Biel, John H.’s team published research in Journal of the American Chemical Society in 77 | CAS: 13444-24-1

Biel, John H. published the artcileAntispasmodics. II. Derivatives of N-substituted-3-piperidols, Recommanded Product: 1-Ethylpiperidin-3-ol, the publication is Journal of the American Chemical Society (1955), 2250-6, database is CAplus.

cf. C.A. 48, 694a. The initial finding (loc. cit.) that the replacement of Et₂NCH₂CH₂ by N-ethyl-3-piperidyl in some standard antispasmodic agents yielded compounds of superior spasmolytic activity prompted a more general investigation of the therapeutic usefulness of a variety of 3-piperidyl derivatives Five classes of compounds were synthesized: (1) substituted acetic acid esters of 3-hydroxypiperidine and 3-mercaptopiperidine derivatives; (2) substituted carbamates of N-methyl-3-hydroxypiperidine; (3) N-substituted-3-piperidyl benzhydryl ethers, as well as their thio isosteres; (4) p-aminobenzoates of N-alkyl-3-piperidol; (5) N-methyl-3-piperidyldiphenylmethyl derivatives RCPh₂Y with Y = CONH₂ and CN. The 1st series of compounds yielded a number of potent antispasmodic agents, of which the disubstituted hydroxyacetates appeared to be the most promising ones. The carbamates in series 2 either inhibited or potentiated acetylcholine spasms in the guinea pig ileum depending on the type of substituent. The benzhydryl ethers (series 3) were active spasmolytic agents. Quaternization of the N produced a 10-fold increase in spasmolytic activity. The compounds in series 4 were local anesthetics comparable to procaine in potency. The diphenylacetamide derivatives (5) were moderate antispasmodics. Phenyl-2-thienylglycolic acid was obtained via a mixed benzoin condensation followed by a benzilic acid type rearrangement. The preparation of 3-mercaptopiperidines is described. A general method for obtaining N-aryl-substituted carbamates was developed. BzH (21.2 g.) and 22.4 g. 2-thiophenecarboxaldehyde in 100 cc. absolute EtOH treated with 20 g. KCN in 40 cc. H₂O, the mixture refluxed 1.5 h. with stirring, treated with 250 cc. 50% aqueous EtOH and refrigerated, the orange-yellow precipitate filtered, washed with H₂O, stirred with 10% aqueous NaHCO₃, filtered, suspended in dilute aqueous K₂CO₃, filtered, washed with H₂O, and recrystallized from aqueous EtOH yielded 21.5 g. 2-thienyl α-phenyl-α-hydroxymethyl ketone (I), m. 132-4°. I (10.6 g.), 5.0 g. NH₄NO₃, 0.1 g. Cu(OAc)₂, and 35 cc. 80% aqueous AcOH refluxed 1.5 h. with stirring, cooled, seeded, allowed to crystallize, diluted with H₂O, and filtered, and the filter cake washed with H₂O gave 10.1 g. Ph 2-thienyl diketone (II), m. 59-60°. II (15.0 g.) in 30 cc. 95% EtOH added to 15 g. KOH in 30 cc. H₂O, the mixture refluxed 10 min., the EtOH distilled off, the residual aqueous alk. solution acidified with dilute HCl, and the precipitate washed with H₂O, recrystallized from 100 cc. C₆H₆, and decolorized with 5 g. Darco yielded 7.3 g. phenyl-2-thienylglycolic acid, white crystals, m. 127-9°. N-Methyl-3-hydroxypiperidine (230 g.) and 484 g. Me