Chloromethyl Ether Research Articles

Determination of Bis(chloromethyl) Ether in Laboratory Air

A quantitative method for the determination of bis(chloromethyl) ether in laboratory air is presented. Preconcentration of air samples on Tenax GC was followed by gas chromatographic-high resolution mass spectrometric analysis with selected ion monitoring of CH 2Cl+ at m/z 48.9844. This is a common fragment ion in the mass spectra of both bis(chloromethyl) ether and the inter nal standard dichloroethane. The method was sensitive to parts per billion levels of bis(chloromethyl) ether in air using a 10-litre sample.

Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA).

A series of phosphonate prodrugs were evaluated in an attempt to increase the oral bioavailability of the anti-HIV agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; 1). The majority of the bis(alkyl ester) and bis(alkyl amide) prodrugs were prepared by alcohol or amine displacement of dichlorophosphonate 2. Basic hydrolysis of the bis(esters) or bis(amides) provided the corresponding monoesters or monoamides. Synthesis of bis[(acyloxy)alkyl] phosphonates 10a-c was accomplished by alkylation of PMEA with the appropriate chloromethyl ether in the presence of N,N'-dicyclohexylmorpholinecarboxamidine. The systemic levels of PMEA following oral administration of a PMEA prodrug to rats were determined by measuring the concentration of PMEA in the urine for 48 h after administration of the prodrug. The oral bioavailability of PMEA employing this method was determined to be 7.8%. Oral dosing with bis(alkyl) phosphonates 3a,b resulted in apparent absorption of the prodrugs (> or = 40%), although neither of the esters were completely cleaved to liberate the parent phosphonate PMEA. The mono(alkyl esters) 7a-e and 8a,b exhibited poor oral bioavailability (< or = 5%). Phosphonamides 5, 6, and 9 were unstable under acidic conditions and provided levels of PMEA comparable to the parent compound after oral administration. Bis[(acyloxy)alkyl] phosphonates 10a-c demonstrated significantly improved oral bioavailabilities of 17.6%, 14.6%, and 15.4%, respectively. When evaluated in vitro against HSV-2, (acyloxy)alkyl phosphonates 10a-c were greater than 200-fold more active than PMEA.

Synthesis of C-6 Pyrimidine Acyclic Nucleoside Analogs as Potential Antiviral Agents

Abstract A number of pyrimidine acyclic nucleosides in which the acyclic moiety is attached to the C-6 position rather than N-1 of the pyrimidine ring have been prepared. This was accomplished via treatment of lithiated 2,4-dimethoxy-5,6-dimethylpyrimidine, or, 2,4-dimethoxy-6-methylpyrirnidine with 1,3-bis-(benzyloxy)-2-propanone, benzyl chloromethyl ether or oxirane, respectively, to give the corresponding key intermediates 6-[3-benzyloxy-2-[(benzyloxy)methyl]-2-hydroxypropyl]-2,4-dimethoxy-5-methylpyrimidine (2a), 6-[3-Denzyloxy-2-[(benzyloxy)methyl]-2-hydroxypropyl]-2,4-dimethoxypyrimidine(2b), 6-(2-benzyloxyethyl)-2,4-dimethoxy-5-methylpyrimidine (3), and2,4-dunethoxy-6-(3-hydroxypropyl)-5-methylpyrimidine (4a). After acidic hydrolysis, followed by debenzylation with boron trichloride these key intermediates were converted to the target C-6 pyrimidine acyclic derivatives. Compounds 6–8b, 11–13, 15, 16, 20, 22, 26, and 29–32 were evaluated for activity against herpes viruses and human immunodeficiency...

Determination of Bis(chloromethyl) Ether in Laboratory Air

Determination of Bis(chloromethyl) Ether in Laboratory Air

Dichloromethane as a source of the CH 22-synthon: A combination of an arene-catalysed lithiation and a barbier-type reaction

The reaction of dichloromethane 1 with an excess of lithium powder (1:7 molar ratio) and a catalytic amount of 4,4′-di- tert-butylbiphenyl (5 mol %) in the presence of a carbonyl compound 2 (1:2 molar ratio) in tetrahydrofuran at −40°C yields, after hydrolysis, the corresponding 1,3-diols 3 in moderate yields. The process can be also applied to more complicated gem-dichloro derivatives such as 7,7-dichlorobicyclo[4.1.0]heptane 6 or methyl dichloromethyl ether 9.

