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All 9 posts | Subject: Amines related to 2,5-dimethoxyphenethylamine | Please login to post | Down | |
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Vitus_Verdegast (Hive Bee) 09-10-03 01:16 No 458032 
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Amines related to 2,5-dimethoxyphenethylamine (Rated as: excellent) |
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PART I Amines related to 2,5-dimethoxyphenethylamine. I. Baltzly, Richard; Buck, Johannes S. Journal of the American Chemical Society (1940), 62 161-4. CODEN: JACSAT ISSN: 0002-7863. Journal language unavailable. CAN 34:10438 AN 1940:10438 CAPLUS Abstract 2,5 (MeO)2C6H3CH2CH2NH2 (I) yields a HCl salt, m. 139° (all m. ps. cor.). I (9 g.), 40 cc. 36% HCHO and 0.1 cc. HCO2H, heated 3 hrs. at 125°, give 2,5-dimethoxyphenethyldimethylamine, b23 159°; HCl salt, m. 148°, rather hygroscopic; the methiodide in H2O and AgCl give 2,5-dimethoxyphenethyltrimethylammonium chloride, m. 184-5.degree., very hygroscopic. 2,5-(MeO)2C6H3Ac and BrCH2CO2Et, condensed by use of Zn-Cu alloy, the ester dehydrated by POCl3 and sapond., give 2,5-dimethoxy-beta-methylcinnamic acid, m. 113.5.degree.; catalytic reduction and sapon. of the ester give beta-(2,5-dimethoxyphenyl)butyric acid, m. 79°; heating in a stream of NH3 at 220-30° for 2 hrs. gives the amide, m. 121°; the Hofmann reaction with NaOCl gives 45% of beta-(2,5-dimethoxyphenyl)propylamine, b1 114°; HCl salt, m. 149-50°; Decker's method (D. and Becker, C. A. 7, 1513) gives beta-(2,5-dimethoxyphenyl)propylmethylamine, whose HI salt m. 131° and HCl salt, m. 146°; the corresponding dimethylamine forms a HCl salt, m. 182-3°; the trimethylammonium chloride m. 159-61° (monohydrate, m. 92°); the iodide m. 139°. CH2(CO2Et)2 and 2,5-(MeO)2C6H3CHO with piperidine give di-Et 2,5-dimethoxybenzalmalonate, m. 183° (decompn.), catalytically reduced to di-Et 2,5-dimethoxybenzylmalonate, m. 156.5.degree. (decompn.); reaction with MeI and EtONa and sapon. give 2,5-dimethoxybenzylmethylmalonic acid, m. 143° (decompn.); heating above 150° gives alpha-methyl-2,5-dimethoxyhydrocinnamic acid, cream, m. 59.5.degree.; amide (II), m. 99° (by heating acid in stream of NH3 at 220-30° for 2 hrs.; the same amide results from 2,5-(MeO)2C6H3CHO and MeCHBrCO2Et with Zn, dehydrating with POCl3, catalytic reduction, sapon. and reaction with NH3); the dehydration with POCl3 or the subsequent distn. results in extensive polymerization, the yield of unsatd. ester being about 20%. Hofmann reaction with II (addn. of II in dioxane to the NaOCl soln.) gives 70% of beta-(2,5-dimethoxyphenyl)isopropylamine, b3 137-40°; HCl salt, m. 117.5.degree.; HI salt, m. 138°; this also results in poor yield by catalytic reduction of 2,5-dimethoxynitropropenylbenzene (Kauffmann, C. A. 11, 2794); Decker's method gives the corresponding methylamine, whose HCl salt m. 98.5.degree.; the dimethylamine, b0.5 118-21°, forms a HCl salt, m. 138-9°; the trimethylammonium chloride, m. 203°, very hygroscopic; the iodide, m. 142°. A Dream Within A Dream (http://www.poedecoder.com/Qrisse/works/dreamw.html) |
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Vitus_Verdegast (Hive Bee) 09-10-03 01:32 No 458036
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PART II (Rated as: excellent) |
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Amines related to 2,5-dimethoxyphenethylamine. II. Baltzly, Richard; Buck, Johannes S. Journal of the American Chemical Society (1940), 62 164-7. CODEN: JACSAT ISSN: 0002-7863. Journal language unavailable. CAN 34:10439 AN 1940:10439 CAPLUS Abstract 2,5-(MeO)2C6H3CHO and BrCH2CO2Et, condensed by the Reformatski.crn.i method, give 80% of Et beta-(2,5-dimethoxyphenyl)hydracrylate, yellow, b1 164-7°; the hydrazide, m. 161.5.degree. (all m. ps. cor.); the Curtius rearrangement yields 5-(2,5-dimethoxyphenyl)-2-oxazolidone, m. 107°, cleavage of which by cold, concd. HCl gives beta-(2,5-dimethoxyphenyl)-beta-hydroxyethylamine-HCl, m. 158.5.degree.; this and the other salts may be crystd. from abs. EtOH by addn. of Et2O or AcOEt or both; the amine also results by reduction of 2,5-dimethoxyphenacylamine-HBr, yellow, m. 195° (decompn.), which is prepd. by condensation of 2,5-(MeO)2C6H3COCH2Br (I) and hexamethylenetetramine and hydrolysis with HBr. I and PhCH2NHMe in Et2O give 2,5-dimethoxyphenacylmethylbenzylamine (II), whose HCl salt, m. 167.5.degree.; reduction with PtO2 and H in EtOH gives beta-(2,5-dimethoxyphenyl)-beta-hydroxyethylmethylamine-HCl, m. 151.5.degree.. II with MeMgI, followed by catalytic reduction, yields beta-(2,5-dimethoxyphenyl)-beta-hydroxypropylmethylamine, whose HCl salt m. 158-9°. 