Dimethylcarbamyl Chloride Research Articles

A Continuous Flow Process for LSN647712 via Double Organometallic Additions to Dimethylcarbamyl Chloride.

The ketone intermediate LSN647712 is a key synthetic intermediate for the drug substance lasmiditan manufacturing process. A three-step connected continuous flow process utilizing a Turbo Grignard reagent, N-methylpiperidin-4-ylmagnesium chloride, and lithiated 2,6-dibromopyridine sequentially added to double electrophile (O═C(++) synthon dimethylcarbamyl chloride (DMCC) was developed to deliver the ketone intermediate in a high chemical yield (>85%). This highly productive (>100 g/h lab system) and intensified process (τ ∼ 3 min) yields the product in high purity upon batch reactive crystallization to form a corresponding hydrobromide salt. In addition to the connected plug flow reactor system, the Grignard reagent, N-methylpiperidin-4-ylmagnesium chloride, was also prepared continuously in CSTR as a more soluble LiCl adduct in THF (Turbo Grignard).

Converting Thiophene in Simulated Coking Crude Benzene to N, N-Dimethyl-2-thiophenecarboxamide by Dimethylcarbamyl Chloride Under Mild Conditions

Since the content of thiophene in coking crude benzene is high, it is necessary to remove it from coking crude benzene for efficient utilization. In this study, an important intermediate, N, N-dimethyl-2-thiophenecar-boxamide, was synthesized from thiophene and dimethylcarbamyl chloride. The influences of the dosages of dimethylcarbamyl chloride and ZnCl2 catalyst, reaction temperature and time on the removal rate were further explored based on the reaction kinetics. The structure of the target product was characterized by means of MS, 1H NMR and 13C NMR. The removal rate of thiophene was 98.14% after the reaction for 2 h and thiophene was almost removed after the reaction for 3 h under the optimal reaction conditions[a molar ratio of n(thiophene): n(dimethylcarbamyl chloride):n(ZnCl2)=1:12:10, 300 r/min, 318 K and 101.325 kPa]. The acylation of thiophene with dimethylcarbamyl chloride was approximately in accord with the first order kinetic equation at 303–323 K. The activation energy was 53.9850 kJ/mol and the pre-exponential factor was 1.4521×109 h−1.

Synthesis and anti-arthritic activity of a series of 1-aryl-3-dimethylamino-1,4-dihydroisoquinolines

1-Aryl-3-dimethylamino-1,4-dihydroisoquinoline ( 1) were synthesised from 1-aryl-1,4-dihydroisoquinol-3-ones ( 2) by heating in dimethylcarbamyl chloride. Compounds bearing electron withdrawing substituents on the 1-aryl ring were active in inhibiting polyarthritis in the rat adjuvant arthritis model, when administered orally. Several compounds were also potent inhibitors of inflammatory cell accumulation. The most potent compound of the series, overall, was the 3′-chloro analogue, 10.

Preparation of pyridostigmine bromide labeled with carbon‐14 and tritium1

Abstract[2‐14C]Pyridostigmine bromide was prepared in 17.6% radiochemical yield with specific activity of 18 mCi/mmol. The reaction sequence involved preparation of 2‐furan[14C]carboxylic acid by carbonation of 2‐lithiofuran, followed by conversion to 2‐amino[14C]methyl furan by lithium aluminum hydride reduction of its carboxamide. Oxidative rearrangement of 2‐amino[14C]methylfuran gave 3‐hydroxy[2‐14C]pyridine which was converted to [2‐14C]pyridostigmine bromide by reaction with dimethylcarbamyl chloride and quarternization with bromomethane. Pyridostigmine bromide labeled in the methyl group of the carbamate function was prepared in 73% yield with specific activity of 37.6 mCi/mmol by reaction of bis‐3‐pyridyl carbonate with [14C]dimethylamine followed by quarternization with bromomethane. [6‐3H]‐Pyridostigmine bromide with specific activity of 22.5 mCi/mmol was prepared by catalytic halogen‐tritium replacement of 2,6‐dibromo‐3‐dimethylcarbamyloxypyridine followed by quarternization with bromomethane and back‐exchanging the labile 2‐tritium.

Oncogene activation in experimental carcinogenesis: the role of carcinogen and tissue specificity.

