Biel, John H.’s team published research in Journal of Organic Chemistry in 26 | CAS: 13444-24-1

Biel, John H. published the artcileCentral stimulants. II. Cholinergic blocking agents, Related Products of piperidines, the publication is Journal of Organic Chemistry (1961), 4096-103, database is CAplus.

cf. CA 48, 694a.–The initial finding that certain disubstituted glycolates of 3-hydroxypiperidine (I) could elicit potent psychotomimetic and antidepressant effects in man suggested a possible relationship between cholinergic blockade and central nervous system stimulatory properties. To investigate this hypothesis, a structural variety of esters of the hydroxypiperidines, hydroxypyrrolidines, and hydroxymethylpyrrolidines was synthesized. The following aspects of this investigation was discussed: (1) the ring contraction obtained during the reaction of the 3-halopiperidines with the free acid; (2) the thermal ring expansion during the distillation of the basic esters; (3) the structure activity relationships with regard to (a) central nervous system stimulation, (b) anticholinergic effects, and (c) the correlation of psychopharmacologic action with cholinergic blockade; (4) the use of these psychotogenic drugs as possible tools in the development of potential antagonists. At present, the conclusion appeared warranted that potent anticholinergic properties were a pharmacol. prerequisite for the characteristic central nervous system effects evoked by this group of compounds The assay method for the isomer ratio of N-ethyl-3-piperidyl phenylcyclopentylglyeolate (II) and N-ethyl-2-pyrrolidyhnethyl phenyleyclopentylglycolate (III) involved an acid hydrolysis of the esters, the extraction of the resulting alcs., and infrared spectrophotometric determination of the ratio of the resulting alcs. Pure samples of N-ethyl-3-hydroxypiperidine (IV) and N-ethyl-2-hydroxymethylpyrrolidine (V) were prepared and infrared spectra taken. Standard mixts, were prepared from IV and V and the absorbance ratio plotted against % pyrrolidyl isomer and given in a figure. Samples of II and III were prepared by ester interchange using pure IV and V. Subsequent hydrolysis of II and III afforded alc. fragments with infrared spectra identical with that of starting materials. Thus, ring contraction did not occur during the esterification of the halopiperidine, resulting in a mixture of isomers. The procedure for the assay was described. N-Ethyl-3-chloropiperidine (VI) and 34.2 g. benzilic acid in 400 ml. iso-PrOH refluxed 12 hrs., evaporated, the residue taken up in H₂O, made alk., the organic phase extracted with Et₂O, dried, evaporated, and the basic ether residue convetted to the HCl salt in iso-PrOH gave 33 g. solids containing 55% N-ethyl-3-piperidyl benzilate-HCl (VII), m. 163-7° (iso-PrOH). The mother liquor from the recrystallization was set aside to give mother liquor A for part B of the experiment The solid recrystallized gave 12.5 g. pure VII, m. 191-2° (alc.). The mother liquor A concentrated to one-fourth gave 12.5 g. N-ethyl-2pyrrolidylmethyl benzilate-HCl (VIII), m. 145-7°. Phenyl-cyclopentylglycolic acid (108.9 g.), 81.1 g. VI, and 625 cc. iso-PrOH refluxed 40 hrs., concentrated