Hydroxy acids Zinc chloride

A mixture of 4.5 g. of 1-hydroxy-2-propanone, 80 ml. of ethyl acetoacetate, 60 ml of 96% ethyl alcohol, and 4 g. of anhydrous zinc chloride is heated under reflux on a steam bath for half an hour. After cooling, it is poured into water and extracted with benzene. The extract is washed successively with a bisulfite solution (twice), dilute aqueous sodium hydroxide, and dilute hydrochloric acid, and is dried over anhydrous sodium sulfate. The benzene is evaporated, giving 4 g. of an almost colorless oil which is saponified by heating with 5 g. of sodium hydroxide in 20 ml. of 96% alcohol for half an hour on a steam bath. Part of the alcohol is evaporated, water is added, and the solution is extracted twice with ether. The aqueous layer is acidified (to Congo Red) with hydrochloric acid (1 1). The resulting solid is removed by filtration and recrystallized from 180 ml. of water yield, about 3 g. It may be purified by steam distillation, affording colorless crystals m. p., 120-122°. 

A mixture of 5 g. of anhydrous zinc chloride (Note 1) and 280 g. (2.00 moles) of 3-hydroxy-2,2,4-trimethyl-3-pentenoic acid /9-lac-tone 2 is placed in a 500-ml. three-necked flask equipped with a sealed stirrer (Note 2), a coarse fritted-glass gas-dispersion thimble, a thermometer immersed in the liquid, and an air-cooled reflux condenser (Note 3). The outlet of the condenser is connected to a bubble counter filled with concentrated sulfuric acid this in turn is vented to the atmosphere through a water scrubber. The flask is immersed in an ice bath, and stirring is started. When the temperature of the mixture is about 10°, anhydrous hydrogen chloride is introduced through the gas-dispersion tube... 

The reaction of 1,3-dihydroxynaphthalene with 3,3-dimethylacrylic acid in the presence of phosphorus oxychloride and zinc chloride yields only 9-hydroxy-2,2-dimethyl-benzo[/]chroman-4-one (585). 2,7-Dihydroxynaphthalene similarly yields the angular ben-zochromanone (586) rather than the alternative linear product (79RRC59). 

An autoclave (Note 1) is charged successively with 600 cc. ( >.5 moles) of approximately 28 per cent aqueous ammonia, 78 g of zinc chloride (0.57 mole) (Notes 2 and 3), and 167 g. of 3-hydroxy-2-naphthoic acid (0.89 mole) (Note 4). The autoclave is dosed, and then, with continuous stirring or shaking (Note 5), il is gradually heated, so that, at the end of three hours, the temperature is 195°. This temperature is maintained for thirty-six hours the pressure is about 400 lb. (Note 6). The autoclave is allowed to cool to room temperature, with continuous stirring or shaking. The cover is removed, the solid is scraped off the walls, and the reaction mixture is transferred to a 5-1. flask. The autoclave is rinsed with two 700-cc. portions of water, which are added to the reaction mixture. 

Sometimes, replacement can be effected by heating with ammonia under pressure in the presence of zinc chloride, e.g., 3 amino-2-naphthoic acid from 3-hydroxy-2-naphthoic acid (70%). ... 

Removal of an AT-oxide function utilizes the usual reagents such as zinc and acetic or hydrochloric acids, sodium borohydride, hydriodic acid, phosphoryl chloride, sodium dithionite, phosphorus trichloride or hydrogenation over Raney nickel. When l-hydroxy-2-methyl-5-phenylimidazole (262) reacts with butyllithium and hexachlofodisilane this also induces dehydroxylation (Scheme 152) (80AHC(27)24l). At times, as with other heterocyclic AT-oxides, deoxygenation with phosphorus halides can introduce a halogen atom at C-2 of imidazole (75JCS(P1)275). 

