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Patented Nov. 26, 1946 I 2,411,611 UNITED;- STATES PATENT OFFICE’ I , 2.411.611 MANUFACTURE or N-(POLYHYDROXY ALKYL ) -ARYLAMINES Franz Bergel, Aaron Cohen, and John Wynne Haworth, Welwyn Garden City, England, as signors, by mesne assignments, to Hoffmann La Roche Inc., Nutley, N. J ., a. corporation of New Jersey No Drawing. Application March 4, 1942, Serial No. 433,341. In Great Britain May 20, 1941 5 Claims. (Cl. 260-211) 2 1 The synthesis of N-(polyhydroxyalkyl)~ The N - (polyhydroxyalkyl) - arylamines are used as intermediates in the preparation of val arylamines, such as arabityl or ribityl xylidines, is described in the literature (of. R. Kuhn, uable pharmaceutical substances. The following examples in which the parts are Berichte der deutschen chemischen Gesellschaft, 1935, 68, 1282 and‘1'765; P. Karrer, Helvetica Chimlca Acta, 1935, 18, 522 and 1130; 1936, 19, by weight illustrate how the process of the in vention may be carried into e?ect:- 264). Its main feature is the formation of a con > 1. Preparation of N-(d-arabityl) -aniline densation product between a sugar and the arylamine and the subsequent or concurrent (a) d-Arabonic acid anilide is prepared in any 10 convenient manner, for example by heating d arabonic acid lactone with aniline, as described The present invention provides a process which by Th. W. J. van Marle (Rec. trav. chim. Pays avoids the use of the sometimes di?lcultly acces hydrogenation to the saturated compound. Bas, 1920, 39, 549-72), for the corresponding 1 sible sugars but employs the arylamides of the compound, or by heating the lactone with aniline more readily available sugar acids of the general formula I, in which the substituents R and R’ 15 in the presence of dilute acetic acid. Alternatively the d-arabonic acid anilide may are hydrogen or identical or different alkyl be prepared from methvl d-arabonate: A mixture groups and in which a: is 3 or 4. Such arylamides of_28.5 parts of methyl d-arabonate and 15 parts may be obtained in known manner by the inter of aniline are heated on the waterbath. The action-of the corresponding arylamine with an ester or lactone or with the acids themselves 20 warm liquid mixture solidi?es after 45 minutes, when 20 parts of methanol are added and the which readily form the lactones.‘ According to heating continued for another 2 hours, while the the invention the amide is treated with an acylat methanol evaporates. The solid mass is trit ing agent to form the corresponding acyl com urated with 50 parts of absolute alcohol and well pound (II), the acyl compound is treated with pressed on a ?lter. The crude anilide is recrys a halogenating agent to‘ form the corresponding tallised from 75% alcohol and has a melting chloroimine (III) and the latter is reduced with point of 198° C. In order to increase the yield, hydrogen in the presence of a hydrogenation the mother liquors are concentrated and another catalyst to form the corresponding N-(poly 5 parts of aniline added. The heating is con acyloxyalkyD-arylamine (IV) which ?nally is hydrolysed to form the N-(polyhydroxyalkyD 30 tinued for several hours and the product arylamine (V). _ isolated in the same way as above. ~ (b) 7.5 parts of the above d-arabonic acid ‘anilide are acetylated by adding the same to a I R, 6. II R! C3 40 ~ (0) A suspension of 4.09 parts of ?nely pow =17 (CHOAc) ,CHaOAc III NHCH?CHOAchCHzOA. IV R! NHCH1(CHOH),CH,OH 3! w acetyl-d-arabonic acid_anilide, which crystallises from alcohol in colourless needles, melting point 161° C. Cl R! R solution of 3 parts of zinc chloride in 50 parts of After being kept at 0° C. for 1 hour, the mixture is al lowed to stand at room temperature for 24 hours and poured into water, precipitating tetra 35 acetic anhydride, which is cooled in ice. V _ dered tetra-acetyl-d-arabonicacid anilide and 2.08 parts of powdered phosphorus pentachloride 45 in 50 parts of dry toluene is heated on the water bath for 1 hour. Hydrogen chloride is