Synthesis of 9-(2-Phosphinomethoxyethyl)adenine and Related Compounds

Alkyl 2-chloroethoxymethyl(diethoxymethyl)phosphinates VII and XIII were prepared by reaction of silyl esters of dialkoxymethylphosphinic acid with 2-chloroethyl chloromethyl ether. Adenine was alkylated with VII and XIII to give [2-(adenin-9-yl)ethoxy]methyl(diethoxymethyl)phosphinates VIII and XIV, bearing the dialkoxymethyl protecting group on the phosphorus atom. Acid hydrolysis of compounds VIII and XIV afforded 9-(2-phosphinoethoxymethyl)adenine (X). Alkyl dialkoxymethylphosphinates V and XI reacted with paraformaldehyde to give hydroxymethylphosphinates XV and XIX which were converted into the synthons XVI, XVII and XVIII capable of introducing a protected hydroxymethylphosphino group on a hydroxy or amino group.

An Improved Synthesis of 2′-Deoxy-9-deazaadenosine and an N-7 Blocked Derivative Useful for the Synthesis of Modified Oligonucleotides Containing 2′-Deoxy-9-deazaadenosine

Abstract As an epimerization resistant synthon in the synthesis of oligo-nucleotides consisting of C-nucleoside analogues, hitherto unknown 5-benzyloxy-methyl-3-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolo[3,2-d]pyrimpyrimidine (7-benzyloxymethyl-2′-deoxy-9-deazaadenosine) was prepared in seven steps from the known 3-amino-2-cyano-4-(2,3-O-isopropylidene-5-O-trityl-β-D-ribofuranosyl)-pyrrolpyrrole (1). Treatment of 1 with benzyl chloromethyl ether in the presence of potassium t-butoxide and 18-crown-6 afforded the N-protected pyrrole 2, which was converted into the 9-deazapurine derivative 3 in high yield by heating in EtOH. 7-Benzyloxymethyl-9-deazaadenosine 4 was obtained from 3 by acid hydrolysis in 2.5% methanolic hydrogen chloride. After protection of the hydroxyl groups of 4 with Markievicz's reagent, the product 5 was converted into the 2′-O-phenoxythiocarbonyl derivative 6. Reduction of 6 with butyltin hydride in the presence of 2,2′-azobis(2-methylpropionitrile), followed by desilylation with triethylammonium fluoride, afforded the desired 7-benzyloxymethyl-2′-deoxy-9-deazaadenosine (8) in high overall yield. The benzyloxymethyl group of 8 was removed by hydrogenolysis over palladium hydroxide (Degussa type) to give 2′-deoxy-9-deazaadenosine (9) in quantitative yield. The structure of 9 is discussed.

Synthesis of 1‐[(3‐Halo‐1‐Hydroxy‐2‐Propoxy)methyl]uracil and Thymine as Potential Antiviral Agents

Abstract3′‐Halogen acyclonucleoside analogs have been prepared. The starting material, benzyl glycidyl ether (5), prepared from eplchlorohydrin and sodium benzyloxidc, underwent ring opening by soft halogen ions to give l‐benzyloxy‐3‐fluoro‐2‐propanol (6), l‐bcnzyloxy‐3‐chloro‐2‐propanol (7), and l‐benzyloxy‐3‐ bromo‐2‐propanol (8) respectively. The treatment of 5 with lithium iodide in the presence of acetic acid provided 1‐benzyloxy‐3‐iodo‐2‐propanol (9). The treatment of 8 with sodium iodide in anhydrous acetone also produced l‐benzyloxy‐3‐iodo‐2‐propanol (9). Chloromethylation of these halohydrins 6‐9 using paraformaldehyde and hydrogen chloride gas produced the chloromcthyl ethers 10‐13. These chloromethyl ethers without further purification were allowed to react with the silylated bases 16‐17, previously prepared by silylating the bases 14‐15 with HMDS in the presence of ammonium sulfate to give 1‐ [(l‐benzyloxy‐3‐halogen‐2‐propoxy)methyl]uracils and thymines 19‐25. The target compounds 26‐33 were obtained respectively after the debcnzylation of 18‐25. Compounds 26, 27, 30 and 31 had no significant cell toxicity in the range of concentrations 0.001‐20 mM. Compounds 26, 27, 28 and 29 have no significant activity against HSV II (for less than 2 mM there is a cytopathic effect). Compounds 30, 31, 32 and 33 show no activity against HSV II virus even at the level 20 mM.

