2 -5-methyl-2 -thio-, preparation

Famotidine. Also known as Pepcid, famotidine [76824-35-6] (AT-(aminosulfonyl)-3-([[2-[(diaminomethylene) amino]-4-thia2olyl] methyl]thio)propariimidamide (2) is a white to pale yellow crystalline compound, freely soluble in glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol. It may be prepared by the method described in Reference 3. 

Fry et al. prepared quaternary salts from 4-methyl- and 4-methyl-thio-quinazoline and found that the same cyanine dyes were obtained by suitable reactions of either salt. An unambiguous synthesis of the 4-methylthio salt (69) from l-methylquinazoline-4-thione (70) proved that both of the salts carried groups on N-1. 

Cotton etal. [14] described an asymmetric synthesis of esomeprazole. Esomeprazole, the (S)-enantiomer of omeprazole, was synthesized via asymmetric oxidation of prochiral sulfide 5-methoxy-2-[[(4-methoxy-3,5-dimethyl pyridin-2-yl)methyl]thio]-lH-benzimidazole 1. The asymmetric oxidation was achieved by titanium-mediated oxidation with cumene hydroperoxide in the presence of (S,S)-diethyl tartarate (DET). The enan-tioselectivity was provided by preparing the titanium complex in the presence of sulfide 1 at an elevated temperature and/or during a prolonged preparation time and by performing the oxidation of sulfide 1 in the presence of amine. An enantioselectivity of 94% ee was obtained using this method. 

An alternate route of preparation for pantoprazole has been reported by Pan Li et al [4], The compound was synthesized by refluxing 5-substituted phenylenediamine (I) with a pyridine derivative (II) in toluene to produce 5-(difluoromethoxy)-2-(((3,4-dimethoxypyridine-2-yl)methyl)thio)-1 /f-benimidazole(III). This reaction is followed by oxidation with m-chloroperbenzoic acid in chloroform to produce pantoprazole. The route of this synthesis is shown in Scheme 2. 

More recently, Wolfrom and Foster found that the d and l enantio-morphs of methyl 3,4-0-isopropylidene-2-0-[(methylthio)thiocarbonyl]-/3-arabinop3Tanoside rearrange, on pyrolysis, to the appropriate 2-methyl-thio)carbonyl] esters. The reductive desulfurization of methyl 3,4-0-isopropylidene-2- S - [(methylthio)carbonylj - 2 - thio -/3 - d - arabinopyranoside (LXVIII) with Raney nickel, to afford a low yield of methyl 2-deoxy-3,4-0-isopropylidene-/3-D-erj/intramolecular rearrangement to LXVIII, and the relationship of the transformation to the Chugaev reaction was discussed. 

Hiinig and Oette prepared azothiadiazoles (85) by oxidative coupling of 3-methyl-l,3,4-thiadiazolin-2(3)-one hydrazones (84) with phenols and diphenylamine. 84 was prepared by reaction of 2-methyl-thio-3-methyl-l,3,4-thiadiazolium ions (82) with benzhydrazide and hydrolysis of the first formed benzhydrazone (83). The coupling to 85 was performed with potassium ferricyanide in alkaline medium. 

This has been prepared by the reaction of the sodium salt of 4-methyl thio-m-cresol (52) with 0,0-dimethylthiophosphoryl chloride in acetone at 50 C [54,55]. 

The first reported solid-phase synthesis of head-to-tail cyclic peptides was based on the intramolecular aminolysis of resin-bound o-nitrophenyl esters. The cyclization proceeds concurrently to cleave the peptide from the resin, after deprotection and neutralization of the AT-terminal residue (Scheme 2A). Accordingly, Fridkin et al. [3] reported the preparation of several simple, unhindered cyclopeptides, such as cyc/o(Ala-Gly-Ala-Ala). Similarly, Flanigan and Marshall [4] obtained activation of the resin-bound peptide ester, after elongation of the peptide chain, by oxidation of the 4-(methyl-thio)phenyl (MTP) linker to a sulfonyl ester. Subsquent deblocking of the A-terminal residue and intramolecular condensation yielded the desired cyclic peptide. However, this method was found not to be suitable for the synthesis of longer and more hindered cyclic peptides [5]. 

It is prepared in two steps. First step being the preparation of 2-(methylthio) phenothiazine by the interaction of 2-chlorophenothiazine with (methyl-thio) sodiiun. The second step involves the condensation of the resulting product with 2-(l-methyl-1-piperidyl) ethyl chloride to obtain the official compound. 

Preparation by reaction of acetyl chloride on 2-(methyl-thio)... 

Preparation by hydrolysis of 3-hydroxy-4-methyl-thio-a-chloroacetophenone chloroacetate with 1 N sodium hydroxide in methanol at r.t. (94%) [4627]. 

Difluorophenyl)methyl]thio -7- [(1 S,2S)-2-hydroxy-l-(hydroxymethyl)propyl] amino thiazolo [4,5 -d]pyrimidin-2(3H)-one 126 (Seheme 56) which are useful for treating a chemokine mediated diseases sueh as asthma, allergic rhinitis, COPD, inflammatory bowel disease, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis, cancer, etc., was prepared in a 7-step process, starting from 4-amino-6-hydroxy-2-mercaptopyrimidine and 2,3-difluorobenzyl bromide [82],... 

Thiazolopyrimidines 144 was prepared, as chemokine receptor modulators, by reacting 3-bromopropanoic acid with 2-amino-5 [(2-fluorophenyl)methyl]thio thiazolo[4,5-d]pyrimidin-7(4H)-one 143 (Scheme 66) in the presence of (iso-Pr)2NEt and Nal in DMF [100],... 

Alkylation in position 3 has a still more pronounced effect. The thiosemi carbazones (101) obtained here were prepared either from 3-methylisothiosemicarbazide hydroiodide or by methylation of thio-semicarbazones. Their cyclization was performed either by boiling in alcohol or by heating to the melting point (102). The presence of... 

D) Preparation of 4-[1 -Methyl-Piperidyl-(4 )]-9,10-Dihydro-4H-Benzol4,5]Cyciohepta[1,2-b] Thiophen-(4)-ol 0.94 g of magnesium filings which have been activated with iodine are covered with a layer of absolute tetrahydrofuran and etched with a few drops of ethylene bromide. A solution of 5.0 g of 1-methyl-4-chloropiperidine in 5 ml of tetrahydrofuran is then added dropwise and boiling then effected for a further hour under reflux. After cooling to room temperature, the solution of 4.5 g of 9,lO-dihydro-4H-benzo[4,5] cyclohepta[1,2-b] thio-phen-(4)-one in 5 ml of tetrahydrofuran is added dropwise. 

Starting from l.l-dichloro-7b-ethoxy-2-methyl-1,1 a,2,7-tetrahydrobenzo[/)]cyclopropa[prepared from the corresponding benzothiopyran by addition of dichlorocarbene, the three 1-benzothiepins 6a-c are formed upon treatment with strong bases, i.e. sodium methoxide or ethoxide in dimethyl sulfoxide.73 The optimal yield of each 1-benzo-thiepin compound depends on the molar equivalents of base, as follows from different ring-opening mechanisms. 

Using azolides, thiazolidindiones can be prepared by condensation of alkoxy-carbamoylimidazoles obtained in situ from O-alkylhydroxylamines and CDI with thio-glycolic acid methyl ester or the imidazolide of thiolactic acid obtained in situ from thiolactic acid and CDI [121]... 

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