Lunsford, Carl D. published the artcilePreparation of 4-amino-1-butanols and some derivatives of pharmacological interest, Synthetic Route of 4543-95-7, the publication is Journal of Organic Chemistry (1957), 1225-8, database is CAplus.
The 4-alkylamino (I) and 4-dialkylamino-1-butanols (II) were prepared by LiAlH4 reduction of the product from equimolar amounts of butyrolactone (III) and a primary or secondary amine. Use of 2 moles amine resulted in N,N’-symmetrically substituted putrescines. The 3-aminopropanols were prepared similarly by the substitution of propiolactone (IV) for III. The 3,4,5-trimethoxybenzoates, the diphenylacetates, and the benzhydryl ethers of some of the II and of N-3-hydroxypropylpiperidine (V) and their quaternary salts were prepared and their pharmacol. activity examined III (68.8 g.) and 104 g. NHBu2 heated 4 hrs. at 150°, the mixture in Et2O added dropwise to 25.1 g. LiAlH4 in 300 ml. Et2O, refluxed 1 hr., the excess hydride decomposed with H2O, the mixture filtered, the filtrate concentrated, and the residue fractionated gave 97.4 g. II (di-Bu derivative), b40 172-5°. When the starting amine refluxed below 150°, the reaction with III was carried out at reflux until the pot temperature reached 150° where it was kept 4 hrs.; when the starting amine was NHMe2 or NHEt2 the reaction was run in a sealed tube at 150°. The following results were obtained in preparing I and II, RR’N(CH2)4OH (RR’N, b.p./mm., % yield, n25D, and d. given): BuNH, 80-0.5°/0.2, 44, 1.4503, 0.8900; PhCH2NH, 137-40°/0.8, 56, 1.5288, -; Me2N, 98°/22, 56, 1.4390, 0.8798; Et2N, 83-5°/0.8, 80, 1.4460, 0.8653; Pr2N, 114°/4.3, 77, 1.4472, 0.8723; Bu2N, 135°/0.3, 62, 1.4502, 0.8616; (CH2)5N, 75°/0.2, 71, 1.4733, 0.9471. III (172 g.) and 180 g. NHMe2 heated 4 hrs. at 200° in 2 sealed tubes, the mixture heated to 125° in vacuo, and reduced with 125 g. LiAlH4 gave 86 g. N,N,N’,N’-tetramethylputrescine, b28 78-80°, n25D 1.4261, d27 0.7864; dipicrate, m. 203-5°. There was also a higher-boiling fraction which proved to be II (di-Me derivative). Similarly, 17.2 g. III, 34 g. piperidine, and 11.4 g. LiAlH4 gave 25 g. 1,4-piperidinobutane, b0.3 117-18°; HCl salt, m. above 300°. IV (28.4 g.) added dropwise to 34 g. piperidine at 5-10° and towards the end of the addition the temperature allowed to rise to 20°, the sirup dissolved in 100 ml. tetrahydrofuran and reduced as above with 11.4 g. LiAlH4, and the product fractionally distilled gave 31 g. V, b25 117-22°, n25D 1.4750, d2925 0.9585; 3,4,5-trimethoxybenzoate hydrochloride, 51% yield, m. 169-71°; diphenylacetate nitrate, 90% yield, m. 115-16°(H2O); diphenylacetate-MeI, m. 144.5-46° (alc.); diphenylacetate-MeBr, m. 165-6° (iso-PrOH). The 3,4,5-trimethoxybenzoic acid and diphenylacetic acid esters of I and II were prepared from the acid chloride with I or II. 3,4,5-Trimethoxybenzoyl chloride (23 g.) in 50 ml. CHCl3 refluxed 2 hrs. with 11.7 g. II (di-Me derivative), the residue partitioned between dilute HCl and Et2O, the acid extract made alk. and extracted with Et2O, dried, and separated gave 26 g. II 3,4,5-trimethoxybenzoate-HCl, m. 122-4°. The quaternary salts of both the esters and the ethers were prepared by addition of MeI or MeBr to the base in Et2O. When crystallization did not occur spontaneously the Et2O was decanted and the oil crystallized from a suitable solvent. The following RCO2(CH2)NR”R’2X were thus formed (R, R’, R”, X, m.p., and % yield given): 3,4,5-(MeO)3C6H2, Me, H, Cl, 122-4°, 75; 3,4,5-(MeO)3C6H2, Et, H, Cl, 140-1°, 97; 3,4,5-(MeO)3C6H2, Et, Me, I, 142.5-44°, 78; 3,4,5-(MeO)3C6H2, Pr, H, Cl, 118-19°, 35; 3,4,5-(MeO)3C6H2, Pr, Me, I, 115-17°, 37; 3,4,5-(MeO)3C6H2, [R’2 = (CH2)5], H, Cl, 156.5-57°, 83; 3,4,5-(MeO)3C6H2, [R’2 = = (CH2)5], Me, I, 171-3°, 35; Ph2CH, [R’2 = (CH2)5], H, Cl, 148-50°, 53; Ph2CH, [R’2 = (CH2)5], Me, I, 69-72°, 34; Ph2CH, [R’2 = (CH2)5], Me, Br, 144-6°, 61. Benzhydryl bromide (49.3 g.) and 69.2 g. 4-dipropylamino-1-butanol in 200 ml. PhMe refluxed 15 hrs., concentrated in vacuo, partitioned between 5% NaOH and Et2O, the extract then extracted with 5% HCl, this made alk. with 20% NaOH, and extracted with Et2O gave 39 g. unchanged II (alkyl = Pr) and 26 g. N-(4-benzhydryloxybutyl)-N,N-dipropylamine, b1.5 175-7°. The following PhRCHO(CH2)4NR’R’ were similarly prepared (R, R’R’N, salt, b.p./mm., or m.p., and % yield given): Ph, Et2N, -, 202-5°/1.4, 68; Ph, Et2N, HBr, 109-11.5°, -; Ph, Et2N, MeBr, 120-1°, 81; Ph, Bu2N, -, 192-4°/1.5, 38; Ph, (CH2)5N, -, 217-20°/2.0, 46; Ph, (CH2)5N, HCl, 135.5-37°, -; Ph, (CH2)5N, MeI, 126-6.5°, 73; p-ClC6H4, Et2N, citrate, 123-4°, 62.
Journal of Organic Chemistry published new progress about 4543-95-7. 4543-95-7 belongs to alcohols-buliding-blocks, auxiliary class Amine,Aliphatic hydrocarbon chain,Alcohol, name is 4-(Butylamino)butan-1-ol, and the molecular formula is C8H19NO, Synthetic Route of 4543-95-7.
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