2,5-(MeO)2C6H3Ac and BrCH2CO2Et, condensed with Zn-Cu alloy, yield after sapon. beta-methyl-beta-(2,5-dimethoxyphenyl)hydracrylic acid, m. 121-2.degree.; the hydrazide, m. 112°, results in 27% yield from the crude washed (but not distd). ester; unsatisfactory results were obtained with the distd. ester or that prepd. from the acid, due to the tendency of the compds. to dehydrate when distd. or subjected to acids; Curtius rearrangement yields 5-methyl-5-(2,5-dimethoxyphenyl)-2-oxazolidone, m. 159°; cold concd. HCl gives b-(2,5-dimethoxyphenyl)-beta-hydroxypropylamine-HCl, m. 174°. Bromohydroquinone di-Me ether, converted into the Grignard reagent and reacted with Me2NCH2CN, the base liberated with NH3, extd. with Et2O and treated with EtOH-HCl, gives 2,5-dimethoxyphenacyldimethylamine-HCl (III), m. 171° (decompn.), catalytic reduction of which yields beta-(2,5-dimethoxyphenyl)-beta-hydroxyethyldimethylamine-HCl, m. 155°; its methochloride, m. 185-6°. The free base from III and MeMgI give beta-(2,5-dimethoxyphenyl)-beta-hydroxypropyldimethylamine-HCl, m. 176.5.degree.; methochloride, m. 213.5.degree.. alpha-Isonitroso-2,5-dimethoxypropiophenone, pale yellow, m. 97-8°, was prepd. by Hartung's method (Patent US1989093, C. A. 29, 1941.7); catalytic reduction yields beta-(2,5-dimethoxyphenyl)-beta-hydroxyisopropylamine-HCl, m. 175-6° (decompn.). The alpha-Br deriv. of 2,5-(MeO)2C6H3COEt with excess of MeNH2 in Et2O gives 2,5-dimethoxy-alpha-methylaminopropiophenone (IV), whose HCl salt, m. 172-3° (decompn.); catalytic reduction yields beta-(2,5-dimethoxyphenyl)-beta-hydroxyisopropylmethylamine, whose HCl salt (V) m. 170°. The alpha-dimethylamino analog of IV m. 154-6° (decompn.); that of V m. 198° (decompn.); the methochloride of the latter m. 221-3° (decompn.). It is assumed that the hydroxyisopropylamine group has the ephedrine, rather than the pseudoephedrine, configuration; the relatively high m. ps. and the methods of prepn. support this view. A Dream Within A Dream (http://www.poedecoder.com/Qrisse/works/dreamw.html) |
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Vitus_Verdegast (Hive Bee) 09-10-03 01:49 No 458038
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PART III (Rated as: excellent) |
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Amines related to 2,5-dimethoxyphenethylamine. III: 2-Hydroxy- and 2-methoxy-5-methylphenylalkanolamines. Ardis, Alan E.; Baltzly, Richard; Schoen, Wm. Wellcome Research Labs., Tuckahoe 7, NY, Journal of the American Chemical Society (1946), 68 591-5. CODEN: JACSAT ISSN: 0002-7863. Journal language unavailable. CAN 40:17724 AN 1946:17724 CAPLUS Abstract cf. C.A. 34, 1626.5, 1627.1. The primary and secondary bases of the phenylethyl- and phenylisopropylamine types reported in Parts I and II have been found to possess potency rather surprising in pressors with MeO rather than HO groups on the rings. The activity of the phenylalkanolamines is considerably greater than that of the bases with no HO group b to the N atom. The compds. in which the 5-MeO group is replaced by a 5-Me group have been prepd. for comparison with the 2,5-di-MeO compds. previously studied. The chief difficulty encountered was the dealkylation in the prepn. of the necessary alpha-bromo ketones. Bromination in CHCl3 and CCl4 did not give satisfactory results but in MeOH was found to be suitable. The calcd. amt. of Br was added to the ketone in about 5 parts of MeOH; in most cases a few drops of concd. HCl was added initially. 2,5-Dimethoxy-alpha-bromopropiophenone, m. 49-9.5.degree.; 2-benzyloxy-5-methyl-alpha-bromoacetophenone (I), m. 85-5..5.degree.; 2-benzyloxy-5-methyl-alpha-bromopropiophenone, m. 58.5-9.5.degree.; 2-methoxy-5-methyl-alpha-bromopropiophenone, m. 17°. The bromo ketones and 2 equivs. of PhCH2NHMe in abs. ether allowed to stand 24-72 hrs., the excess of the amine removed as the HBr salt, the filtrate treated with an excess of Ac2O (2-3 hrs.), and the soln. extd. with dil. HCl, give the alpha-(benzylmethylamino) ketones (analyzed as the HCl salts). 2-Benzyloxy-5-methyl-alpha-(benzylmethylamino)acetophenone (II), m. 154-6°; 2-HO analog, m. 186.5-7°; II with Pd-C gives 2-hydroxy-5-methyl-alpha-(methylamino)acetophenone, m. 204-6°; 2-hydroxy-5-methyl-alpha-(benzylmethylamino) propiophenone, m. 185-6°; this reacts slowly with CH2N2 to give the 2-Me ether, m. 211.5-13.5.degree.. 5,2-Me(PhCH2O)C6H3COCH2Br, reacted with (CH2)6N4, gives an amine whose soly. was so similar to that of NH4Cl that it could not be freed of inorg. material; reduction with Pd-charcoal in 95% EtOH gives 2-hydroxy-5-methyl-alpha-aminoacetophenone, pale yellow, m. 222-5.degree. (decompn.); 2-Me ether, m. 201.5-3° (decompn.). 