As mentioned earlier, meso-inositol, and indeed all the inositols, are readily converted to aromatic compounds by oxidation. Posternak found that inosose has the tendency to form phenolic compounds under very mild conditions. On attempted acetylation of inosose with acetic anhydride in the presence of either pyridine or sodium acetate the expected pentaacetate was not obtained the product was 1,2,3,5-tetra-acetoxybenzene (XXXVII). Similarly, the treatment of inosose pentaacetate with boiling acetic anhydride and pyridine or sodium acetate gave the same product. Inosose pentabenzoate was prepared by the use of benzoyl chloride and zinc chloride. Under the influence of pyridine or sodium acetate in acetic acid the pentabenzoate lost two molecules of benzoic acid to give l-hydroxy-2,3,5-tribenzoxybenzene (XXXVIII). 

Amination. For the conversion of 2-hydroxy-3-naphthoic acid into 3-amino-2-naphthoic acid, an autoclave is charged successively with aqueous ammonia, zinc chloride, and 2-hydroxy-3-naphthoic acid, and closed. With constant agitation... 

Naproxen was introduced to the market by Syntex in 1976 as a nonsteroidal antiinflammatory drug in an optically pure form. The original manufacturing process (Scheme 1) before product launch started from P-naphthol (1) which was brominated in methylene chloride to produce 1,6-dibromonaphthol (2). The labile bromine at the 1-position was removed with bisulfite to give 2-bromo-6-hydroxy-naphthalene that was then methylated with methyl chloride in water-isopropanol to obtain 2-bromo-6-methoxynaphthalene (3) in 85-90% yield from p-naphthol. The bromo compound was treated with magnesium followed by zinc chloride. The resultant naphthylzinc was coupled with ethyl bromopropionate to give naproxen ethyl ester that was hydrolyzed to afford the racemic acid 4. The final optically active naproxen (5) was obtained by a classic resolution process. The racemic acid 4 was treated with cinchonidine to fonn diastereomeric salts. The S -naproxen-cinchonidine salt was crystallized and then released with acid to give S -naproxen (5) in 95% of the theoretical yield (48% chemical yield) [8,9]. 

The reaction of Ph(CH2)2PCl2 with zinc chloride at 170°, followed by hydrolysis with hot hydrochloric acid and oxidation with bromine affords 1-hydroxy-1,2,3,4-tetrahydro-phosphinoline 1-oxide (17) in very good yield, incomplete oxidation yields 1,2,3,4-tetrahydrophosphinoline 1-oxide. 

Two more recent examples may be cited 3-Amino-2-naphthoic aicd, which cannot be obtained in 70% yield by the Bucherer reaction, has been prepared by beating 3-hydroxy-2-naphthoic acid with aqueous ammonia and zinc chloride for 36 h in an autoclave at... 

The Ci9 conjugated aldehyde component was reacted with the lithium derivative of this Cg acetal in ammonia to afford an hydroxy compound which was dehydrated under mild acidic conditions to the fully conjugated C25 substance. Chain extension with ethyl vinyl ether in the presence of boron trifluoride-zinc chloride and mild acidic deethanolation gave the Cjt acetal which was then converted with prop-1-enyl ethyl ether under the same conditions to the required C30 structure of dehydro-p-apocarotenal. Lindlar partial reduction followed by isomerisation afforded the final product. The route is shown in Scheme 14b Scheme 14b... 

Phosphorus pentachloride381,625-628 and phosphorus pentabromide629,630 are the most common reagents of choice. This method is a classical one in which a wide range of sulphonic acids may be used (equation 159). However, compounds with hydroxy, alkoxy or amino functionalities may not be used since side-reactions occur. Complexation of the PCI5 with zinc chloride apparently improves the yields of sulphonyl chlorides627. 

The methyl homologue, 1-hydroxy-3-methylxanthone, has been synthesised in 3 % yield from equimolar proportions of salicyloylurea and orcinol in the presence of orthophosphoric acid, phosphorus oxychloride and anhydrous zinc chloride by heating at 150 C for 5 hours (ref. 125). 

---