Techniques of molecular biology have been used to determine the relationship of cellular oncogenes to mechanisms of experimental carcinogenesis. Model systems involving three direct-acting alkylating carcinogens, two organ sites, and two species have been employed to elucidate the relationships between carcinogenic etiology, tissue specificity, and activation of known and novel oncogenes. Dimethylcarbamyl chloride, a reactive acylating agent, induces tumors of both the rat nasal mucosa and mouse skin whose DNA is devoid of NIH 3T3 transforming activity. Beta-propiolactone-induced rat nasal carcinomas contain a novel oncogene, 6 to 9 kb in size, whereas a mouse skin carcinoma induced by this agent possesses an H-ras oncogene activated by a 61st codon A to T transversion mutation. The novel oncogene activated in rat nasal tumors induced by beta-propiolactone is distinct from one found in methylmethane sulfonate-induced tumors. The implications of these findings for understanding how oncogenes fit into general mechanism of carcinogenesis are discussed.

Commentary: Oncogene Activation in Experimental Carcinogenesis: The Role of Carcinogen and Tissue Specificity

Techniques of molecular biology have been used to determine the relationship of cellular oncogenes to mechanisms of experimental carcinogenesis. Model systems involving three direct-acting alkylating carcino? gens, two organ sites, and two species have been employed to elucidate the relationships between carcinogenic etiology, tissue specificity, and activation of known and novel oncogenes. Dimethylcarbamyl chloride, a reactive acylating agent, induces tumors of both the rat nasal mucosa and mouse skin whose DNA is devoid of NIH 3T3 transforming activity. /J-propiolaetone-induced rat nasal carcinomas contain a novel oncogene, 6 to 9 kb in size, whereas a mouse skin carcinoma induced by this agent possesses an H-ras oncogene acti? vated by a 61st codon A to T transversion mutation. The novel oncogene activated in rat nasal tumors in? duced by p-propiolactone is distinct from one found in methylmethane sulfonate-induced tumors. The implications of these findings for understanding how oncogenes fit into general mechanism of carcinogenesis are discussed.

Detection of novel non-ras oncogenes in rat nasal squamous cell carcinomas.

Rat nasal squamous cell carcinomas induced by inhalation of three direct-acting alkylating agents yielded DNA containing activated oncogenes with no homology to any member of the ras family. The novel NIH 3T3 transforming oncogenes from tumors induced by beta-propiolactone and methylmethane sulfonate are distinct from each other based on restriction analysis. The gene isolated from beta-propiolactone-induced tumors is between 6 and 9 kb in size. None of the tumors induced by dimethylcarbamyl chloride contained positive DNA in the NIH 3T3 focus assay or in the nude mouse cotransfection assay. The rat nasal tumor model is apparently ideally suited for analysis of the roles of carcinogen and tissue specificity in oncogene activation, especially related to novel (non-ras) transforming oncogenes.

Carcinogenicity of Acylating Agents: Chronic Bioassays in Mice and Structure-Activity Relationships (SARC)

A small number of acylating agents are known to be carcinogenic. The structure-activity relationships and carcinogenicity (SARC) of these compounds are reviewed in this report. In addition, the results of chronic bioassays of three previously untested compounds are described. Female ICR/Ha Swiss mice, 30–50 per group, were used in all tests. The test duration was 18–22 months. Diethylcarbamyl chloride (DECC), ethyl chloroformate (ECF), and dichloroacetyl chloride (DCAC) were tested by repeated skin application, in two-stage carcinogenesis with phorbol myristate acetate (PMA) as promoter, and by repeated subcutaneous injection. Dimethylcarbamyl chloride was used as a positive control together with control groups. All three compounds showed marginally significant incidences of papillomas and carcinomas when tested as initiators. ECF and DCAC did not show skin tumorigenicity in the repeated skin application tests. DECC showed weak carcinogenicity compared to DMCC. Subcutaneous injection resulted in the same pattern of tumorigenicity. Thus, the four acylating agents showed the following decreasing order of carcinogenicity: DMCC > DECC > ECF ≅ DCAC. All four compounds hydrolyze rapidly in water, with the following decreasing order of rate of hydrolysis: DCAC > DMCC ECF ≅ DECC. Their mechanisms of hydrolysis are: DMCC, DECC, and DCAC, SN1; ECF, SN2. There is no clear correlation between rate or mechanism of hydrolysis and carcinogenicity of these acylating agents.

Relationships between the levels of binding to DNA and the carcinogenic potencies in rat nasal mucosa for three alkylating agents

Three direct-acting carcinogens, beta-propiolactone (BPL), methylmethane sulfonate (MMS), and dimethylcarbamyl chloride (DMCC), were evaluated for their carcinogenic potencies in the nasal mucosa of rats and for their abilities to bind in vivo to rat nasal mucosal DNA. The relative carcinogenic potencies of BPL and MMS corresponded well with their overall levels of binding to nasal mucosal DNA. DMCC, however, the most potent carcinogen of the three compounds, produced the lowest level of binding to nasal mucosal DNA. These results indicate that the DNA adducts formed by DMCC in rat nasal mucosa DNA are more readily expressed as cancer than those formed by BPL or MMS.