to dryness, the residue dissolved in 1 1. H₂O, extracted with Et₂O, saturated with NaHCO₃ solution, and the combined ether extracted dried, and evaporated The residue in 500 ml. Me₂CO treated with Et₂O-HCl gave 111.5 g. mixture A 91.5 g. sample recrystallized gave 52 g. VII. The average isomer ratio from various experiments of VIII versus VII was found to be 70:30 as determined by infrared spectroscopy. The filtrate gave 35.3 g. residue, m. 177-8°. The isomer ratio was the same as for the higher-melting material. The lower m.p. may be due to a different diastereoisomeric mixture Me phenylcyclopentylglyeolate (106 g.), 64.5 g. N-ethyl-3hydroxypiperidine (IX), 1.5 g. NaOMe, and 1.26 1. heptane refluxed, the catalyst removed by filtration, the filtrate washed, the organic phase dried, evaporated, and the 136.5 g. residue treated with Et₂O-HCl gave 88 g. N-ethyl-3-piperidyl phenyleyclopentylgiycolate-HCl (X), m. 214-16° (isoPrOH). X by infrared spectrum was pure. A 70:30 mixture of VII-VIII (55 g.) converted to the free base esters with aqueous NaHCO₃, extracted with Et₂O, evaporated, and the high-boiling ester distilled in vacuo gave 45 g. product, b₀.05, 166-8°. Conversion of the base to the HCl salt gave the high-melting stereoisomer, m. 232-3°. The filtrate afforded 22% X. In subsequent runs this yield was as high as 40%. KOH (5.6 g.), 10.1 g. 2-pyrrolidyhnethanol, 11 g. EtBr, and 100 cc. alc. heated 2 hrs. at 100° in a pressure bottle gave 9 g. N-ethyl-2-pyrrolidylmethanol (XI), b₂ 8 50-1°. XI (10.6 g.), 19.3 g. Me phenylcyclopentylglycolate, 1 g. NaOMe, and 200 cc. heptane refluxed 4 hrs., the filtrate washed, dried, steam distilled, and the 23.7 g. product acidified with HCl in Et₂O gave 21.3 g. N-ethyl-2-pyrrolidylmethyl phenylcyclopentylglycolate-HCl (XII), m. 185-6° (MeCN). XII was shown by infrared assay to be pure. 3-Hydroxypiperidine (XIII) (65 g.) and 150 cc. PhMe refluxed 6 hrs. with 56.5 g. β-benzyloxyethyl chloride, the solid collected, the filtrate concentrated, and the product distilled gave 60 g. N-(βbenzyloxyethyl)-3-hydroxypiperidine (XIV), b_1.1 150°, n²⁵D 1.5321. XIV (38.8 g.), 36.3 g. Me benzilate, 0.6 g. NaOMe, and 400 cc. heptane refluxed, evaporated, and the 67 g. product in Me₂CO treated with HCl gave 50 g. N-(β-benzyloxyethyl)3-piperidyl benzilate-HCl (XV), m. 172° (MeOH). XV (24.1 g.), 3 g. Pd-C, and 150 cc. MeOH reduced at 60 lb./sq. in. at 25° gave 18.2 g. N-(β-hydroxyethyl)-3-piperidyl henzilate-HCl, m. 150-1°. N-Benzyl-3-piperidyl benzilate (20’g.), 3 g. AcOH, 3.5 g. 10% Pd-C, and 200 ml. McOH reduced at 25° at 60 lb./sq. in. H pressure and acidified gave 16.8 g. 3-piperidyl benzilate-HCl, m. 178-80° NaOH (14.3 g.), 36 g. XIII, and 300 co. 90% alc. refluxed 3 hrs. with 42 g.