Radical Reduction of C-Cl Bonds in Chlorofluoro Ethers

Reduction of C-Cl bonds in 2,2-dichloro-1,1,2-trifluoroethyl trichloromethyl ether (I), 2-chloro-1,1,2-trifluoroethyl trichloromethyl ether (II), and 2,2-dichloro-1,1,2-trifluoroethyl dichloromethyl ether (III) with 2-propanol, 2-butanol, cyclohexanol, tetrahydrofurane, diethyl ether, and 1,3-dioxolane initiated photochemically and by radiation has been investigated. Beside the main reduction products - 2-chloro-1,1,2-difluoroethyl trichloromethyl ether (IV) and 2-chloro-1,1,2-difluoroethyl chloromethyl ether (V) - it was also possible to prove the formation of 1,2-dichloro-1,2-bis(2-chloro-1,1,2-trifluoroethoxy)ethane (VI), 1-chloro-1,2-bis(2-chloro-1,1,2-trifluoroethoxy)ethane (VII), and 1,2-dichloro-1,2-bis(2-chloro-1,1,2-trifluoroethoxy)ethene (VIII). The structure of products was confirmed by elemental analysis, MS, IR, 1H NMR and 19F NMR spectra and by GLC comparison of the elution times with those of standards. The relative reduction ability of the solvents used in the reduction rate order of C-Cl bonds in the compounds (CCl3 &gt; CFCl2 &gt; CHCl2 and CFClH) are given.

Approaches to chemically modified enzymes as synthetic catalysts

Attempts to introduce new catalytic activities of potential use in synthetic transformations into enzyme active sites are described. Substitution of the naturally occurring zinc in carboxypeptidase A by several metals known to catalyse hydrogenation was investigated; a new protein characterised as a rhodium carboxypeptidase was isolated but it failed to show activity as a hydrogenation catalyst for the reduction of a series of dehydroamino acid amides. Horse liver alcohol dehydrogenase was investigated for its potential to act as an oxygen transferase via Lewis acid catalysis. A series of cyclohexenyl and phenylribosides together with new alkenyl(arenyl)oxymethylenoxyethanols was prepared for evaluation as substrates; in the course of this study, novel neighbouring group participation by the oxygen atom of a chloromethyl ether was observed. Although the binding of potential oxygen acceptors (alkenes and aromatic compounds) and oxygen donors (hydrogen peroxide and alkyl hydroperoxides) was demonstrated, oxygen transfer did not occur with the combinations investigated. In contrast to the failure of the above metalloenzymes to catalyse new reactions, papain modified at the active site sulfhydryl group by thiazolium salts and pyridinium salts was shown to exhibit reactions characteristic of the covalently attached cofactor. Thus the thiazolopapains acted as decarboxylation catalysts for pyruvate and, the pyridinopapains could be reduced to dihydropyridines which reduced electrophilic carbonyl substrates with small enantiomeric excess.

Study Design for Assessing Exposures of Embalmers for a Case-Control Study. Part I. Monitoring Results

Abstract Epidemiologic studies of embalmers and funeral directors have found excess risks of mortality due to leukemia and brain cancer. To investigate specific occupational exposures that might account for these associations, a case-control study of these diseases among embalmers is under way. To quantify exposure levels for this study, a series of embalmings was performed using an experimental design to determine the effect of certain work parameters on the concentration of airborne contaminants. Personal exposures and area concentrations of formaldehyde, methanol, phenol, and particulates were measured during 25 embalmings while controlling the level of ventilation, the concentration of the embalming solution, and the type of case (autopsy or intact body). In addition, bischloromethyl ether (BCME) and selected microorganisms (total, fungi, and bacteria) were measured during a few embalmings. Personal formaldehyde exposures ranged from 0.31 to 8.72 parts per million (ppm) for full-period exposures (51-1...

