagents and products.

Alkylation of pyrazoles with ethylene chlorohydrin under phase transfer catalysis

Alkylation reactions of pyrazoles with ethylene chlorohydrin under phase transfer catalysis were studied. Effect of solvent nature on alkylation process was established. 3(5)-Methylpyrazole alkylation products were isolated and identified.

Sterilization of medical devices by ethylene oxide, determination of the dissipation of residues, and use of Green Fluorescent Protein as an indicator of process control.

Ethylene oxide (EO) is used to sterilize Oxygenator and Tubing applied to heart surgery. Residual levels of EO and its derivatives, ethylene chlorohydrin (ECH) and ethylene glycol (EG), may be hazardous to the patients. Therefore, it must be removed by the aeration process. This study aimed to estimate the minimum aeration time for these devices to attain safe limits for use (avoiding excessive aeration time) and to evaluate the Green Fluorescent Protein (GFP) as a biosensor capable of best indicating the distribution and penetration of EO gas throughout the sterilization chamber. Sterilization cycles of 2, 4, and 8 h were monitored by Bacillus atrophaeus ATCC 9372 as a biological indicator (BI) and by the GFP. Residual levels of EO, ECH, and EG were determined by gas chromatography (GC), and the residual dissipation was studied. Safe limits were reached right after the sterilization process for Oxygenator and after 204 h of aeration for Tubing. In the 2 h cycle, the GFP concentration decreased from 4.8 (+/-3.2)% to 7.5 (+/-2.5)%. For the 4 h cycle, the GFP concentration decreased from 17.4 (+/-3.0)% to 21.5 (+/-6.8)%, and in the 8 h cycle, it decreased from 22.5 (+/-3.2)% to 23.9 (+/-3.9)%. This finding showed the potentiality for GFP applications as an EO biosensor.

Chalcogen-containing analogs of ethylene glycol and its derivatives

Ethylene chlorohydrin when reacted with elemental chalcogens or dimethyl dichalcogenides in the hydrazine hydrate-alkali system forms chalcogen-containing analogs of ethylene glycol and its derivatives (dichalcogenated β-diglycols, chalcogenated ethanols, and chalcogenated methyl cellosolves).

Dehydrochlorination of 4-hydroxy-3,5-di-tert-butylbenzylidene chloride with aprotic nonionogenic reagents

47 We showed previously that 4-hydroxy-3,5-ditertbutylbenzylidene chloride ( I ) reacted with nonionogenic aprotic reagents, such as triethyl orthoformate ( II ) [1] and esters of phosphorus(III) acids ( III ) [2], via nucleophilic displacement and underwent dechloroalkoxylation and dechlorophosphorylation to form acetal and diphosphonate, respectively. We studied previously unknown reactions of gemdichloride I with ethylene oxide ( IV ), vinyl ethyl ether ( V ), N , N , N ', N 'tetramethylmethanediamine ( VI ), and dimethyl(4hydroxy-3,5-ditertbutylbenzyl)amine ( VII ). The aim of this study is to establish the structure of reaction products and to determine the general reaction scheme and reaction conditions. We have found that, as distinct from reagents II and III , compounds IV – VII show dehydrochlorinating ability toward gemdichloride I . The main reaction product is 4-chloromethylene-2,6-ditertbutylcyclohexadien-2,5-one VIII . The coproducts of the reaction are ethylene chlorohydrin ( IX ), 1-chloro-1-ethoxyethane ( X ), dimethylamine hydrochloride ( XI ), dimethyl(chloromethyl)amine ( XII ), and amine hydrochloride XIII , respectively.

Alkylation of Pyrimidine Derivatives with Ethylene Chlorohydrin.

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The P-N bond cleavage during the phase transfer alkylation of N-alkyldiphenylphosphinic amides