2-Methoxy-5-methyl-alpha-isonitrosopropiophenone, prepd. from the ketone and MeNO2, pale yellow, m. 101.5-2.degree.; 2-benzyloxy analog, m. 95.5.degree.. The amino ketones were reduced to the amino alcs. by Pt oxide in alc. or H2O; the isonitroso compds. can be reduced by Pt alone or in 2 steps by Pd-charcoal followed by Pt; the compds. were isolated and analyzed as the HCl salts: beta,2-Dihydroxy-5-methylphenethylamine, m. 144-4.5.degree.; 2-Me ether, m. 144-5.degree.. beta,2-Dihydroxy-alpha,5-dimethylphenethylamine, 5,2-Me(HO)C6H3CH(OH)CH(NH2)Me, m. 214-14.5.degree.; 2-Me ether, m. 218° (decompn.). beta,2-Dihydroxy-N,5-dimethylphenethylamine, 5,2-Me(HO)C6H3CH(OH)CH2NHMe (as acid oxalate), m. 151°; 2-Me ether, compd., m. 167.5-8.5.degree.. beta,2-Dihydroxy-N,a,5-trimethylphenethylamine, 5,2-Me(HO)C6H3CH(OH)CH(NHMe)Me, m. 197.5-8°; 2-Me ether, m. 186-7°. p-HOC6H4CHO and EtNCO in ether give the urethan, m. 90-2.degree.; the cyanohydrin (m. 82°), hydrogenated in alc. HCl, gives 4-(ethylcarbamyloxy)phenethylamine (HCl salt), m. 220° (decompn.). N-Benzyl-4-(ethylcarbamyloxy)-N-methylphenethylamine (HCl salt), m. 199.5-200°; (4-ethylcarbamatophenylethyl)methylamine (HCl salt), m. 208°. p-MeC6H4COEt and PhCH2Cl with KOH in MeOH give 84% of 2-benzyloxy-5-methylpropiophenone, b3 176-9°, m. 43°. 2-Benzyloxy-5-methylbenzaldehyde, b1 150-5.degree., m. 58.5-9°, 80%; condensation with BrCH2CO2Et and sapon. yield beta-(2-benzyloxy-5-methylphenyl)hydracrylic acid, m. 120.5-1.5.degree.; the hydrazide, m. 179.5-80°, was prepd. without trouble, but in the next stage of the Curtius rearrangement gave negligible yields of the desired 5-(2-benzoyloxy-5-methylphenyl)-2-oxazolidone, m. 150-50.5.degree., probably because of the insoly. of the hydrazide (and perhaps also of the azide). I and o-C6H4(CO)2NK, refluxed in xylene, gave N-(2-benzyloxy-5-methylphenacyl)phthalimide, m. 150°; a satisfactory reduction method could not be found. A Dream Within A Dream (http://www.poedecoder.com/Qrisse/works/dreamw.html) |
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Vitus_Verdegast (Hive Bee) 09-10-03 02:17 No 458044
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Pharmacology of compounds related to 2C-H (Rated as: good read) |
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Pharmacology of compounds related to b-2,5-dimethoxyphenethylamine. I: The ethyl, isopropyl, and propyl derivatives. Hjort, Axel M.; Randall, Lowell O.; De Beer, Edwin J. Wellcome Labs., Tuckahoe, NY, Journal of Pharmacology and Experimental Therapeutics (1948), 92 283-90. CODEN: JPETAB ISSN: 0022-3565. Journal language unavailable. CAN 42:25873 AN 1948:25873 CAPLUS Abstract The toxicity, pressor activity, mydriatic activity, and action on isolated smooth muscle were detd. for the HCl salts of the 24 compds. of the type 2,5-(MeO)2C6H3R, where R is: .sbd.CHOHCH2NH2 (code no. 831), .sbd.CHOHCH2NHMe (832), .sbd.CHOHCH2NMe2 (833), .sbd.CHOHCH2NMe3+ (834), .sbd.CHOHC(Me)HNH2 (839), .sbd.CHOHC(Me)HNHMe (840), .sbd.CHOHC(Me)HNMe2 (841), .sbd.CHOHC(Me)HNMe3+ (842), .sbd.C(Me)OHCH2NH2 (835), .sbd.C(Me)OHCH2NHMe (836), .sbd.C(Me)OHCH2NMe2 (837), .sbd.C(Me)OHCH2NMe3+ (838), .sbd.CH2CH2NH2 (819), .sbd.CH2CH2NHMe (820) (cf. C.A. 28, 7367.2), .sbd.CH2CH2NMe2 (821), .sbd.CH2CH2NMe3+ (822), .sbd.CH2C(Me)HNH2 (827), .sbd.CH2C(Me)HNHMe (828), .sbd.CH2C(Me)HNMe2 (829), .sbd.CH2C(Me)HNMe3+ (830), .sbd.C(Me)HCH2NH2 (823), .sbd.C(Me)HCH2NHMe (824), .sbd.C(Me)HCH2NMe2 (825), .sbd.C(Me)HCH2NMe3+ (826). Most of the compds. were not very toxic to mice. A powerful and prolonged pressor action was shown by 831, 832, 839 (most active), and 840. In general, pressor activity was limited to the primary and sec-amines of the Et and iso-Pr series, and the presence of a beta-hydroxy group increased the pressor activity. A beta-methyl group was always inhibitory to pressor action. The tertiary and quaternary bases had little or no effect on blood pressure. The beta-hydroxyisopropylamines and the compds. contg. quaternary N enhanced adrenaline activity. 821 combined pressor properties with the ability to reverse the action of adrenaline. The ability to diminish the depressor action of acetylcholine was shown by the primary, sec-, and tert-amino 2-hydroxyethyl compds. and the sec- and tert-amino beta-hydroxyisopropyl compds., excepting 839. This property was absent in compds. contg. a quaternary N atom or a beta-methyl group, or lacking a beta-hydroxy group, with the single exception of 825. All of the compds. contracted isolated guinea pig and rabbit uteri, and all relaxed isolated rabbit intestine. Pressor activity was correlated strongly with mydriatic potency. Exophthalmos, salivation, and pilomotor effects in mice were usually, but not always, assocd. with pressor properties. A Dream Within A Dream (http://www.poedecoder.com/Qrisse/works/dreamw.html) |
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merbst (Newbee) 12-28-03 01:38 No 479385 |
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Part IV full text (Rated as: please don't post so long articles when I'm stoned, dammmit!) |