OCCUPATIONAL LUNG CANCER

The Contribution of Occupational Exposures to Lung Cancer. The overall importance of occupational agents as a cause of lung cancer has been a controversial subject since the 1970s. A federal report, released in the late 1970s, projected a surprisingly high burden of occupational lung cancer; for asbestos and four other agents, from 61,000 to 98,000 cases annually were attributed to these agents alone. Many estimates followed, some much more conservative. For example, Doll and Peto estimated that 15% of lung cancer in men and 5% in women could be attributed to occupational exposures. A number of population-based case-control studies also provide relevant estimates. In a recent literature review, Vineis and Simonato cited attributable risk estimates for occupation and lung cancer that ranged from 4% to 40%; for asbestos alone, the estimates ranged from 1% to 5%. These estimates would be expected to vary across locations and over time. Nevertheless, these recent estimates indicate that occupation remains an important cause of lung cancer. Approaches to Prevention. Prevention of lung cancer mortality among workers exposed to agents or industrial processes that cause lung cancer may involve several strategies, including eliminating or reducing exposures, smoking cessation, screening, and chemo-prevention. For example, changes in industrial processes that have eliminated or reduced exposures to chloromethyl ethers and nickel compounds have provided evidence of reduced risk of lung cancer following these changes. Although occupational exposures are important causes of lung cancer, cigarette smoking is the most important preventable cause of lung cancer. For adults, the work site offers an important location to target smoking cessation efforts. In fact, the work site may be the only place to reach many smokers. As many as 70% of smokers participating in a work site program reported that they would not seek out other programs for smoking cessation. Furthermore, these programs may be as effective as other smoking cessation programs, with abstinence approaching 30%. By creating a supportive social environment, policies restricting smoking in the workplace may also assist smokers trying to quit. Screening of workers at high risk of lung cancer, with periodic chest radiography and sputum cytology, offers potential methods for early detection that may improve prognosis. However, the failure of those procedures to improve outcome from lung cancer among high-risk smokers makes screening of workers of doubtful value. Both epidemiologic and experimental evidence suggest that dietary factors may modify the risk of lung cancer. To date, attention has been focused on vitamin A and carotenoids.(ABSTRACT TRUNCATED AT 400 WORDS)

Some novel homochiral derivatizing agents for the gas chromatographic analysis of enantiomeric secondary alcohols

Some novel homochiral derivatizing agents for the determination of enantiomeric composition of chiral alcohols have been synthesised. The reactions of the reagents with alkan-2-ols and the gas chromatographic behaviour of the resulting diastereoisomeric derivatives have been examined. The most promising reagents are ( S)-(+)-tetrahydro-5-oxo-2-furanmethyl chloromethyl ether, and ( S)-(+)-2-methylcarboxypropyl chloromethyl ether. Despite having five bonds between chiral centres in their diastereoisomeric derivatives, resolution was readily achieved on common, conventional stationary phases.

Quantum chemical calculation of force and electrooptical parameters and steric characteristics of electronic interactions in haloethers

oromethyl ether (VI); R I = CH2CH2CI , R 2 = CH 3 - 2-chloroethyl methyl ether (VII); R I = CH3, R 2 = C6H s - anisole (VIII); R I - CH2CI, R 2 = C6H ~ - phenyl chloromethyl ether (IX); R l = CHCI2, R 2 = C6H ~ pheny! dichloromethyl ether (X); R l = CH3, R 2 = C6HsCH 3 - p-methylanisole (XI); R l = CH2CI, R 2 = C6H~CH 3 - p-tolyl dichloromethyl ether (XII); R l = CHCI 2, R 2 = C~H~CH 3 - p-tolyl dichloromethyl ether (XIII). The calculation was done on theES-1046 computer using the program package in [6, 7]. As the initial values of the bond lengths and bond angles, we took the experimental data obtained by electron diffraction in[8, 9], which were then optimized. The force constants were calculated for the equilibrium geometry of the molecules. The potential function was approximated by a fourth-degree polynomial, and the fourth-order and third-order terms were included only for the bond stretching coordinates. The electrooptical parameters were calculated in terms of the MINDO/3 charge model. For large molecules, a number of coordinates in the alkyl and phenyl fragments were fixed and only the parameters of the ether group were calculated. The values of the force constants and electrooptical parameters calculated by the quantum chemical method were scaled using the factors which were fixed for each bond type; these factors were determined based on experimental data from IR spectra, and were assumed to be invariant in the series of studied molecules and for different conformations of the compounds. The calculation results, together with the "experimental" values of the force constants and the electrooptical parameters, obtained by solving the inverse spectral problem, are presented in Table i. On the whole, we observe good agreement between the experimental and calculated values of the molecular parameters. This is evidence that the force and electric fields we obtained earlier in [4, 5] are correct. Analysis of the calculation results shows that in methyl chloromethyl ether, as a result of the n-o* interaction of the unshared electron pair of the oxygen atom and the antibonding orbital of the C-C1 bond, alternation of the Ci-O and C2-O bond lengths occurs,