benzilate in 3.0 l. heptane refluxed with stirring to solution, the refluxing solution treated with 10.0 g. NaOMe in 2.0-g. portions during 8-9 h. while removing 75 cc. MeOH, the mixture concentrated to 0.5 volume and diluted with 2 l. Et₂O, the Et₂O-heptane solution washed, dried, and filtered, the solvent removed in vacuo, the oily residue dissolved in 1300 cc. iso-PrOH, the solution acidified with HCl in Et₂O, and the precipitate filtered gave 555 g. N-methyl-3-piperidyl benzilate HCl salt, m. 221-3°; activity against acetylcholine-induced spasms in the guinea pig ileum 0.6 (atropine 1.0) (the spasmolytic activities will be given in parentheses); free base, b_0.20 198-9°; methobromide, m. 234-6° (0.50). Similarly were prepared the following esters of 1-methyl-3-piperidol (acid, b.p./mm. of base, m.p. of HCl salt, m.p. of methobromide given): Ph₂CHCO₂H, -, – (0.01), -; Ph₂NCO₂H, 190-2°/0.15, 215-16° (0.001), 273-4° (0.001); phenylthienylglycolic acid, -, 227-8° (2.0), -; HOCH₂CHPhCO₂H, 160-8°/0.10, -, [H₂SO₄ salt, m. 75° (decomposition) (0.10)], -. 1-Butyl-3-hydroxypiperidine (8.0 g.) and 6.0 g. Et₃N in 50 cc. C₆H₆ treated with stirring with 11.5 g. Ph₂CHCOCl in 50 cc. C₆H₆ below 70°, the mixture held 2 h. at 70° and filtered, and the filtrate fractionated in vacuo yielded 15.5 g. 1-butyl-3-piperidyl diphenylacetate (III), b_0.10 188-91°; III treated in iso-PrOH with MeBr gave III.MeBr, m. 143-5° (0.006). Similarly was prepared the benzilate analog HCl salt (0.06) and the methobromide, m. 144-6° (0.20). Phenylcyclohexylglycolic acid (31.0 g.), 25.0 g. 1-ethyl-3-chloropiperidine, 70 cc. absolute iso-PrOH refluxed 20 h., the solvent distilled off, the residual oil neutralized with dilute aqueous HCl and extracted with Et₂O, the aqueous phase basified with NaOH and extracted with Et₂O, and the extract dried, and distilled gave 24.0 g. 1-ethyl-3-piperidyl phenylcyclohexylglycolate (IV), b_0.05 166-7°; HCl salt, m. 215-17° (0.20). Similarly were prepared the following esters of 1-ethyl-3-piperidol (acid, b.p./mm., and m.p. HCl salt given): Ph₂CHCO₂H, -, – (0.01) [methobromide (0.07)]; Ph₂CHCSOH, -, – (0.20); phenylcyclohexylacetic acid, -, – (0.06); phenylcyclopentylacetic acid, 154-78°/0.04, 181-3° (0.05); phenylcyclopentylglycolic acid, 201°/0.40, 205-7° (0.75); phenylpropylglycolic acid, 150°/10, 166-7° (0.10); phenylthienylglycolic acid, -, 181-2° (0.30); dicyclohexylacetic acid, 151-61°/0.10, 184-5° (0.01); cyclopentylpropylacetic acid, 118-20°/0.03, 116-18° (0.01). In the same general manner were prepared the following esters: 1-isopropyl-3-piperidyl diphenylacetate, b_0.55 180-4°; HCl salt, m. 134-6° (0.002); 1-(β-phenylisopropyl)-3-piperidyl diphenylacetate HCl salt, m. 161-2° (0.0014); 1-methyl-3-piperidyl acetate methiodide, m. 171-2°. 