Pyridines, chloro-, synthesis from

All carotenoid sulphates have been prepared by partial synthesis from the corresponding carotenols by reaction with a sulphur trioxide/pyridine complex prepared from chloro-sulphonic acid and pyridine [8-10], followed by sodium salt formation by addition of NaOH or, for alkali-labile carotenoids, NaCl [11], Scheme 1. The presumed mechanism is that S-0... 

A third synthesis which has resulted in the preparation of rieinine and a number of its derivatives is due to Schroeter, Seidler, Sulzbacher and Kanitz,i2 who foimd that cyanoacetyl chloride polymerises spontaneously to 6-chloro-2 4-dihydroxy-3-cyano-pyridine. The di-sodium derivative of this with methyl sulphate produces A -methyl-6-chloro-4-hydroxy-3-cyano-2-pyridone (6-chlororicininic acid), the mono-sodium derivative of which, with methyl bromide or sulphate, is converted into 6-chlororicinine and the latter is reduced by zinc and sulphuric acid to rieinine. A fourth synthesis, starting from 3-nitro-4-pyridone, is due to Reitmann. ... 

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

Reaction of pyridines with dialkyl acetylenedicarboxylates in the presence of isocyanates in dry CH2C12 at room temperature produced 1-substituted 2-oxo-l,9a-dihydro-2/7-pyrido[l,2-tf]pyrimidine-3,4-dicarboxylates <2004TL1803>. One-pot, three-component synthesis of 1-substituted 2-oxo-l,llb-dihydro-2//-pyrimido[2,l- ]iso-quinoline-3,4-dicarboxylates and 4-(3-chloro-4-methylphenyl)-3-oxo-4,4a-dihydro-3/7-pyrimido[l,2-tf]quinoline-l,2-dicarboxylate was realized by the reaction of isoquinoline and quinoline with isocyanates and dialkyl acetylenedicarboxylates <2004S861>. Diastereomeric mixtures of l-tosyl-2-aryl-l,llb-dihydro-2/7-pyrimido[2,Ttf]isoquinoline-3,4-dicarboxylates were obtained from isoquinoline, iV-tosyl-benzaldehyde imines, and DMAD <2002OL3575>. 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

Since bromo(pyridine)cobaloxime(III) was not commerically available and its synthesis was not convenient36, we utilized chloro(pyridine)bis(dimethylglyoximato)-cobalt(III) (Equation 3) (also known as chloro(pyridine)cobaloxime (III)) instead. It has four cathodic waves in polarography when observed in acetonitrile. Its half wave potentials are located at -0.65, -1.45, -2.42, and -2.92 volts vs the Ag/AgNC>3 electrode, corresponding to the reduction of the cobalt from +3 to +2, +1, and 0, and the reduction of the ligand, respectively. 

Thorpe-Ziegler synthesis of 3-aminoindoles with additional functional groups was used as part of the synthesis of condensed indoles [e.g., azepines (94) were obtained from 3-amino-2-benzoylindoles (93) (91JHC379) (Scheme 24)]. In these cases the nature of the substituent R is important for a smooth reaction (Ac < Bz < 2-N02-benzoyl, but no reaction when R = H). With 2-chloro-3-(/V-bromoacetyl-/V-methylamino)pyridine and o-benzoylaminobenzonitriles (95), the condensed pyridodiazepinones 97 and 99 (95H753) were obtained via intermediates 96 and 3-aminoindoles intermediate (via 98) 3-aminoindoles followed by substitution of the 2-chloro substituent by the resulting 3-amino group (Scheme 25). 

As previously mentioned, the methyl group of 2-(p-tolyl)-s-triazolo-[l,5-a]pyridine is inert under the conditions of the Anil Synthesis. However, introduction of a chlorine atom in ortho position to this methyl group enables reaction to be carried out at 20°-30°C (Section II,E,3). Thus, for example, from 2-(3-chloro-4-methylphenyl)-j-triazolo[l,5-a]pyridine (19) and Schiff s base 171, the stilbene 172 is formed. In the case of 2-phenyl-7-methyl-j-triazolo[l,5-a]pyridine (173), however, reaction with 171 gives the styryl derivative 174, without additional activation of the methyl group.19... 

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