β-(4-methylpiperazino)ethyl chloride-HCl gave 16.3 g. 1- [β-(3-hydroxypiperidino) ethyl] 4-methylpiperazine, b_0.6 120-2°, n²⁵D 1.5061. XIII (101.4 g.) in 500 co. C₆H₆ refuxed 4 hrs. with 53.8 g. β-dimethylaminoethyl chloride gave 73.2 g. N-(β-dimethylaminoethyl)-3-hydroxypiperidine, b_0.9 92-4°, n²⁵D 1.4822. XIII (68 g.), 67 g. NEt₃, 132 g. a-bromoacetal, and 400 cc. PhMe refluxed 4 hrs., the HBr salt removed, the filtrate washed, and distilled gave 91 g. a-(3-hydroxypiperidino)acetal (XVI), b_0.6 98-100°, n²⁵D 1.4632. XVI (32.6 g.) left 3 hrs. at 25° under N with 75 cc. concentrated HCl, evaporated, the residue diluted with 150 cc. H₂O, neutralized, treated overnight at 25° with 17.5 g. 1-amino-4methylpiperazine, the oil extracted with tetrahydrofuran, and concentrated gave 32.4 g. crude hydrazone (XVII). XVII in 100 cc. tetrahydrofuran refluxed 4 hrs. with 5.2 g. LiAlH₄ gave 23.7 g. 1-methyl-4-[β(2-hydroxypiperidino)ethylamino]piperazine, b₀._.03 147-9°. XIII (50.5 g.) and 50.5 g. H₂O with 128 g. 30% H₂SO₄ treated during I hr. with 85 g. NaNO₂ and 150 cc. H₂O, the solution stirred 1 hr. at 25°, the oily layer extracted with CHCl₃, the combined extracts washed with 40% KOH, and evaporated gave 40.9 g. N-nitroso-3-hydroxypiperidine (XVIII). XVIII (40.9 g.) in 300 co. tetrahydrofuran treated in 1.5 hrs. with 17.5 g. LiAlH₄ in 500 cc. tetrahydrofuran, the mixture refluxed 1 hr., decomposed, and the product distilled gave 25.9 g. 1-amino-3-hydroxypiperidine(XIX),b_0.45 84-6°. XIX(60g.) and 38.5 g. Et formate refluxed 5 hrs., and the product distilled gave 41.5 g. N-formylamino-3-hydroxypiperidine (XIXa), b_1.2 165°. XIXa (40.3 g.) and 250 cc. tetrahydrofuran added in 1.5 hrs. to 13.3 g. LiAlH₄ in 500 cc. tetrahydrofuran, refluxed 3 hrs., decomposed with 40 cc. 40% aqueous KOH, the salts removed, and the product distilled gave 25.9 g. N-methylamino-3-hydroxypiperidine, b_1.2 83-6°, n²⁵D 1.4972. XIII (50 g.), 50 g. NEt₃, 62.5 g. PhCH₂Cl, and 250 cc. PhMe refluxed 4 hrs. and the product distilled gave 65 g. Nbenzyl-4-hydroxypiperidine, b_0.7 122-3°, n²⁵D 1.5514. The following XX.HCl were prepared (C₅H₉ = cyclopentyl) (R, R¹, R², ring position, Y, % yield, m.p. given): Et, Ph, C₅H₉, 3, –, –, 212-13° Me, C₆H₁₁, Ph, 3, –, 76, 222° H, Ph, Ph, 3, –, 96.5, 178-80° PhCH₂, Ph, Ph, 3, –, 75.0, 222-3° Me₂NCH₂CH₂, Ph, Ph, 3, –, 68.0, 237-8° PhCH₂OCH₂CH₂, Ph, Ph, 3, –, 69, 172° PhCH₂, Ph, Ph, 2, CH₂, 67.2,211° HOCH₂CH₂, Ph, Ph, 3, –, 98.5, 1522.5° H, Ph, Ph, 2, CH₂, 81, 199-200° Me, Ph, Ph, 2, CH₂, 44.3,230° PhCH₂, Ph, Ph, 4, –, 78.2, 194-5° Me, Ph, Ph, 2, CHCH₃, 31.4, 230° H, Ph, Ph, 4, –, 88, 1802° Me, C₅H₉, Ph, 3, –, 58.7, 209-10° Et, Ph, C₅H₉, 4, –, 43.5, 220-1°; Me, Ph, Ph, 4, –, –, 213-14° Me, Ph, Ph, 2, CH₂CH₂, 26.7, 145-7° MeNH, Ph, Ph, 3, –, 30.0, 158-60° Me, Ph, Ph, 4, –, 53, 215-16°. The following XXIII.HCl were prepared (R, R¹, R², ring position, Y, % yield, m.p. given): Et, Ph, C₅H₉, 2, CH₂, 30, 186° Me, Ph, C₅H₉, 3, –, 31, 169-70° Et, Ph, C₅H₉, 3, –, 42, 165-6°. The following compounds were prepared (% yield and m.p. given): 3-pyridylmethyl benzilate, 29.2,189° N-methyl-3piperidyl methyldiphenylacetate, 71, 216-17° 3-piperidyl diphenylacetate, 56.0, 171-2° XXI, 53, 257° XXII, 77, 237-9°. The central nervous system stimulation and E.D.₅₀ values were given in a table for 36 compounds of the above types.

Journal of Organic Chemistry published new progress about 13444-24-1. 13444-24-1 belongs to piperidines, auxiliary class Piperidine,Alcohol, name is 1-Ethylpiperidin-3-ol, and the molecular formula is C7H15NO, Related Products of piperidines.

Referemce:
https://en.wikipedia.org/wiki/Piperidine,
Piperidine | C5H11N – PubChem