1-Methyl-3-hydroxypiperidine (V) (23.0 g.) in 150 cc. iso-PrOH treated slowly with stirring with 37.0 g. p-O₂NC₆H₄COCl, the mixture refluxed 3 h. with stirring, cooled, and filtered, and the crude product recrystallized from EtOH gave 32 g. 1-methyl-3-piperidyl p-nitrobenzoate HCl salt (VI), m. 218-19°. VI (15.0 g.) in EtOH hydrogenated over 3.0 g. 10% Pd-C at 60 lb. pressure, and the mixture filtered and evaporated in vacuo yielded 13.0 g. p-aminobenzoate HCl salt of 1-methyl-3-piperidol (VII), m. 126° (slow decomposition). Me₂NCOCl (32.3 g.), 34.5 g. V, and 100 cc. dry pyridine refluxed 3 h., cooled, and poured into 700 cc. ice water, the mixture treated with solid NaOH and extracted with Et₂O, and the extract dried and distilled gave 44 g. N,N-dimethylcarbamate of VII, b_3.0 101-3°; methobromide, m. 205-6° (0.00005); (HCl salt, m. 198-9°); the base treated in Me₂CO with an equivalent amount PhCH₂Cl, the solution kept 3 wk at room temperature, and the precipitate filtered gave 7.0 g. PhCH₂Cl salt, m. 199-201°. NaNH₂ (10.8 g.) in 75 cc. dry PhMe treated with 36.6 g. PhCH₂NHPh in 40 cc. dry PhMe, the mixture refluxed 3 h. with stirring, treated with 19.1 g. ClCO₂Me in 40 cc. PhMe, refluxed 4 h. with stirring, and filtered, and the filtrate fractionated gave 36.5 g. Ph(PhCH₂)NCO₂Me (VIII), b_0.035 132-3°. V (19.2 g.) in 600 cc. heptane treated with 40.2 g. VIII, the mixture refluxed and treated with 1.3 g. NaOMe, the MeOH separated through a Dean-Stark trap, the residual mixture concentrated to 0.5 volume, diluted with 300 cc. Et₂O, and filtered, the filtrate washed, dried, and evaporated, and the residual oil fractionated in vacuo yielded 19.3 g. N-phenyl-N-benzylcarbamate of V, b_0.025 169-71°; methobromide, m. 123-4° (0.006). In a similar manner was prepared dibutylcarbamate of V, b_1.0 111-12°; methiodide, m. 103-4° (0.005). In the usual manner was also prepared 1-ethyl-3-piperidyl p-aminobenzoate-HCl, m. 120° (decomposition). V (11.5 g.) added to 2.3 g. molten Na in 150 cc. hot PhMe, the solution refluxed with stirring, treated with 24.7 g. Ph₂CHCl, refluxed 5 h. with stirring, and filtered, the filtrate extracted with 10% HCl, the acid extract washed with Et₂O, made strongly alk., and extracted with Et₂O, and the extract dried and distilled gave 4.5 g. benzhydryl ether (IX) of V, b_0.11 160-1°; IX.HCl, m. 70° (decomposition) (0.01); IX.MeBr, m. 186-7° (0.10) (from iso-PrOH). Ph₂CHCl (40.4 g.) and 46.0 g. V in 100 cc. PhMe refluxed 24 h. with stirring, the mixture filtered, and the filtrate fractionated gave 37.0 g. IX, b_0.08 140-7°. NaOH (13.5 g.) in 27 cc. H₂O added with stirring to 25.1 g. [Ph₂CHSC(NH₂)₂] Cl and 90 cc. EtOH, the mixture stirred 0.5 h. at 40°, treated with 15.4 g. 1-ethyl-3-chloropiperidine (X), refluxed 2 h. with stirring, cooled, poured into 500 cc. H₂O, and extracted with Et₂O, and the extract dried and distilled gave 23.1 g. 1-ethyl-3-piperidyl thiobenzhydryl ether (XI), oil, which was too heat-labile to be distilled XI in Et₂O-iso-PrOH treated with HCl in Et₂O gave XI.HCl, m. 145-6°; XI.MeBr, m. 158-61° (0.075). X (133 g.) and 69 g. AcSH in 500 cc. absolute iso-PrOH refluxed 15 h., the alc. distilled off, the oily residue treated with 250 cc. H₂O and 400 cc. Et₂O, the mixture treated with 134 g. K₂CO₃ in 200 cc. H₂O, the aqueous phase extracted repeatedly with Et₂O, and