Isonicotinic acid preparation

Trifluoromethylpyridine can be prepared ia 25—65% yield from nicotinic acid and sulfur tetrafluoride (434,439). An alternative method is the passage of chlorine iato a mixture of ( -picoline and hydrogen fluoride ia an autoclave (190°C, 3 MPa) (440). 4-Trifluoromethylpyridine is prepared ia 57% yield from isonicotinic acid and sulfur tetrafluoride. 

The des-ethyl derivative 251 of Flavopereirine was prepared similarly starting from 2-chloro isonicotinic acid methyl ester 250 (Scheme 81). The resulting hydrochloride was converted into the pseudo-cross-conjugated... 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Fig. 4 Reflectance spectra of the reaction products formed when isonicotinic acid hydrazide (Isoniazid) reacts with lactose. Reflectance spectra are shown for (A) the initially prepared material, and for samples illuminated for (B) 4 hours, (C) 10 hours, (D) 21 hours, and (E) 44 hours. (Data adapted from Ref. 31.)...

The checkers used ethyl isonicotinate purchased from K and K Laboratories, Inc., Jamaica, New York, or prepared by esterification of isonicotinic acid as described by La Forge 4 for nicotinic add. 

Condensation of isoniazid (isonicotinic acid hydrazide) with any a" -3-ketosteroid in acidic medium affords a yellow color conjugate, allowing the determination of 10-40 pg of the steroid [73]. The reagent is prepared by dissolving 0.8 g of isoniazid in 100 mL of methanol containing 1 mL of concentrated HCl, and then 12.5 mL of this solution is further diluted to 100 mL with methanol. To a 2 mL methanolic sample solution of the 3-ketosteroid is added 2 mL of the reagent. The mixture is allowed to stand at room temperature for an hour, and then the absorbance of the resulting colored solution is measured at 380 nm. In a 1 cm spectrophotometer cell, an absorbance of 0.3 will be produced by 42 pg of cortisone, 34 pg of prednisolone, 29 pg of prednisone, or 32.5 pg of dexamethasone [72]. 

Several other complexes with N-donor ligands have been prepared.1065 The complexes CoM(NCS)4(L)6 (M = Zn or Cd L = 2-, 3- or 4-cyanopyridine, nicotinamide, ethyl nicotinate or isonicotinic acid hydrazide) are best formulated as CoL6M(SCN)4. The complexes CoHg(SCN)4L2 (L = 2-, 3- or 4-aminopyridine, 3-cyanopyridine or ethyl nicotinate) possess only bridging SCN ligands, and have the polymeric structure (139). On the other hand, the complexes CoZn(NCS)4L2 (L = 2-, 3- and 4-aminopyridine) contain both bridging and terminal SCN groups, and are postulated to have the dimeric structure (140). 

Isonicotinic acid (128) has been prepared from 4-picoline (19)192,193 or from 4-ethylpyridine (132).194-197 Using 4-ethylpyridine and a Pt anode resulted in higher yields.193 Platinum was slightly better for oxidizing 4-methylpyridine (19) but 132 was oxidized in good yield at a Pb02 anode.192,195 The conclusions reached in each of these separate reports seem to be unclear as to... 

Isonicotinic acid hydrazide compound with 4-aminosalicylic acid may be prepared from the same components by using 750 parts of water by volume as a solvent. 

The height of the anodic wave in alkaline solution corresponds to a four-electron reaction, but a preparative oxidation at pH 11 (phosphate buffer) produced 1,2-diisonicotinoylhydrazine (252) by a two-electron reaction. At pH 13 the oxidation required 2.9 electrons per molecule and about 45% isonicotinic acid and 55% 252 was formed. The reaction has been formulated as Scheme 28. 

In the drug-discovery field, chemists can use NIR to monitor the progress of reactions. Hearn and co-workers reported a NIR method to monitor the preparation of compounds for screening as antituberculosis drugs. The reaction of isonicotinic acid hydrazide (INH) with carbonyl compounds in the preparation of Schiff bases was followed. Forbes, Persinger, and Smith " described a NIR conformance test method to assay and identify two chemical intermediates used in the manufacture of Loracarbef, a carbacephalosporin. 

Isoniazid, U5P. Isonicotinic acid hydru/.ide. isonicoti-nyl hydrazide. or INH (Nydrazid) (K curs as a nearly culoi-less crystalline solid that is very soluble in water. It is prepared by reacting the methyl ester of isonicotinic acid iih hydrazine. 

Anileridine hydrochloride is prepared by the condensation of the ethyl ester of 4-phenylhexahydro-isonicotinic acid carbamate with 4-aminophenethyl chloride and subsequently treating the base with hydrochloric acid. 

An extensive series of derivatives of nicotinaidehyde, isonicotinaidehyde, and substituted isonicotinic acid hydrazide have been prepared and investigated for their tubercuiostatic activity, isoniazid hydrazones were found to possess activity, but these compounds were shown to be unstabie in the gastrointestinai (Gi) tract, reieasing the active isonicotinic acid hydrazide (i.e., iNH). Thus, it wouid appear that their activity resuited from the iNH and not from the derivatives (17,18). Substitution of the hydrazine portion of iNH with aikyi and araikyi substituents resuited in a series of active and inactive derivatives (19,20,21,22). 

All photometric measurements were made witii a Bausch and Lomb Spectronic 2000 instrument. Matched silica cuvettes were used in all measurements and tiie li t path was 10 mm. The pH was measured with a Crison Model 501 pH meter fitted witii a combined glass electrode. The pH meter was standardised against 0.05 M potassium hydrogen phtiialate (pH = 4.01 at 25 °C). Solutions for absorbance and pH measurements were prepared by mixing 2 mL of 2 x 10 M stock solution of isonicotinic acid in water, 2.5 mL of sodium perchlorate and a few drops of sodium hydroxide or perchloric acid at different concentrations. The solutions were then diluted to 25 mL with distilled water. Absorbance was measured against a solvent blank and the pH checked after the absorbance measurements. The temperature was kept at 20 1 °C."... 

Pyridyl)-4ff-l,2,4-triazole-3-thiol [l,2-Dihydro-5-(4-pyridinyl)-3H-l,2y4-triazole-3-thlone] [14910-06-6] M 178.2, m 301-303 (dec), 305-308 (dec), 308-313 , 320-322 (dec), 321-322 (dec), pKes,(d 3.5 (py N), pKj stp) 9 (SH). This thio-l,2,4-triazole was prepared and purified as for the 3-pyridyl-isomer above but by using isonicotinic acid derivatives. It has mild diuretic and natriuretic activity. [Blackman et al. J Chem Soc C 661 1967, Beyerman et al. Rec Trav Chim Pays Bas 73 109 1954, Yale Piala JMeJ Chem 9 42 1966, Yoshida Asai J Pharm Soc Jpn 74 948 1954, Chem Abstr 49 10937 1955, Beilstein 26 IV 2129], 5-(4-Pyridyl)-4H-l,2,4-triazole-3-sulfonic add hydrate was obtained by oxidising the 3-thiol with saturated aqueous KMn04 25° (1 hour), decomposed with EtOH, filtered, precipitated as the Ag salt, filtered off, and decomposed with 5% HCl, then evaporated, and the residue was recrystallised from H2O. It decomposed on heating. [Blackman et al. J Chem Soc C 661 19677 ... 

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