Benzoyl piperidine

Benzoyl piperidine thus obtained is a straw-colored viscous liquid. Upon long standing. 0j seeding with crystalline benzoyl piperidine, the compound crystallizes in long, colorless needles which melt at 440. The literature reports 48° as the melting point of the pure material. 

Using 180 g. of pyridine in place of the i3o g. suggested, and a corresponding increase in the other chemicals except the sodium and alcohol, a yield of 300-326 g. of benzoyl piperidine is obtained. This is a smaller percentage yield (70-75 per cent of the theoretical amount) but the actual yield more than repays for the excess of pyridine used (see also Note 8). 

A reflux condenser Sr cm Tbftg with inner tube 2 cm. in diameter is recommended If tt smtdtei condenser is employed, 

Unless the purity of the pyridine is known, it should be dried with solid sodium hydroxide and distilled before use. For this work a fraction boiling at 112-1170 was used. 

If the alcohol solution is allowed to cool before the addition of the water, it solidifies and is remelted only with difficulty. If it is desired to suspend the process, the water should be added first and then the solution will not solidify. 

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Trimethylene dibromide (Section 111,35) is easily prepared from commercial trimethj lene glycol, whilst hexamethylene dibromide (1 O dibromohexane) is obtained by the red P - Br reaction upon the glycol 1 6-hexanediol is prepared by the reduction of diethyl adipate (sodium and alcohol lithium aluminium hydride or copper-chromium oxide and hydrogen under pressure). Penta-methylene dibromide (1 5-dibromopentane) is readily produced by the red P-Brj method from the commercially available 1 5 pentanediol or tetra-hydropyran (Section 111,37). Pentamethylene dibromide is also formed by the action of phosphorus pentabromide upon benzoyl piperidine (I) (from benzoyl chloride and piperidine) ... 

Benzoyl piperidine. In a 1-litre three-necked flask, equipped with a mechanical stirrer, separatory funnel and a thermometer, place 85 g. (99 ml.) of redistilled piperidine (b.p. 105-108°) and a solution of 53 g. of sodium hydroxide in 400 ml. of water. Stir the mixture and introduce during the course of 1 hour 140 g. (115-5 ml.) of redistilled benzoyl chloride maintain the temperature at 35-40°, Cool to room temperature and extract the benzoyl piperidine with ether. Wash the ethereal solution with a little water to remove any dissolved sodium hydroxide, and dry with anhydrous potassium carbonate. Remove the ether on a water bath and distil the residue under diminished pressure (Fig. II, 20, 1). Collect the benzoyl piperidine at 184—186°/15 mm. it is an almost colourless viscous liquid and crystallises on standing in colourless needles m.p. 46°. The yield is 170 g. 

The Class III antiarrhythmic agent under development by Eisai is a meth-ylsulphonylamino-substituted benzoyl piperidine, E-4031 (67). In guinea-pig papillary muscle E-4031 increased APD90 by 25% at a eoncentration of 10 [190] and increased ERP in ferret papillary muscle by 25% at 58 nM... 

A group from Spain patented a similar synthesis of risperidone (1) using similar synthetic transformations but in a different sequence (Scheme 2). Reaction of 2-aminopyridine with 2-acetylbutyrolactone in polyphosphoric acid at 160 °C afforded alcohol 15, which was hydrogenated to 16 and then converted to chloride 10 with thionyl chloride. Benzoyl piperidine 19 was prepared in a similar manner as in Scheme 1. In contrast to Scheme 1, 19 was alkylated with 10 prior to conversion to the 1,2-... 

Beckmann rearrangement of, 729,741 p-Benzoquinone, 745 Benzoylacetone, 865 o-Benzoylbenzoic acid, 728, 739 Benzoyl chloride, 791, 792 Benzoyl glycine, 584 Benzoyl peroxide, 807 determination of, 809 Benzoyl piperidine, 489, 492 P-Benzoylpropionic acid, 728, 737 P-Benzoylpropionitrfle, 911, 912 Benzoyl-p-toluidide, 582, 583 Benzyl acetate, 780, 783 Benzylacetophenone, 726, 734 Benzyl alcohol, 706,711, 811,812,884 N-Benzylamid es 394 table of, 395 ... 

Any sodium hydroxide carried into the distilling flask causes decomposition of the benzoyl piperidine during distillation and consequently a considerably lower yield results. For this reason it is well to wash the product carefully in the separatory funnel with a little water after the alkaline solution has been drawn off. 

Benzoyl piperidine is much given to superheating, making distillation difficult. 

If piperidine is available, benzoyl piperidine for use in the preparation of pentamethylene bromide (p. 70) may be prepared by direct benzoylation. A mixture of 105 g. of sodium hydroxide (2.6 moles), 170 g. of piperidine (2.0 moles) (b. p. 104-1080) and 800 cc. of water are treated with 280 g. (2 moles) of benzoyl chloride using the apparatus and procedure described above the temperature is kept at 35-40°. The oily product is separated after dilution with 250 cc. of benzene if necessary (Note 5), dried with a small quantity of potassium carbonate and distilled. The portion boiling at 172-1740/12 mm. weighs 330-345 g. (87-91 per cent of the theoretical amount). The first few... 

Benzoyl piperidine has been prepared only by the action of benzoyl chloride on piperidine in the presence of alkalies.1... 

Pentamethylene bromide has been prepared by the action of fuming hydrobromic acid on pentamethylene glycol,2 or 1,5-diphenoxypentane 2 by the action of hydrobromic acid on an acetic add solution of 1,5-di-isoamyloxypentane 4 and by the action of phosphorus pentabromide on benzoyl piperidine.5... 

The amine group in primary amines can be replaced by halogen by warming the benzoyl derivative with phosphorus pentachloride or phosphorus pentabromide. Oftentimes, the separation of the halide from the benzonitrile, which is also formed, is troublesome. The process has been applied mostly to high-moIecuIar-weight amines obtained by the Hofmann degradation of acid amides or by reduction of nitriles." Diamines lead to dihalogen derivatives." If N-benzoyl piperidines are treated, substituted pentamethylene halides are formed. An example is the synthesis of pentamethylene bromide by the action of phosphorus pentabromide on N-benzoyl piperidine (72%). ... 

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