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Journal of the American Chemical Society Vol 70 March 1948, pg 1084 Amines Related to 2,5-Dimethoxyphenethylamine. IV. 2,5-Diethoxy, 2-Hydroxy-5-methoxy and 2-Hydroxy-5-ethorryphenylalkanolamines BY WALTER S. IDE AND RICHARD BALTZL In continuation of our studies on this interesting family of pressors, we report the preparation of the primary and secondary ,R-hydroxy-,R-(2,5-diethoxypheny1)-ethylamines and isopropylamines, and their analogs having hydroxyl groups in the 2-position with me+oxyl or ethoxyl groups in the 5-position. The 2,5-diethoxy family (I-IV) was prepared by a line of synthesis shown in the upper part of Chart I. In the main, this approach resembles that used in Paper 112 of this series to prepare the corresponding dimethoxy compounds. The 2,5-diethoxyphenylalkanolamines and their precursors tend to be more soluble and less readily crystallized than their methoxy analogs and were usually isolated in lower yield. The preparations of the 2-hydroxy-5-alkoxyphenylalkanolamines (V-XII) largely followed the scheme used in Paper I11 of this series8 for the 2-hydroxy-5-methylphenylalkanolamines. These syntheses are outlined in the lower part of Chart I. A few comments are in order. In the first preparation of the aminoalcohol VII, the isonitrosoketone VIIb was reduced directly with platinum in ethanolic hydrogen chloride solution. Compound VI1 was obtained without difficulty although it later became apparent that other substances were present in the mother liquors. In a later preparation, palladized charcoal was used for the first stage of the reduction and the 2-benzyloxyaminoketone hydrochloride, VIIa, was isolated as the major product. It is rather surprising that the 2-benzyl group was retained in the presence of this catalyst; the only rational explanation is that the sample of palladized charcoal had been partially inactivated. Successive hydrogenations of VIIa with fresh palladized charcoal and with platinum yielded VII. In the preparation of Compound IX, the usually reliable hexamethylenetetramine method broke down, only traces of chloroform-insoluble material being obtained from the reaction of hexamethylene tetramine and IXC.~ The bromoketone was then treated with benzhydrylamine6 but apparently considerable tertiary as well as secondary amine was formed and the desired product was not readily separated. The synthesis of IX was finally accomplished by treating IXc with dibenzylamine. The reaction was slow and far from quantitative (in contrast to similar reactions with benzylmethylamine) but the tertiary amine IXb was isolated easily. On hydrogenation with palladized charcoal, IXb absorbed two mols of hydrogen rapidly at room temperature and a third more slowly at 65°.6 At the time this work was started, attempts were made to prepare amino alcohols having the 2-hydroxyl group protected in form of an ester. The acetylation of 2-hydroxy-5-methoxypropiophenone yielded 2-acetoxy-5-methoxypropiophenone (XIIId) which was brominated in methanol (with de-esterification) to 2-hydroxy-5-methoxy- a-bromopropiophenone (XIIIc) . Carbethoxylation of 2-hydroxy-5-methoxypropiophenone followed by nitrosation gave 2-ethylcarbonato-5- methoxy-a-isonitrosopropiophenone (XIVb) , On hydrogenation it was found that the carbethoxyl was lost and this line of synthesis was abandonedas Since Compounds 111, IV, VII, VIII, XI and XI1 were prepared by hydrogenation of ketones in weakly acidic solution, it is reasonable to assume that they possess the ephedrine rather than the pseudo ephedrine configuration. Physiological Properties.-An extended report on the pharmacology of these substances will be published elsewhere. Briefly, the 2- hydroxy-5-methoxyphenylalkanolamines resemble rather closely their 2,5-dimethoxy analogs which are powerful, long-acting pressors, but are somewhat less potent and less toxic. Potency falls off in the other two classes, the 2,5-diethoxyphenylalkanolamines being the least active, and also the most toxic. Of the Compounds I-IV, only Compound I11 is at all comparable to the 2,5- dimethoxy series in length of action. Experimental Physical and analytical data on the substances isolated in pure form are presented in Table I. All melting points are corrected. 2-Hydroxy-5-alkoxyketones and 2,SDiethoxyketones. -These compounds were prepared by Friedel-Crafts reactions between hydroquinone dialkyl ethers and the appropriate acyl chlorides or anhydrides. Since in these Friedel-Crafts reactions there is little tendency to form tarry or polymeric material, anhydrides were not superior to acyl chlorides for our purposes. In our hands some ohydroxy ketone was always formed even under conditions designed to minimize dealkylation (addition of aluminum chloride to the other reactants below 5’ and short reflux times). The amount of dealkylation could, however, be held below 20% under mild conditions. When more drastic conditions were employed (addition of acyl chloride last without temperature control and with longer reflux times) up to about 40% of 2-hydroxy-5-alkoxyketone could be obtained. With hydroquinone dimethyl ether the 2,5dimethoxyketones were still isolated in 4M0y0 yield together with small amounts of starting material. With hydroquinone diethyl ether, dealkylation seemed to be easier and the more drastic conditions resulted in extensive formation of 2,5dihydroxyketones which were not conveniently se arated at this point. Mixtures of the 2-hydroxyd-e&xy and of 2,5dihydroxyketones were usually benzylated, giving products easily separable by distillation. 