evolved. The toluene and phosphorus oxychloride are re moved under reduced pressure. The residual oil is dissolved in ether, ?ltered clear, concentrated, 50 and light petroleum (boiling point 40-60" C.) is addedto the concentrate. On cooling, the cor responding chloroimine (III, where R=R'=H) separates in colourless needles of melting point 102° C. ((1) Catalytic hydrogenation of. the above 55 2,411,611 - 4 3 R'=CI-l’s). It separates in colourless needles, melting point 72° C. ohloroimine-is carried out by shaking a solution of 1.5 parts of the ohloroimine in 40 parts of dry ethyl acetate with hydrogen in the presence of 0.2 part of 25% palladised charcoal and 0.2 part (e) 2.5 parts of the last mentioned tetra-acetyl compound are mixed with a solution or 7 parts of crystalline barium hydroxide in 150 parts of of platinum oxide and 0.3 part of anhydrous so dium acetate. When the hydrogen uptake is com water and re?uxed for three-quarters of an hour. The excess of barium hydroxide is precipitated plete, the solution is ?ltered, evaporated to dry ness, and the residual basic material crystallised as carbonate from the resulting solution by the from aqueous methyl alcohol, from which passage of carbon dioxide. After ?ltering, the 10 clear solution is evaporated to dryness under re N-(tetra-acetyl-d-arabityl) -aniline duced pressure. The product is extracted from the residue by boiling alcohol, which is then ?l tered hot. On cooling the alcoholic extracts, 75-'l6° C. N-(d-arabityl)-p-toluidine separates in colour (e) 1.7 parts of the last mentioned tetra 15 less needles, melting point 179° C. separates in colourless plates, melting point acetyl compound are mixed with a solution of 6 3. Preparation of N-(d-ribityl)~b-toluidine parts of crystalline barium hydroxide in 100 parts (a) d-Ribonic acid-p-toluidide is prepared in of water and re?uxed for three-quarters of an hour. The excess of barium hydroxide is precip any convenient manner. For example, a mix itated as carbonate from the resulting solution 20 ture of 10 parts of d-ribonic acid lactone and 12 parts of p-toluidine, 100 parts of water, and 10 by the passage of carbon dioxide. After ?lter ing, the clear solution is evaporated to dryness under reduced pressure. parts of glacial acetic acid is heated on the water bath overnight in an open vessel. A solid mass The product is ex is formed, which is recrystallised from butyl al tracted from the residue by boiling alcohol, which is then ?ltered hot. On cooling the alcoholic ex 25 tracts, N-(d-arabityD-aniline separates in col ourless needles, melting point 157-159” C. 2. Preparation of N-(d-arabityl) -t0luidine (a) d-Arabonic acid-p-toluidide is prepared in 30 any convenient manner. For example, a mixture of 8 parts of d-arabonic acid lactone, 10 parts of p-toluidine, 80 parts of Water and 10 parts of acetic acid is heated on the water bath for 24 cohol, yielding d-ribonic acid-p-toluidide, which forms colourless needles, melting point 157-158° C. In order to increase the yield, the butyl alco hol mother liquors are evaporated to dryness and the residue heated for a further 24 hours, and the product isolated as above. (b) 10 parts of the above d-ribonic acid-p toluidide are acetylated by adding the same to a solution of 4 parts of zinc chloride in 60 parts of acetic acid anhydride, which is cooled in ice. hours in an open vessel. A solid mass is formed 35 After being kept at 0° C. for an hour, the mix which is triturated with alcohol, ?ltered and washed with ether, yielding d-arabonic acid-p toluidide, which crystallises from alcohol in col ourless needles, melting point 199-200° C. ture is allowed to stand at room temperature overnight and poured into water, precipitating tetra-acetyl-d-ribonic acid-p-toluidide, which crystallises from alcohol in colourless needles, (b) 7.3 parts of the above d-arabonic acid-p 40 melting point 120-121° C. toluidide are acetylated by adding the same to a (0) Suspension of 12 parts of ?nely powdered solution of 3 parts of zinc chloride