Carcinogenicity study with sodium dichromate in rats

Solutions of sodium dichromate were administered to Sprague Dawley rats by intratracheal instillations over a period of 30 months. Dosage was 0.01, 0.05 or 0.25 mg/kg, five times a week, or 0.05, 0.25 or 1.25 mg/kg once a week. Each group consisted of 40 male and 40 female rats. Groups left untreated or given saline served as negative controls. The highest chromate dose proved to be within the range of the maximum tolerable amount. The main determinant of effect was the concentration of chromate instilled, not the total dose per week. Non-neoplastic pulmonary lesions, which occurred predominantly in the highest dose group, were fibrotic regions containing residual distorted bronchiolar lumens or cellular inflammatory foci containing alveolar macrophages, proliferated epithelium and chronic inflammatory thickening of alveolar septa. Fourteen rats given 1.25 mg/kg sodium dichromate had a total of 20 lung tumours (12 benign, 8 malignant). One rat given 0.25 mg/kg once a week had a malignant tumour. Tumours were generally small and were non-fatal. A comparable solution of calcium chromate, which was tested at the two highest dose levels, had virtually the same effect. The positive controls, benzo(a)pyrene and dimethylcarbamyl chloride, induced a high rate of fatal malignant tumours in the respiratory tract.

Chemical mutagenesis testing in Drosophila. IV. Results of 45 coded compounds tested for the National Toxicology Program.

Results from Drosophila mutagenicity tests of 45 chemical compounds assayed for the National Toxicology Program are presented. Nine compounds were judged positive and four equivocal in the sex-linked recessive lethal test. The nine positive compounds were acetin, allyl glycidyl ether, cyclophosphamide, 1,2-dibromo-3-chloropropane, 2,3-dibromo-1-propanol, dimethylcarbamyl chloride, 1,2-epoxy-butane, lasiocarpine, and N-nitrosopiperidine. The results for chloral hydrate, maleic hydrazide, propantheline bromide, and trifluralin were equivocal. Of the nine compounds positive in recessive lethal induction, only two--allyl glycidyl ether and dimethylcarbamyl chloride--failed to induce translocations. The remaining 32 were judged to be nonmutagenic under the conditions used.

Carcinogen specificity in the activation of transforming genes by direct-acting alkylating agents.

DNAs from rat nasal and mouse skin carcinomas and fibrosarcomas induced by the alkylating agents methylmethane sulfonate (MMS), beta-propiolactone (BPL), and dimethylcarbamyl chloride (DMCC) were tested for their ability to transform NIH3T3 cells by DNA transfection. Each of eight MMS-induced rat nasal carcinomas and two of five BPL-induced mouse skin tumors were positive in the transfection assay while all of four fibrosarcomas and six carcinomas induced by DMCC were negative. Anchorage independent growth, tumorigenicity in nude mice, and secondary transfection confirmed the transformed phenotype of the positive transfectants. The transfectants from MMS-induced tumor DNAs did not contain restriction fragments homologous to rat H-, K- or N-ras oncogenes although exogenous (rat) tumor-derived DNA sequences were detected in transfectant genomes by Southern analysis. In contrast a BPL-induced mouse skin tumor showed evidence of containing activated H-ras. These results suggest specificity among causal chemical carcinogens for activation of transforming genes in experimental tumors.

Formation of 6-dimethylcarbamyloxy-dGuo, 6-dimethylamino-dGuo and 4-dimethylamino-dThd following in vitro reaction of dimethylcarbamyl chloride with calf thymus DNA and 6-diethylcarbamyloxy-dGuo following in vitro reaction of diethylcarbamyl chloride with calf thymus DNA