2 -Benzyloxy-5-alkoxyketones.-The crude alkali-soluble fractions from Friedel-Crafts reactions were benzylated in methanol with potassium hydroxide and benzyl chloride, slightly less than one equivalent of each being added initially with two later additions of half equivalents at two-hour intervals. Stirring was found to be desirable in order to minimize bumping. The products were washed with alkali, dried over potassium carbonate and distilled zn uacuo. Yields varied from 60-9070 dependent largely on the amount of dihydroxyketone present. a-Bromoketones.-Bromination was carried out in methanol solution as described in Paper I11 of this series.* Yields of pure product varied between 55 and 90%, the lower yields corresponding to the lower-melting and more soluble compounds. a-Isonitrosopropiophenones .-The propiophenones were nitrosated by the methyl nitrite method of Hartung and Crossley.7 Yields were from 50-75% of pure isonitrosoketone. Tertiary Aminoketones.-The technique used in the reaction of benzylmethylamine with the a-bromoketones was that of Ardis, Baltzly and Schoen.8 It became apparent during the course of this work that the acetic anhydride treatment was not adequate to remove traces of secondary amine from the tertiary aminoketones and, due largely to this defect, only two of the six a-benzylmethylamines were obtained analytically pure. One of these, IIb, was isolated in an 89% yield, the other (VIb) in only 20%. The quantities of benzylmethylamine hydrobromide precipitated from the reaction mixture were in all cases approximately the calculated amount and it is believed that the reaction itself is effectively quantitative. Of the four tertiary aminoketones that had to be reduced as crude preparations, two afforded pure a-methylaminoketones (Xa and XIIa) after debenzylation. The yields of Xa and XITa were 90 and 55%, respectively, reckoned on the crude tertiary aminoketones employed. In the other two lines of synthesis, only the final aminoalcohols (IV and VIII) were completely pure-the intermediates were crystalline but apparently contaminated with tenacious impurities. Compound IXb (2-benzyloxy-5-ethoxy-~~dibenzylaminoackophenone) was prepared by treating 0.05 mole of the corresponding bromoketone (1x4 with 0.1 mole of dibenzylamine in 500 cc. of absolute ether at room temperature. After standing 40 hours, 7 g. (0.025 mole) of dibenzylamine hydrobromide was obtained. Only 3 g. more separatecl after standing three days longer. The filtrate from the salt was extracted with water, allowed to stand three hours with 5 cc. of acetic anhydride and then shaken with 1 N hydrochloric acid solution. At this point, a copious precipitate formed and was filtered off. After recrystallization of this solid, analysis showed it to be the desired product (IXb) . The yield was 60%. The technique of Simonoff and Hartung6 might have given better results but seemed inadvisable at the time. a-Methy1aminoketones.-The palladized charcoal reduction of the a-benzylmethylaminoketone hydrochlorides removed the N-benzyl groups smoothly and the 2-benzyl group when present. Compounds IIa, Xa and XIIa were isolated in good yield. The product of the reduction of VIb was hydrogenated directly with platinum without attempting the isolation of the intermediate. The precursors of IV and VIII, although crystalline, could not be purified so as to give satisfactory analyses. When debenzylation can be applied to a pure substance the reaction is usually quantitative. The reduction of IIb, for example, gave the calculated quantity of IIa, and after two recrystallizations the yield was 75%. a-Amhoketonee.-Compound Va was prepared by the hexamethylenetetramine method. The initial product of the hydrolysis with alcoholic hydrogen chloride of the addition compound from hexamethylenetetramine and Vc was not readily separated from ammonium chloride. The crude product, contaminated with ammonium chloride, was debenzylated with palladized charcoal yielding Va which was purified easily. The yield was 55% from the bromoketone Vc. A similar situation had been found with the 5-methyl analog.' The debenzylation of IXb afforded IXa in quantitative yield. The aminopropiophenones IIIa and VIIa were prepared by reduction of the corresponding isonitroso ketones with palladized charcoal in alcoholic hydrogen chloride solution. Yields were 60-70% of pure material. The reduction of XIb to XI was performed in two stages with no attempt to isolate the intermediate aminoketone. Aminoalcoho1s.