Synthesis and thermochemical properties of some fluorine-containing formals

Fluorination of bis(2-fluoro-2,2-dinitroethyl) and bis(2,2,2-trinitroethyl) thionocarbonates by elemental fluorine gave bis(2-fluoro-2,2-dinitroethyl) and bis(2,2,2-trinitroethyl) difluoroformals. The reaction of 2,2,2-trinitroethyl nitrate with 2-fluoro-2,2-dinitroethyl chloromethyl ether gave 2-fluoro-2,2-dinitroethyl 2′,2′,2′-trinitroethyl formal. The standard heats of combustion and formation of the synthesized formals were determined by combustion in a calorimetric bomb. Increments of substitution of the trinitromethyl group by the fluorodinitromethyl group and of the H atom by F in the methylene group for formals were calculated and recommended for rough calculations. It was shown that it is possible to evaluate ΔHf0 of the formals by the method of increments and group contributions.

Trinitroethyl ethers of substituted alcohols

The influence of the trinitromethane salt cations and the substituents in the alkyl moiety of chloromethyl ethers of alcohols on the yields of trinitroethyl ethers of the substituted alcohols formed from them was established. On this basis a representative series of previously unavailable trinitroethanol ethers was synthesized.

Angular hydroxymethylation of functionalized decalin systems

Functionalized β-dicarbonyl bicyclic compounds were hydroxymethylated at the angular position as the (benzyloxy) methoxy derivatives with diisopropylethylamine (DIPEA) and benzyl chloromethyl ether in the presence of paraformaldehyde

日本における労働衛生の発展

This paper was presented as a Lucas Lecture 1990 before the Faculty of Occupational Medicine, Royal College of Physicians, United Kingdom. It describes the development of occupational health in Japan including primitive industrialization (mining, smelting and others) back as far as the 8th century. The modern industrialization of Japan began slightly over one hundred years ago, i.e. from the beginning to the middle of the Meiji era. Before World War II, Japanese workers in industry suffered terrible working conditions, represented by a booklet published in 1925 entitled "The Tragic History of Female Workers" by Wakizo Hosoi. At that time a pioneer named Dr. Gito Teruoka was hard at work. He literally became the "Father of Occupational Health" in Japan. He established the Kurashiki Institute of Science of Labour in 1921 in Kurashiki City located in western Honshu, which is the main island of Japan. At the beginning of the Showa era, from 1930 to 1950, various types of occupational diseases were reported and the situation was overviewed by Dr. Juko Kubota. The rapid industrialization immediately after World War II during which workers were exposed to chromium, benzidine, beta 2-naphthylamine, arsenic, vinyl chloride monomer, asbestos, bischloromethyl ether and other chemicals gave rise to occupational cancer. The Ministry of Labour (MOL) was established in 1947 and the Labour Standard Law enacted. As a result, the incidence of tuberculosis decreased rapidly and occupational health emphasized the early detection of tuberculosis. After tuberculosis was nearly eradicated, more complicated working conditions developed in various industries. MOL enacted the Industrial Safety and Health Law in 1972 and occupational health practices improved greatly. Furthermore, in 1988 MOL amended the Law and announced guidelines on maintenance and promotion of health for the work population. However, there is a great disparity in occupational health services between large establishments and small factories. The University of Occupational and Environmental Health, Japan, (UOEH) was established in 1978 to promote occupational health sciences as well as to train and foster occupational health personnel to meet the short supply of occupational health physicians. However, there is no authority that establishes standards for occupational health physicians and nurses. The urgent necessity of establishing an authorized institution for the qualification of occupational health personnel is emphasized.

Reactions of carbonyl compounds with benzyl chloromethyl ether of diiodomethane in the presence of samarium(II) iodide or metallic samarium. New routes to 1,2-diols, iodohydrins and cyclopropanols

Carbonyl compounds react with benzyl chloromethyl ether in the presence of samarium(II) iodide to afford the corresponding addition products which, when subsequently hydrogenolysed, yield 1,2diols. Simple aldehydes and ketones react with diiodomethane in the presence of samarium metal to give iodohydrins in good yields. Under similar reaction conditions, α-halogeno substituted ketones and aromatic 1,4-diketones are converted into cyclopropanols. These cyclopropanations have been shown to proceed through the initial generation of samarium enolates, followed by the Simmons Smith type reaction. A novel transformation of esters to cyclopropanols via tandem one-carbon homologation is also described.

Photoelectron spectra and structure of phenyl chloromethyl ethers

Photoelectron spectra and structure of phenyl chloromethyl ethers