The rodent carcinogens dimethylcarbamyl chloride (DMCC) and diethylcarbamyl chloride (DECC) react with dGuo (pH 7.0–7.5, 37°C, 4 h) to form the O 6-acyl derivatives 6-dimethylcarbamyloxy-2′-deoxyguanosine (6-DMC-dGuo) and 6-diethylcarbamyloxy-2′-deoxyguanosine (6-DEC-dGuo), respectively. Reaction of DMCC with dThd under identical conditions yielded 4-dimethylamino-thymidine (4-DMA-dThd). Compounds 6-DMC-dGuo and 6-DEC-dGuo undergo a nucleophilic aromatic substitution reaction with dimethylamine (DMA) to form 6-dimethylamino-2′-deoxyguanosine (6-DMA-dGuo) via displacement of the C-6 dialkylcarbamyloxy moiety. The substitution reaction did not take place when diethylamine or NH 3 were substituted for DMA. The structures of the new compounds 6-DMC-dGuo, 6-DEC-dGuo, 4-DMA-dThd and 6-DMA-dGuo were deduced from chemical analyses and syntheses, UV and nuclear magnetic resonance (NMR) spectra and electron impact, isobutane chemical ionization and source insertion isobutane chemical ionization mass spectra. It was postulated that 4-DMA-dThd was formed following reaction of the transient intermediate 4-DMC-dThd with DMA formed by hydrolysis of DMCC. Calf thymus DNA was reacted in vitro with DMCC (pH 7.0–7.5, 37°C, 4 h) and the modified DNA hydrolyzed enzymatically to 2′-deoxynucleosides. Compounds 6-DMC-dGuo, 4-DMA-dThd and 6-DMA-dGuo were identified in the hydrolysate by high-pressure liquid chromatography (HPLC). In an indentical manner 6-DEC-dGuo was identified following in vitro reaction of DECC with calf thymus DNA. Compounds 6-DEC-dGuo and 6-DMC-dGuo possess novel structures with respect to the types of adducts known to be formed between carcinogens and bases in DNA. The implications of these findings with respect to chemical mutagenesis and carcinogenesis is discussed. The structural relationship between N 4-dimethyl-5-methylcytosine (4-dimethylamino-Thy) formed in DNA following in vitro reaction with DMCC and 5-methylcytosine, the only modified base found in vertebrate DNA is noted.

Carcinogenic activity of alkylating agents.

Administered by 1 or more routes into female ICR/Ha Swiss mice, 17 direct-acting alkylating agents and related compounds were tested for carcinogenic activity. The routes of administration were skin, 2-stage tumorigenesis on skin, subcutaneous (sc) injection, and intraperitoneal (ip) injection. Dimethylcarbamyl chloride, a potent carcinogen to skin, induced a high incidence of sarcom3S at the injection site after sc or ip injection. Four of the other 15 compounds (ethyl bromoacetate, 2,3- dichloro-p-dioxane, glycol sulfate, and diethy-β,γ-epoxypropylphosphonate) tested through sc injection induced significant incidences (P< 0.01) of sarcomas at the injection site. Whereas sarcomas were induced by most compounds tested by sc injection, only 2 of these, dimethylcarbamyl chloride and 1,2,4,5,9,10-triepoxydecane, also induced carcinomas upon application to skin.

New compounds: N,N-Dimethyl-[3-(1-alkylpiperidyl)]carbamates, Potential Cholinesterase Inhibitors

The synthesis of 10 piperidine carbamates was carried out by condensation of various 3-hydroxypiperidines with dimethyl-carbamyl chloride or, alternatively, by treatment of the hydroxy compound with phosgene followed by dimethylamine. Changes were made in the length of the alkyl chain substituted on the heterocyclic nitrogen. The compounds were developed as potential cholinesterase inhibitors as a continuation of previous studies.

Dipole moments of some molecules in dilute benzene solutions

The dipole moments of bromochloromethane, bromodichloromethane, bromotrichloromethane, dimethylcarbamyl chloride, dimethylcarbamyl fluoride, vinyl formate, phenyl chlorothiolformate, γ-valerolactone, and 2-iodopropene were determined in dilute benzene solutions at 25 °C. The observed magnitudes of the dipole moments are rationalized in terms of molecular electronic charge distributions.

Kinetics of the hydrolysis of acyl chlorides in pure water

The activation parameters ΔH≠, ΔS≠, and ΔCP≠ for the hydrolyses of a series of alkyl chloroformates and dimethylcarbamyl chloride in water have been determined. The results indicate that, with increasing electron donation to the chlorocarbonyl group, the mechanism changes from bimolecular to unimolecular (SN1) displacement at this position. For isopropyl chloroformate, some concurrent alkyl–oxygen bond fission is also indicated. The bimolecular mechanism involves reversible addition of water to the carbonyl group followed by ionization of the carbon–chlorine bond.

New Compounds. The Acylation of Biphenyl and Dimethylcarbamyl Chloride

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNew Compounds. The Acylation of Biphenyl and Dimethylcarbamyl ChlorideJ Saunders, R Slocombe, and Edgar HardyCite this: J. Am. Chem. Soc. 1950, 72, 7, 3312Publication Date (Print):July 1, 1950Publication History Published online1 May 2002Published inissue 1 July 1950https://doi.org/10.1021/ja01163a135RIGHTS & PERMISSIONSArticle Views95Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (150 KB) Get e-Alerts Get e-Alerts