-With the exception of Compound I, all the aminoalcohols were prepared by hydrogenation of the corresponding aminoketone hydrochlorides with platinum catalyst. Yields of pure compounds were 40 to 90% dependent largely on losses in crystallization. Compound I was prepared by the line of synthesis indicated in Chart I and followed by Baltzly and Buck,* in the preparation of the 2,5dimethoxy analog. The substances shown in Chart I are those actually isolated. The 2,5diethoxybenzaldehyde was prepared in 57% yield by the Gattermann reaction. The product from the Reformatzky reaction of this aldehyde and ethyl bromoacetate was saponified in the cold and the P-hydroxy acid IC (yield 72%) was purified by recrystallization. Reesterification was accomplished by the use of diazomethane (to avoid dehydration) and the ester was refluxed directly with alcoholic hydrazine hydrate forming Ib, in effect quantitatively. The azide obtained from Ib by the action of cold nitrous acid was taken up in benzene and dried briefly. Cautious warming of the benzene solution of the azide produced the oxazolidone Ia in 67% yield from the hydrazide. Cleavage with cold concentrated hydrochloric acid* afforded I, yield 50% after two crystallizations. Acknowledgment.-The authors wish to express their gratitude to Mr. Samuel W. Blackman for the microanalyses here reported. . Summary The primary and secondary aminoalcohols of the 2,5-diethoxy, 2-hydroxy-5-methoxy and 2- hydroxy-5-ethoxyphenethyl and phenylisopropylamine series have been prepared. (1) This work is part of a joint research being carried out in collaboration with a pharmacological group in the same laboratories. (2) Baltzly and Buck, THIS JOURNAL, 62, 164 (1940). (3) Ardis, Baltzly and Schoen, ibid., 68, 591 (1946). (4) Although this bromoketone is not especially active the failure of the preparation cannot be attributed to sluggishness since IXc reacts with reasonable speed with benzylmethylamine, benzhydrylamine and dibenzylamine. We are inclined to suspect that the initial reaction product was relatively soluble in chloroform and was accordingly exposed to the further reactions with bromoketone that should be possible from the conventional formula for hexamethylenetetramine hut which are usually avoided by the precipitation of the first reaction-product. In the work reported in Paper I11 of this series it was found that if the temperature in a hexamethylenetetramine reaction was above 30-40°, the usual reaction product sometimes failed to precipitate. The original paper on this method as applied to phenacyl halides (Mannich and Hahn, Bcr., 44, 1642 (1911) states that the reactions were carried out at room temperature but gives no indication that this condition is essential. (5) Cf. Suter and Ruddy, THIS JOURNAL, 66, 747 (1944). (6) Cf. Simonoff and Hartung, J. Amer. Pharmaceutical Assoc., 86, 306 (1946). Obviously, this method involves a cleavage of benzylphenacylamine. It has gradually become apparent that although the benzyl group is usually removed preferentially from benzylphenacyl, benzyl 8-hydroxyphenethyl and benzyl phenethylamines, these other groups have considerable labilizing effect, cleavage being achieved under conditions comparable with those required for cleavage of dibenzylamines. (7) Hartung and Crosdey, "Organic Syntheses," 16, 45 (1936). (8) Cf. Schroeter, German Patent, 220,852. |
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merbst (Newbee) 12-28-03 01:45 No 479387 |
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I have part I-V in PDF format, and I will... | ||||||
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I have part I-V in PDF format, and I will email them to rhodium to put on his site. I noticed parts 1-3 on this thread are only the Abstract, I will provide full text versions of each if anybody is interested. I will post the full text of part V in my next post on this thread. |
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merbst (Newbee) 12-28-03 09:57 No 479447 |
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Part V (Rated as: good read) |
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Journal of the American Chemical Society Vol. 72 382 Amines Related to 2,5-Dimethoxyphenethylamhe. V. 2,5-Dihydroxy and 2-Methoxy-5-hydroxy Derivatives BY RICHARD BALTZLY,* JOHANNES S. BUCK* AND WALTER S. IDE Interest in the 2,5-dialkoxylated type of pressor was first aroused by the study of the properties of 2,5-dimethoxyphenethylmethylamine.~ This substance was at that time unique as being the only ring-alkoxylated pressor of considerable potency.' It was also unusual as possessing considerable activity when given orally. Whereas ordinarily the hydroxy pressors are far more potent than their ethers, 2,5-dihydroxyphenethylmethylamine was of about the same potency as its dimethyl ether and its action was shorter.' When a more extended series of 2,5-dialkoxyphenethylamines had been prepared, comparison was sought between two other members and their demethylated analogs. Demethylation of 2,5-dimethoxyphenethylamine and of /3-(2,5- dimethoxyphenyl) -isopropylamine afforded the corresponding dihydroxy compounds of which only the first could be obtained crystalline. Both were tested, the latter as a solution of the crude preparation, and gave results similar to those previously reported by Hjort4 although 2,5-dihydroxyphenethylamine6* was somewhat superior to its N-methyl derivative and resembled closely the dimethoxy pressors. Oral activity was, however, largely absent. It later became apparent