Thiomethylation

In a similar way, the a-haloketones gives the corresponding 2-thiomethyl-3-ethylthia2olium salts (722). 

A wide variety of products can be obtained by thioalkylation (42). The reactants ate usually an aldehyde, a thiol, and either a phenol, a sulfone, an amine, or a heterocychc compound. Phenols primarily react with formaldehyde in a process known as thiomethylation (eq. 26). Other types of reactions are depicted in equations 27 and 28. 

For a viable commercial process, the selection of materials and the choice of synthetic route is governed primarily by cost, not by overall yield. The selection of starting material is dictated usually by the desked C-3 substituent. For cephalosporins containing 3-acetoxymethyl or 3-(substituted)methyl such as 3-thiomethyl and 3-aminomethyl derived moieties, the most dkect synthetic route is from cephalosporin C, whereas pencillin V or G is the preferred starting material for the synthesis of the C-3 methyl cephalosporins. The three chemical transformations (2), (5), and 6) can potentially be carried out in a variety of ways, the precise sequence being determined by a balance of competing factors such as cost and optimization of yield (87). 

The early chemistry leading to these derivatives was originally carried out via the 6a-(methylthio) derivative (17) which was prepared by way of a Schiff s base (39). The 6a-thiomethyl group could then be displaced by various nucleophiles giving rise to 6a-methoxy or other 6a-substituted penicillins. A stereo-specific one-step introduction of a methoxy group at C-6 in penicillins provided a simple entry to 6a-methoxy penicillins (40) in yields ranging from 50—62%. 

Alkylidene-2,3-dihydropyridazines (124) are synthesized by coupling of 3-thiomethyl-pyridazinium salts with active methylene compounds in the presence of potassium carbonate in DMF (Scheme 39) (79TL4837). 

Azaquinolizinium iodide, 2-methyl-4-thiomethyl-synthesis, 2, 574 1-Azaquinolizinium perchlorate synthesis, 2, 575... 

Isoquinolin-1 -one, 3-(4-methoxyphenyl)-1,2-dihydro-synthesis, 3, 685 Isoquinolin-l-one, 3-methylthio-synthesis, 2, 403 Isoquinolin-l-one, 3-thiomethyl-syn thesis... 

Purine, l-methyl-2-methylthio-6-thioxo-l,6-dihydro-amination, 5, 560 Purine, 9-methyl-8-phenyl-dipole moments, 5, 521 Purine, 9-methyl-8-phenyl-6-thiomethyl-dipole moments, 5, 521 Purine, 6-methylsulfonyl-synthesis, 5, 597... 

Purine, 2-methylthio-6,8-diphenyl-ring transformations, 3, 308 Purine, 9-methyl-6-thiomethyl-dipole moments, 5, 521... 

Pyridine, 2,6-di(2-pyridyl)thiomethyl-synthesis, 2, 435 Pyridine, 2-ethoxy-iV-oxide... 

Chemical Designations - Synonyms Mercaptomethane Methanethiol Methyl sulfidrate Thiomethyl alcohol Chemical Formula CH3SH. 

In a prostaglandin synthesis, a carbonyl group was protected as an oxime that had its hydroxyl group protected against Collins oxidation by the phenyl-thiomethyl group. The phenylthiomethyl group is readily removed to give an oxime that is then cleaved to the carbonyl compound. ... 

A somewhat more circuitous route is required to prepare sulfonamide-containing pyrimidines unsubstituted at 2. Thus, acylation of the 2-thiomethyl pyrimidine, 147, with the sulfonyl chloride, 88, affords 148. Removal of sulfur by means of Raney nickel (149) followed by deacetylation gives sulformethoxine (113). ... 

Replacement of the terminal nitrogen of the piperazine by carbon is said to enhance the antiemetic activity of the phenothiazines at the expense of the other pharmacologic effects. The simplest compound in this series, pipamazine (88), is prepared by alkylation of nipecotamide (87) with the chloropropyl phenothiazine (58). Preparation of the analogous sulfoxide begins with acetylation of the thiomethyl compound, 89 [prepared by a route... 

The sulfur analogue of the Hauser ortho-substitution rearrangement provides access to an arylacet-ic NSAID. Reaction of the aminobenzophenone 176 with ethyl methylthioacetate and tert-butyl hypochlorite gives the intermediate 178. The reaction probably proceeds by way of formation of the S-chlorinated sulfonium derivative 177 displacement on sulfur will lead to the salt 178. Treatment with triethylamine leads initially to the betaine 179. Electrocyelic rearrangement of that transient intermediate leads, after rearomatization, to the homoanthranilic acid 180. Internal ester-amine interchange leads then to indolone 181 [45]. The thiomethyl group is then removed with Raney niekel. Saponifieation of intermediate 182 affords bromfenac (183) [46J. 

A closely related oxygenated heterocyclic system devoid of acidic groups interestingly shows quite different biological activity. Thus, condensation of the benzofuran hydroxyketone 66 with ethyl thiomethyl acetate (67) probably proceeds initially by formation of the acylation product 68. Intramolecular dehydration leads to formation of a pyran ring. There is thus obtained the hypo-cholesterolemic agent timefurone (69) [14],... 