Phase transfer NH alkylation of N alkyldiphenyl phosphinic amides 1 is successful in the presence of an aqueous 50% 1 or solid2 alkali and a phase transfer cata lyst. It is worth noting that the reaction can proceed in the absence of a phase transfer catalyst, as demonstrated ear lier3 for alkylation of P(O)H acids. We synthesized the known4 dialkylamide 2 in high yield from N methylamide 1a in benzene without phase transfer catalyst, using aqueous 50% alkali or the anhydrous heterogeneous system NaOH—K2CO3/CH2Cl2 (Scheme 1). However, attempted alkylation of amide 1a with methyloxirane in aqueous alkali (50% NaOH—CH2Cl2) failed: we re covered the starting reagent only. With systems of stronger basicity, reactions of amide 1a with ethylene chlorohydrin (NaOH—K2CO3/C6H6) and methyloxirane (50% NaOH/DMSO) did not yield the expected N (2 hydroxyalkyl) derivatives; instead, we obtained diphenylphosphinic acid* (3) as a major reaction product (78—90%) arising from cleavage of the P—N bond. Attempted alkylation of N (2 hydroxy ethyl)diphenylphosphinic amide (1b) with methyl iodide (NaOH—K2CO3/DMSO, 35 °C, 5 h) also gave acid 3 in 76% yield.

Alkylation of pyrimidine derivatives with ethylene chlorohydrin

Alkylation of 6-methyluracil, 5-fluorouracil, uracil-5-ammonium sulfate, 5-hydroxyuracil, 5-hydroxy-6-methyluracil, 3,6-dimethyl-5-hydroxyuracil, and 1,3,6-trimethyl-5-hydroxyuracil with ethylene chlorohydrin in water-alcohol medium in the presence of KOH was investigated.

N-Haloalkylation Reaction in the Presence of Trichloroacetic Acid

N-Substituted ureas, thioureas, and related compounds find applications in industry, engineering, agriculture, and medicine, therefore the interest of researchers is still attracted by the synthesis of these substances. We formerly investigated the nucleophilic substitution of a hydroxy group in alkoxyand alkylthio-substituted 1,2-chlorohydrins by weak N-nucleophiles, like urea and thiourea, in the presence of trifluoroacetic acid [1, 2] and in a mixture of sulfuric and acetic acids [3]. From these reactions resulted various alkoxyand alkylthio-substituted carbamides and thiocarbamides. The practical value of N-alkylation reactions used nowadays is limited by the requirement to perform them in the concentrated mineral acids. The processes of this type in the presence of trichloroacetic acid were not described in the literature. It turned out that the piperidine, a stronger base than urea, reacted with ethylene chlorohydrin in the presence of trichloroacetic acid affording in a 65% yield N-(2chloroethyl)piperidine (I).

Determination of ethylene chlorohydrin as marker of spices fumigation with ethylene oxide

Ethylene oxide (EO) is a gas used to sterilize spices, drugs, packaging materials, medical devices, polyester fibers, plastics and synthetic rubber. When the aeration step foreseen for spices is not properly carried out, residues of EO and its derivative ethylene chlorohydrin (ECH), produced by reaction with chlorine ions always present in the matrix, can be found in these products. In this way, the reactivity of EO with chlorides in spices provides a suitable marker to confirm the use of EO for fumigation. The ECH derived from spontaneous transformation during the storage and forcibly obtained during the first step of the extraction can be evaluated in spices by a simple GC/MS analytical method, without derivatization. It has been proven that the EO molecule is carcinogenic for humans; it has been classified as a category 1 carcinogen by the International Agency for Research on Cancer (IARC): ECH, as EO, is a mutagenic substance. This paper shows the results concerning 25 pepper samples purchased on the Italian market. The limit of detection for ECH was assumed to be 20 μg/kg (LOD) and was calculated by spiking a matrix pepper that had not been treated with EO. The limit of quantitation was assumed to be 100 μg/kg (LOQ), i.e. 5 times LOD. The reliability of the method was verified by recovery and repeatability tests. Recovery average values are 60–70% (CV%=9.6–5.5) for the concentration range 100–500 μg/kg. Only 56% of pepper samples analyzed did not contain ECH at detectable levels, and only 24% of pepper samples contained ECH at levels lower than LOQ. Three samples had a content ranging between 0.2 and 3.3 mg/kg and two samples showed a content of ECH higher than 5 mg/kg.

Damage of office supply, personal use items, and over-the-counter medical devices after sterilization by ethylene oxide gas, electron beam, and gamma radiation.

