Pyridine phosphorus pentachloride

About a decade ago 6-APA and 7-ADCA were mainly produced by chemical deacylation of penicillin G, penicillin V or phenylacetyl 7-ADCA, the last of which was derived from chemical ring expansion of oxidized penicillin G. As a result of the fact that these processes were rather complex and employed hazardous reagents, for example pyridine, phosphorus pentachloride, nitrosyl chloride and dichlorome-thane, alternative processes have been developed. Penicillin amidases (E. C. 3.5.1.11) catalyze the hydrolysis of the linear amide bond in penicillin molecules producing both the P-lactam nucleus, 6-APA and the corresponding side chain without affecting the P-lactam amide bond in the four-membered ring. Based on their substrate specificity the penicillin amidases are grouped into three classes[591 ... 

Chloro-4-Carbethoxy-6-Ethyl-Pyridine 26 grams of the product just obtained are treated with 81 grams of phosphorus pentachloride in 45 cc of phosphorus oxychloride. The phosphorus oxychloride is distiiled off in a vacuum and the residue is treated with absoiute aicohoi. After distillation there are obtained 24 grams of product having a boiling point of 127° to 131°C/8 mm. 

The factors affecting the preparation of the cyclic chlorophosphazenes from phosphorus pentachloride and ammonium chloride continue to receive attention. For example, the yields and reaction times for the preparation of the series, (NPCla) ( — 3—7), varied with the fineness of the ammonium chloride, the nature and volume of the solvent, and added catalysts such as phosphoryl chloride. A procedure, giving due consideration to these factors, was described for the preparation of N3P3CI6 in good yield (88% of cyclic products) and in a relatively short time (2J h). The cyclic chlorophosphazenes can be obtained in even shorter times ca. 10 min) by addition of four moles of pyridine to remove the hydrogen chloride formed ... 

Benzoic anhydride has been prepared in rather a poor yield by the action of benzoyl chloride on sodium benzoate, barium oxide at 150°, benzoic acid at 160-200°, sodium nitrite, lead nitrate, or anhydrous oxalic acid also by treating sodium benzoate with phosphorus pentachloride or sulfm chloride. More important methods consist in treating benzotrichloride with sulfuric acid,i° and in the action of sodium carbonate upon benzoyl chloride in presence of pyridine. 

Xanthone is unreactive towards hydrazine and phenylhydrazine. The oxime is obtained by reaction of xanthione (xanthene-9-thione) with hydroxylamine, or from xanthone and hydroxylamine in pyridine. When the oxime is heated in water with phenylhydrazine, the phenylhydrazone is formed. In acid solution, xanthone reacts normally with 2,4-dinitro-phenylhydrazine but xanthone-1 -carboxylic acid (435) gives the pyridazinone (436), possibly via the hydrazone (57JCS1922). When the oxime is heated with phosphorus pentachloride it undergoes a Beckmann rearrangement to give the amide (437) (70MI22300). 

Oxo-7-phenylacetylamino-5-thia-l-aza-bicyclo[4.2.0]oct-l-ene-2-carboxylic acid benzhydryl ester Phosphorus pentachloride/pyridine reagent... 

The 8-oxo-7-phenylacetylamino-5-thia-l-aza-bicyclo[4.2.0]oct-l-ene-2-carboxylic acid benzhydryl ester is reacted with phosphorus pentachloride/pyridine reagent in methylene dichloride, and the reaction mixture is thereafter cooled to -35°C and treated with methanol to produce hydrochloride of 7-amino-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester. This hydrochloride is reacted with 4-(3-aminothiophen-2-yl)-5-oxohex-3-enoic acid 3-methylbut-2-enyl ester. Then 7-[2-(2-benzoylamino-thiazol-5-yl)(3-tert-butyl-4,4-dimethylpent-2-enoxycarbonyl)-pent-2-enoylamino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid synthesized is reacted with aluminum chloride in anisole and diluted hydrochloric acid and then with dimethylmalonate to give 5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2Z)-2-(2-amino-4-thiazolyl)-4-carboxy-l-oxo-2-butenyl)amino)-8-oxo-, (6R,7R)- (Ceftibuten). 