the extract dried and distilled gave 87.4 g. 1-ethyl-3-piperidyl thioacetate (XII), b_0.35 66°, n_D²⁰ 1.4963. XII (88.3 g.) added with stirring at room temperature to 1200 cc. 6% aqueous NaOH, the mixture stirred 2 h. at 20°, the solution neutralized with 94 cc. glacial AcOH, saturated with 800 g. (NH₄)₂SO₄, and extracted continuously with Et₂O, and the extract distilled gave 39 g. 1-ethyl-3-mercaptopiperidine (XIII), b_1.7 57.5°, n_D²⁰ 1.4956. XIII (11.7 g.) in 25 cc. treated with stirring and cooling with 14.8 g. p-O₂NC₆H₄COCl in 50 cc. PhMe, the solution refluxed 0.5 h., cooled, and filtered, and the filter residue recrystallized twice from iso-PrOH yielded 19.3 g. 1-ethyl-3-piperidyl p-nitrothiobenzoate-HCl salt, white crystals, m. 149-51°. Ph₂CHCN (116 g.) and 23.4 g. NaNH₂ in 500 cc. dry PhMe refluxed 6 h. with stirring, the hot mixture treated with 160 g. X in 200 cc. dry PhMe, the mixture stirred 20 h. with refluxing, cooled, and extracted with 10% aqueous HCl, the acid extract washed with Et₂O, made alk. with 200 g. KOH in 200 cc. H₂O, and extracted with Et₂O, and the extract dried and fractionated yielded 140 g. 1-methyl-x-(diphenylcyanomethyl)piperidine (XIV), b_0.05 182-6°. XIV (58.0 g.) in 250 cc. EtOH treated with 19.0 g. MeBr, the mixture kept 3 days at room temperature, the precipitate filtered off to yield 40.0 g. product (fraction A), m. 259-61° (decomposition), the filtrate evaporated to dryness, the residue suspended in 200 cc. iso-PrOH, and the insoluble material filtered off yielded 33.0 g. product (fraction B), m. 255-63° (decomposition); the filtrate evaporated to dryness gave 4.5 g. addnl. B; A recrystallized twice from EtOH yielded 30.0 g. XIV.MeBr, m. 263-5° (decomposition); B recrystallized 3 times from iso-PrOH yielded 17.0 g. isomeric XIV.MeBr, m. 278-81° (decomposition); a mixture of A and B melted at 238-42° (decomposition). XIV (50 g.) heated 3 h. on the steam bath with 500 cc. 90% H₂SO₄, the mixture poured onto ice, neutralized with 700 cc. concentrated NH₄OH, and extracted with Et₂O, the white solid separating in the aqueous and the Et₂O phase filtered off to yield 6.4 g. material (fraction C), m. 216-24°, the Et₂O distilled off, the residue suspended twice in 100 cc. boiling Me₂CO and filtered to give 10.3 g. insoluble material (fraction D), m. 227-8°, the combined Me₂CO filtrates evaporated to dryness, and the oily residue crystallized from Et₂O, and the Et₂O suspension filtered gave 5.2 g. material (fraction E), m. 150-3°. C and D combined and recrystallized from 5:1 CHCl₃-heptane yielded 6.0 g., material (fraction F), m. 228-30°. E (3.08 g.) in 25 cc. Me₂CO and 5 cc. iso-PrOH treated with 0.95 g. MeBr yielded 3.90 g. gave 1-methyl-x-diphenylcarboxamidomethylpiperidine (XV).MeBr, m. 259-60° (decomposition). F (2.5 g.) in 25 cc. EtOH gave with 0.70 g. MeBr 1.8 g. isomeric XIV.MeBr, m. 315-16°.

Journal of the American Chemical Society 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, Recommanded Product: 1-Ethylpiperidin-3-ol.

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