After letters containing Bacillus anthracis spores entered the U.S. mail in 2001, a problem emerged regarding how to decontaminate the letters, packages, and personal items in offices that received these letters. The effects of three sterilization methods (i.e. ethylene oxide gas [EO], electron beam [e-beam] radiation, and gamma radiation) were evaluated for a variety of office supply and equipment, personal use items, and over-the-counter medical devices. No single sterilization method was suitable for all items that could be mailed or found in an office. Damage or discoloration was evident for some items by each sterilization method. There were changes in the color of certain items, such as some of the packaging material, some pacifiers, some of the fabrics, and the nylon stockings after e-beam and gamma radiation. Both e-beam and gamma radiation damaged all film samples. Following EO sterilization and normal aeration, there were a number of samples with high (above 250 microg/g) levels of EO and samples with detectable ethylene chlorohydrin levels. The data would suggest that certain items exposed to EO sterilization must be further aerated prior to use, or discarded. Generic descriptions of products (such as plastics) or grouping of items (such as condoms) were not sufficient to predict what is safe in terms of EO residual levels remaining on an item. Successful decontamination of a wide variety of items will require careful selection of different sterilization methods.

Synthesis of Monochloroacetic Acid from Ethylene Chlorohydrin

The possibility of preparing monochloroacetic acid by oxidation of ethylene chlorohydrin with nitric acid was examined.

Decomposition of ethylene, a flower-senescence hormone, with electrolyzed anode water.

Electrolyzed anode water (EAW) markedly extended the vase life of cut carnation flowers. Therefore, a flower-senescence hormone involving ethylene decomposition by EAW with potassium chloride as an electrolyte was investigated. Ethylene was added externally to EAW, and the reaction between ethylen and the available chlorine in EAW was examined. EAW had a low pH value (2.5), a high concentration of dissolved oxygen, and extremely high redox potential (19.2 mg/l and 1323 mV, respectively) when available chlorine was at a concentration of about 620 microns. The addition of ethylene to EAW led to ethylene decomposition, and an equimolar amount of ethylene chlorohydrine with available chlorine was produced. The ethylene chlorohydrine production was greatly affected by the pH value (pH 2.5, 5.0 and 10.0 were tested), and was faster in an acidic solution. Ethylene chlorohydrine was not produced after ethylene had been added to EAW at pH 2.6 when available chlorine was absent, but was produced after potassium hypochlorite had been added to such EAW. The effect of the pH value of EAW on the vase life of cut carnations was compatible with the decomposition rate of ethylene in EAW of the same pH value. These results suggest that the effect of EAW on the vase life of cut carnations was due to the decomposition of ethylene to ethylene chlorohydrine by chlorine from chlorine compounds.

Some applications of state-of-the-art capillary gas chromatography in the pharmaceutical industry

Some challenging pharmaceutical applications performed with state-of-the-art capillary gas chromatography (CGC) are presented. For assay and purity determinations cool on-column (COC) injection is the preferred injection technique. A fast CGC headspace method is described to determine residual solvents in pharmaceutical products. Ethylene oxide and ethylene chlorohydrin, originating from the sterilisation of packaging materials, were measured in pharmaceutical formulations in a fully automated sequence with excellent retention time and peak-area reproducibility.

Regularities and features of the reaction of 2-amino-6-nitro- and 2,6-diaminobenzothiazoles with ethylene chlorohydrin

The alkylation of 2-amino-6-nitro- and 2,6-diaminobenzothiazoles by ethylene chlorohydrin has been studied. A comparative analysis has been made of the composition of these reaction mixtures and of those obtained from other 2-aminobenzothiazoles using this reaction. The structure of the synthesized compounds was confirmed using IR and 1H NMR spectroscopy, mass spectrometry, and X-ray diffraction and via alternative syntheses.

院内製剤「ＩＶＨ用ヘパロック‐シリンジ注」の開発と評価

The most important aspect of an indwelling inter vascular catheters is to maintain the patency of the catheter. We recently developed a Heparin Lock Flush Solution Kit for use with center vein catheters (only in use at our Hospital). The kit consists of a syringe filled with 9 mL of normal saline (NS) and 1 mL of heparin (1000 IU/mL). We performed the following tests to evaluate the stability, sterility, seal, and dust identification in the preparation. The stability and sterility data indicated that heparin maintained its potency and had no bacterial contamination for 3 months. Testing the seal of the syringe indicated that the seal remained patent at a temperature range of 5°C to 60°C. We also found that even if we sterilized a syringe made of polypropylene using ethylene oxide gas (EOG), no toxins (i.e., ethylene oxide, ethylene chlorohydrin, ethylene glycol) were produced. Next, we examined the preparation time and cost to evaluate the practical benefit of developing the kit. According to our results, the estimated preparation time and cost were 43% and 29% less than for previous methods, respectively. Finally, we put a label on the medicine kit to prevent any misuse by the medical staff.