To a solution of 1 gram of 16-dehydropregnenolon-3p-acetate in 10 ml pyridine is added 0.22 gram of hydroxylamine hydrochloride, and the mixture is allowed to stand at room temperature for four days. One gram of 16-dehydropregnenolon-3p-acetate oxime is dissolved in 30 ml of hot dioxane, and then the solution is cooled in an ice bath until about one-half of the dioxane has solidified. Then 1 gram of phosphorus pentachloride is added and the mixture is shaken until all the dioxane has melted. The mixture is maintained at 35°C, for seventy-five minutes, then an excess of ice is added and the solution is again allowed to stand at 35°C. After about thirty minutes, a solution of 5 ml of concentrated hydrochloric acid in 10 ml of water is added, and the mixture is diluted with water, extracted with ether and the ethereal extract washed with dilute sodium hydroxide solution. The ether is removed on a steam bath and the residue is worked up to yield dehydro-isoandrosterone. 

Since sulfonation of pyridine iV-oxide is about as difficult as is that of pyridine itself and takes place at the 3-position,17 it has been assumed18 that, in fuming sulfuric acid, pyridine iV-oxide reacts only in the salt form (3), when the prediction is that substitution at C-3 would take place. It is, however, difficult to account for the fact that bromination, even at 110° in the presence of iron powder, does not occur.17 Bromination in chloroform solution in the presence of acetic anhydride and sodium acetate (when the O-acetate is the the probable substrate) take place readily, however, to give 3,5-dibromopyridine JV-oxide.19 The predicted order of nucleophilic reactivity, on the basis of both atom localization energies and ground-state v-electron density calculations, is 4 > 2 > 3. The same order is predicted for the nucleophilic substitution reactions of the salts of pyridine JV-oxide. In actual practice, iV-alkoxypyridinium derivatives undergo nucleophilic attack preferentially at C-2.20-23 The reaction of some pyridine iV-oxides with phosphorus pentachloride may involve the formation... 

Although the mechanism of chlorination of pyridine A-oxides by the action of phosphorus oxychloride, phosphorus pentachloride, or sulfuryl chloride has not been established, it seems most likely that some of these reactions involve intra- or inter-molecular attack by chloride ion or potential chloride ion following complexing at oxygen (see Sections II and IV). With a few exceptions, they are therefore more appropriately discussed under the heading of nucleophilic substitutions (Section IV, A, 3). One such exception may be the reaction of A-hydroxy-4-pyridone with sulfuryl chloride, which ultimately gives l,2,2,3,3,5,6-heptachloro-2,3-dihydro-4-pyridone (65). It has been proposed that the first step in this reaction is the formation of 3,5-dichIoro-AT-hydroxy-4-pyridone.157 If this is so, then it must involve electrophilic attack at the two /3-positions, followed by the more usual nucleophilic substitutions. 

In contrast to the ease of N-functionalization, shown in Scheme 1, the triazolopyridine nucleus is resistant to direct nuclear oxidation or electrophilic additions. Electrophilic additions will occur on aryl substituents for example, nitration of l-phenyltriazolo[4,5-c]pyridine (26) and sulfonation of 2-phenyl-2i/-triazolo[4,5-6]pyridine (28) occur exclusively in the para position of the phenyl ring <34LA(514)279, 38MI 710-01). Nuclear functionalization was observed when l-( -butyl)-5-methyl-tri-azolo[4,5-c]pyridinium iodide (30) was treated with potassium ferricyanide to afford triazolopyridin-4-one (31), as shown in Scheme 2. Similarly, the iodide (30) is converted by either phosphorus oxychloride-phosphorus pentachloride, or bromine or nitric acid to 7-substituted triazolopyridin-4-ones (32) <37LA(529)288>. 

When primary amines react with a-acylaminoketones the resulting Schiff bases can be cyclized in the presence of phosphoryl chloride, phosphorus pentachloride, or triphenylphosphine and triethylamine in hexachloroethane to give 1-substituted imidazoles (11) (Scheme 2.1.4). The starting a-acyl-aminocarbonyls are readily prepared from a-amino acids by reduction with sodium amalgam [31, 32] or by the Dakin-West reaction [33, 34], which is most conveniently conducted in the presence of 4-(AUV-dimethylamino)pyridine (DMAP) as an acylation catalyst [35 37]. 

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