Chemical Name 7-[D-(-)-0 -(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-a-(4-hydroxyphenyl )acetamidol -3-[(1-methyl-1 H-tetrazol-5-yl)thiomethyl] -3[Pg.266]

D-(-)-a-Amino-p-hydroxyphenylacetamido] -3-[5-(1 -methyl-1,2,3,4-tetrazolyl)-thiomethyl]-A3[Pg.266]

To a suspension of 3.0 g of 7-[D-(-)-a-amino-p-hydroxyphenylacetamido] -3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl] -A3arboxylic acid in 29 ml of water was added 0.95 g of anhydrous potassium carbonate. After the solution was formed, 15 ml of ethyl acetate was added to the solution, and 1.35 g of 4-ethyl-2,3-dioxo-1 -piperazinocarbonyl chloride was added to the resulting solution at 0°C to 5°C over a period of 15 minutes, and then the mixture was reacted at 0°C to 5°C for 30 minutes. After the reaction, an aqueous layer was separated off, 40 ml of ethyl acetate and 10 ml of acetone were added to the aqueous layer, and then the resulting solution was adjusted to a pH of 2.0 by addition of dilute hydrochloric acid. Thereafter, an organic layer was separated off, the organic layer was washed two times with 10 ml of water, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 10 mi of acetone, and 60 ml of 2-propanol was added to the solution to deposit crystals. The deposited crystals were collected by filtration, washed with 2-propanol, and then dried to obtain 3.27 g of 7-[D-(-)-a-(4-ethyl-2,3-dioxo)-1 -piperazinocarbonylamino)-p-hydroxyphenylacetamido] -3-[5-(1 -methyl-1,2,3,4-tetrazolyl)thiomethyl]-A product forms crystals, MP 1BB°C to 190°C (with decomposition). 

Diphenylmethyl 7j3-amino-7a-methoxy-3-(1 -methyltetrazol-B-yD-thiomethyl-l -oxa-dethia-3-cephem-4-carboxylate Aluminum chloride Sodium-2-ethylhexanoate... 

To a stirred suspension of p-(p-methoxvbenzyloxy)-phenylmalonic acid (125 mg) in methylene chloride (3 ml) are added triethylamine (55 All) and oxalyl chloride (26 AH) at -15°C, and the suspension is stirred for 40 minutes at 0°C. The mixture Is added to a solution of diphenylmethyl 7 -amino-7a-methoxy-3-(1 -methyltetrazol-5-yl)thiomethyl-1 -oxadethia-3-cephem-4methylene chloride (3 ml) and pyridine (63 AH), and the mixture is stirred for 30 minutes at 0°C. The reaction mixture is diluted with ethyl acetate, washed with aqueous 2 N-hydrochloric acid and water, dried over sodium sulfate, and concentrated to give crude product (212 mg), which Is chromatographed on silica gel (20 g) and... 

To a solution of 7 (d-p-hydroxyphenyl-0i-carboxyacetamido-7(l-methoxy-3-(1-methyl-tetrazol-5-vl)thiomethyl-1-oxadethia-3-cephem4-carboxylic acid (359 mg) in methanol (7 ml) is added a solution of sodium 2-ethylhexanoate in methanol (2 mols/liter 1.73 ml) at room temperature. After stirring for 10 minutes, the reaction mixture is diluted with ethyl acetate, stirred for 5 minutes, and filtered to collect separated solid, which is washed with ethyl acetate, and dried to give disodium salt of 7 (a-p-hydroxyphenyl-a-carboxyacetamido)-7Q -methoxy-3-(1-methyl-tetrazol-5-vl)thiomethyl-1-oxadethia-3-cephem4-carboxylic acid (342 mg). Yield 885%. Colorless powder. MP decomposition from 170°C. 

C) Preparation of 2-Methyl-3-(2,2,2-Trifluoroethyl)Thiomethyl-6-Chloro-7-Sulfamyl-3,4-Dihydro-1,2,4-Benzothiadiazine-1,1-Dioxide To 4.6 g (0.015 mol) of 4-amino-2-chloro-5-(methylsulfamyl)benzenesulfonamide in 30 ml of the dimethyl ether of ethylene glycol is added 4.08 g (0.02 mol) of 2,2,2-trifluoroethylmercaptoacetaldehyde dimethylacetal followed by 1 ml of ethyl acetate saturated with hydrogen chloride gas. The resulting solution is refluxed for 1.5 hours, cooled and then slowly added to cold water dropwise with stirring. The crude product is filtered, dried and recrystallized from isopropanol (3.2 g), MP 202° to 202.5°C. A second recrystallization from isopropanol raised the MP to 202°... 

A similar Knoevenagel-type condensation takes place between methyl methyl-thiomethyl sulfone and aromatic aldehydes. In this reaction, use of K2C03 (2 mol equiv) as base and refluxing in isopropanol gave the best result178. 

The absorption at 375 nm is assigned to the radical anion. OH radicals were found to give an optically active transient which absorbs at 360 nm and which is assigned by the authors to the radical anion formed by the reaction of OH with the sulfur atom of the thiomethyl bond of MTMSO,... 

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