Assessment of cancer risk from ethylene oxide residues in spices imported into New Zealand

Quantitative estimates of cancer risks from ethylene oxide (ETO) residues were constructed based on 200 retail samples of various spices in New Zealand. Two samples of cinnamon contained detectable ETO. The highest value encountered was 15 ppm. ETO was not detected in the remaining 198 samples. However, 31 samples had detectable levels of ethylene chlorohydrin (ECH) and/or ethylene bromohydrin (EBH). A conservative estimate of ETO intake, based on average spice consumption, was 3.4×10 −6 mg/kg/day. Cancer potency factors for ETO ranging from 0.29 to 0.55 (mg/kg/day) −1 were used to form cancer risk estimates. The resulting estimates of average lifetime excess cancer risk was 0.8×10 −6 to 1.7×10 −6. The US 97.5 percentile value for spice consumption (2.8 kg spices per year), gave an extreme upper-end estimate of lifetime cancer risk of approximately 1.4×10 −5. These risks are practically negligible considering the conservative assumptions used in estimating exposure to ETO. The exposures to ECH and EBH are 200–300-fold higher than to ETO. These compounds are of lesser potency to ETO in terms of mutagenicity or carcinogenicity in studies to date. However, the precise contribution of these compounds to the cancer risk estimate is uncertain due to large toxicological data gaps, including the absence of a 2-year cancer bioassay by the oral route.

An evaluation of the capacity of differently prepared demineralised bone matrices (DBM) and toxic residuals of ethylene oxide (EtOx) to provoke an inflammatory response in vitro

Demineralised bone matrix (DBM) is a form of allogeneic tissue graft widely used in oral and maxillofacial procedures. There is a long history of controversy relating to the suitability of ethylene oxide gas (EtOx) as a terminal sterilisation agent for this graft, relating to its effects on the clinical performance of the grafts. Furthermore, the generation of a toxic residual chemical (ethylene chlorohydrin, ECl) during the ethylene oxide sterilisation of patellar tendon allografts has been implicated in the failure of these grafts owing to the induction of a localised inflammatory response. In this study we have investigated the capacity of a range of different DBM preparations, and ECl dilutions, to induce the production of three pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-1 β (IL-1 β), and tumour necrosis factor alpha (TNF- α) from human peripheral blood mononuclear cells (PBMNCs). The levels of EtOx and ECl in EtOx terminally sterilised DBM and mineralised bone grafts were measured by gas chromatography. It was found that the only factor capable of rendering DBM pro-inflammatory was the presence of small (<20 micrometre diameter) DBM particles. No other processing or sterilisation technique resulted in the DBM becoming pro-inflammatory. Although it was also found that DBM, when EtOx-sterilised, retained more ECl than mineralised bone grafts following a standard EtOx sterilisation protocol, ECl did not provoke an inflammatory response in vitro at levels up to and including those which are cytotoxic to PBMNCs.

Acute ethylene chlorohydrin poisoning: experience of a poison control center.

Ethylene chlorohydrin (CAS 107-07-3), a chemical once used in hastening grape vine sprouting in Taiwan, has caused severe toxicity upon acute exposure. Although such use of ethylene chlorohydrin is now prohibited in Taiwan, poisoning still occurs following its illegal use. Since data concerning human ethylene chlorohydrin poisoning remain rare, we report our experience in treating acute ethylene chlorohydrin-poisoned patients. A retrospective analysis was conducted to evaluate patients with ethylene chlorohydrin poisoning reported to Taiwan Poison Control Center during 1985-1998. Seventeen patients with ethylene chlorohydrin poisoning were identified. There were 11 male and 6 female patients, ranging in age from 2 to 70 years (median 53 years). The intent of exposure was suicide in 5, accident in 9, and occupational exposure in 3 patients. Oral ingestion was the most common route of exposure (14 patients). Seven out of the 17 patients died within 24 hours due to metabolic acidosis and respiratory failure. Ethanol therapy, used in 2 patients, had no apparent benefit. Moderate or mild poisoning was characterized by gastrointestinal effects only and an uneventful recovery. Ethylene chlorohydrin can result in severe metabolic acidosis, respiratory failure, coma, and death after acute exposure.