that optimal activity was to be expected only with an hydroxyl group in the side chain.E We decided to attempt preparation of further 2,5-dihydroxy types, but as extreme experimental difficulties were anticipated (since these are derivatives of hydroquinone) it seemed best to prepare a few specimens for test and only to complete the series if preliminary results gave promise that the effort would be rewarded. The scheme of synthesis followed is outlined in Chart I. Use of quinacetophenone as starting material gave access also to derivatives of the 2-methoxy-5-hydroxy type and operations in that series were carried out in parallel. Observations from various laboratories, confirmed and summarized by Hjort' had been to the effect that in pressors a m-hydroxyl group was especially beneficial. It was assumed that benzylation of quinacetophenone would take place first at the 5- hydroxyl. This assumption was justified by the properties of the monobenzyl ether isolated. The 2-hydroxyl was then methylated and the benzyl group removed by hydrogenolysis at a later stage of the synthesis. In actual operations serious difficulties were encountered only in the last stage. The 2,5-dihydroxy-a-aminoketone hydrochlorides, IIa and IVa, were unexpectedly stable, probably due to chelation. On reduction of the carbonyl group, however, the substances became extremely sensitive. Compound 11, p-hydroxy-/3-(2,5-dihydroxypheny1)- ethylamine hydrochloride was isolated but could not be obtained free from color. Its N-methyl derivative did not crystallize and, probably because of that, rapidly decomposed. Compound 111, /3-hydroxy-&(2-methoxy-5-hydroxyphenyl)-ethylmethylamine hydrochloride was not abnormally sensitive. Compounds I1 and III were tested and exhibited pressor characteristics very similar to those reported6 for their 2,5-dimethoxy analogs without the side chain hydroxyl group. Both were much inferior to 8-hydroxy-/3-(2,5-dimethoxyphenyl)-isopropylamine hydrochloride (Compound 839) requiring 3-4 times as large a dose to provoke a 50 mm. rise in blood pressure and one that lasted only twenty to thirty minutes as compared with the two-hour pressure elevation produced by Number 839. The toxicity relationships were relatively favorable (LDW = about 700 mg./kg. body weight in mice) but it was fairly clear that other substances of this type would not be of outstanding interest and that any results from completing the series would not be proportionate to the effort involved. Experimental Physical and analytical data for the new substances prepared are presented in Table I. Quinacetophenone.-The original directions of Nencki and Schmidt lead to poor results. In our hands the yield of product sublimed in vacuo by their procedure was 3%. This was increased to about 12% if the reaction mixture, after complete addition of hydroquinone, was refluxed vigorously for one and one-half hours. A yield of 40% of sublimed material was obtained in one run during which one equivalent of acetic anhydride was added in small portions during this reflux period. The purification of quinacetophenone by recrystallization is accompanied by serious losses. The best procedure was to sublime the crude precipitate at latm. pressure. Benzylation of Quinacetophenone.-The quinacetophenone was dissolved in ten volumes of 95% ethanol and heated until refluxing was vigorous. Alkali (as 40% sodium hydroxide solution) and benzyl chloride were added in portions to the boiling solution. When 0.2 mole of quinacetophenone, 0.35 mole of benzyl chloride and 0.3 mole of alkali were used, 46% of the starting material was isolated as pure 2-hydroxyd-benzyloxyacetophenone (IIIe) and 25y0 as pure 2,5-dibenzyloxyacetophenone (IIe). Use of larger quantities of benzyl chloride and of alkali resulted in larger yields of IIe and smaller of IIIe. After rduxing two hours the alcohol was evaporated and the residual material partitioned between ether and 10% sodium hydroxide solution. The sodium salt of IIIe has a tendency to precipitate during the extractions. The free phenol, precipitated by acidification, is markedly yellow and gives an intense coloration with alcoholic ferric chloride solution. When dissolved in sodium hydroxide solution and methylated with dimethyl sulfate (100% excess of alkylating agent and alkali used) on the steam-bath IIIe affdrded a-methoxy-5-benzyloxyacetophenone (IIId) in 90% yield. Preparation of the Bromoketones IIc and IIIc.-Bromination of IIe and IIId in methanol as described by Ardis, Baltzly and Schoens gave 2,5-dibenzyloxy-a-bromoacetophenone (IIc) in 88% yield and 2-rnethoxy-5-benzyloxya- bromoacetophenone in 54% yield. Both were free of 2- hydroxy ketones as shown by negative tests with ferric chloride. The Aminoketone Hydrochlorides, IIa, IIIa and IVa.- The primary aminoketone hydrochloride IIa was prepared from IIc and hexamethylenetetramine by the conventional method followed by hydrogenation with palladized charcoal to remove the benzyl groups. The intermediate 2,5- dibenzyloxy-a-aminoacetophenone hydrochloride was obtained in crystalline form but contaminated by ammonium chloride that could not be separated by crystallization.*~9 The secondary aminoketone hydrochlorides, IIIa and IVa, were prepared by the reaction of benzylmethylamine (2 mols) in ether with the bromoketones IIIc and IIc followed by hydrogenation over palladized charcoal. In both cases the intermediate benzylmethylaminoketone hydrochlorides could not be crystallized. This is not unusual with substances of this type. After the protective benzyl groups had been removed by hydrogenolysis, IIIa and IVa were purified without difficulty. The Aminoalcohol Hydrochlorides, II and III.-Reduction of IIa, IIIa and IVa with Adams catalyst in 90%ethanol proceeded smoothly. The reduction product of III, p-hydroxy-~-(2-methoxy-5-hydroxyphenyl)-ethylmethylamine hydrochloride, III, was also isolated and purified with ease. The corresponding 2,5-dihydroxy derivative, expected from the reduction of IVe, could not be induced to crystallize. The solutions darkened rapidly and resulted in unmanageable tars. In the case of IIa, the product, p-hydroxy-p-(2,5-dihydroxyphenyl) -ethylamine hydrochloride crystallized without difficulty, but could not be obtained free of color although charcoaled repeatedly and crystallized under nitrogen. 2,5-Dihydroxyphenethylamine Hydrochloride (I) .-Five grams of 2,5-dimethoxyphenethylamine was dissolved in 35 cc. of concentrated hydrochloric acid and heated at 170C for two hours in a glass bomb. The dark brown solution was evaporated to dryness in vacuo giving a dark gum that crystallized overnight. It was crystallized repeatedly from ethanol--ether mixtures with charcoaling, but could not be obtained in a colorless form although analytically pure. Demethylation by the same procedure of p-(2,5-dimethoxypheny1)- isopropylamine gave colored material that could not be induced to crystallize. Samples received preliminary testing in solution. Summary 1. The preparation of Beta-hydroxy-Beta-(2,5-dihydroxyphenyl)-ethylamine, of 2,5-dihydroxyphenethylamine and of Beta-hydroxy-Beta-(2-methoxy-5-hydroxyphenyl)-ethylmethylamine as their hydrochlorides is described. 2. As pressors these compounds are inferior to the corresponding 2,5-dimethoxy compounds. (1) This work is part of a joint research carried out in collaboration with a pharmacological group in these laboratories. (2) Present address: Sterling-Winthrop Research Institute. Rensselaer, New York. (3) Buck, Txis JOURNAL, 64, 3661 (1932). (4) Hjort, J. Pharmacol. Exptl. Theraput., 62, 101 (1934) (5) Raltzly and Buck, TEII JOURNAL, 02, 181 (1940) (5a)Neuberger (Biochcm. J., 48, 606 (1948)) has recently reported this substance. His characterization (m. p. 169-170") is in reasonable agreement with ours. (6) Hjort, Randall and de Beer, J Pharmacol Exptl Therapeut. 93, 283 (1948) (7) Nencki and Schmid, J. Prakt. Chem., II, 23, 546 (1881). (8) Ardis, Baltzly and Schoen, THIS JOURNAL, 68, 591 (1946). (9) Cf. Idc and Baltnly, ibid., 70, 1084 (1948). |
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merbst (Newbee) 12-31-03 08:40 No 479949 |
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Since the OCR of Adobe Acrobat can't handle... (Rated as: good read) |
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Since the OCR of Adobe Acrobat can't handle low resolution scans of old scientific journals as well as a human, here are the original PDFs on Rhodium's site for whomever is interested. https://www.rhodium.ws/pdf/archive/merbst/Amines%20related%20to%202-5-dimethoxyphenethylamine%201.pdf https://www.rhodium.ws/pdf/archive/merbst/Amines%20related%20to%202-5-dimethoxyphenethylamine%202.pdf https://www.rhodium.ws/pdf/archive/merbst/Amines%20related%20to%202-5-dimethoxyphenethylamine%203.pdf https://www.rhodium.ws/pdf/archive/merbst/Amines%20related%20to%202-5-dimethoxyphenethylamine%204.pdf https://www.rhodium.ws/pdf/archive/merbst/Amines%20related%20to%202-5-dimethoxyphenethylamine%205.pdf For anyone interested in OCRing old journals using Acrobat Reader, just upgrade to version 6.01 then click the down arrow to the right of the "T with a dashed square around it" on the second row of the toolbar. Choose the "Column Select Tool" and then drag a square around the text you would like to capture, then right click Copy and paste it into a text document. Then spend the time to go through the text document and correct the OCR errors or else it will look like the above post  .
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Rhodium (Chief Bee) 07-05-04 00:35 No 517490 
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Synthesis of 2C-H via its phenylpropionamide (Rated as: good read) |
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Hydroxy- and Dihydroxyphenylethylmethylamines and Their Ethers Johannes S. Buck J. Am. Chem. Soc. 54, 3661-3665 (1932) (https://www.rhodium.ws/pdf/2ch.phenylpropionamide.pdf) The Hive - Clandestine Chemists Without Borders |
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