in 45 parts of tetra-acetyl-d-ribonic acid-p-toluidide and '7 acetic anhydride, which is cooled in ice. After parts of powdered phosphorus pentachloride in being kept at 0° C. for 1 hour, the mixture is al 50 parts of dry toluene is heated gently on the lowed to stand at room temperature overnight 4. water bath for 11/2 hours. The toluene and phos and poured into water, precipitating tetra-acetyl phorus oxychloride are removed under reduced d-arabonic acid-p-toluidide, which crystallises pressure, ?nally at 0.2 mm. 50 parts of toluene from alcohol in colourless needles, melting point are again added to the residue and the evapora 167-168” C. tion is repeated under reduced pressure. The (c) A suspension of 4 parts of ?nely powdered ?nal residue is dissolved in 60 parts of hot pe tetra-acetyl-d-arabonic acid-p-toluidide and 2 parts of phosphorus pentachloride in 30 parts of dry toluene is heated on the water bath for 1 hour. Hydrogen chloride is evolved. The toluene troleum ether (boiling point 100-120° C.), the so lution is ?ltered and the solvent evaporated un der reduced pressure. A further portion of tolu ene is added and the evaporation repeated once and phosphorus oxychloride are removed under 55 more to remove the last traces of phosphorus reduced pressure. The residue is extracted with oxychloride. The desired ohloroimine is obtained, dry ether, which leaves a small portion of un as a pale yellow oil. changed tetra-acetyl-d-arabonic acid-p-toluidide (d) Catalytic hydrogenation of the above ohloroimine is carried out by shaking 9 parts of trated and light petroleum (boiling point 40-60° 60 the ohloroimine in 100 parts of dry ethyl acetate C.) is added until the mixture is turbid. On cool with hydrogen in the presence of 0.8 part of 25% ing, the corresponding ohloroimine (III, where palladised charcoal and 0.1 part of platinum oxide ' behind. The ?ltered ethereal solution is concen R=H and R’=CH3) separates in colourless nee dles, melting point 82° C. and 5 parts of anhydrous sodium acetate. The hydrogen uptake is sometimes slow at ?rst but ((1) Catalytic hydrogenation of the above 65 can be speeded up by addition of a few drops 01’ ohloroimine is carried out by shaking a solution palladous chloride solution. When the hydrogen of 1.6 parts of the ohloroimine in 30 parts of ethyl uptake is complete, the ethyl acetate solution is acetate with hydrogen in the presence of 0.05 ?ltered and extracted several times with dilute part of 25% palladised charcoal and 0.1 part of hydrochloric acid. The acid layer is made alka platinum oxide and 0.3 part of anhydrous sodium 70 line with sodium carbonate solution, and the basic acetate. When the hydrogen uptake is complete, material extracted with ether. The ether is dried the solution is ?ltered, evaporated to dryness and over sodium sulphate and evaporated, leaving the residual basic material crystallised from a N-(tetra-acetyl-d-ribityl)-p-tolu.idine as a, yel small amount of methanol, yielding N-(tetra low oil. acetyl - d - arabityl) - p - toluidine (IV, R=H, (e) 1 part of the last mentioned tetra-acetyl 2,411,011 5 (e) 4.5 parts of the above mentioned tetra-' compound is mixed with a solution of 3 parts of crystalline barium hydroxide in 50 parts of acetyl compound are hydrolysed by mixing with a solution of 12 parts of crystalline barium hy water and boiled under re?ux for half an hour. droxide in 200 parts of water and re?uxing for The excess of barium hydroxide is precipitated three-quarters of an hour or by dissolving in 9 as carbonate from the resulting solution by the parts of methanol, adding 1.8 parts‘ of sodium passage of carbon dioxide. After ?ltering, the hydroxide in 22.5 parts of water and heating the clear solution is evaporated to dryness under re mixture on the water bath for half an hour, duced pressure. The product is extracted from during which time some of the methanol distils the residue by boiling alcohol, which is then ?ltered hot. On cooling the alcoholic extracts, l0 ‘off. In the ?rst case, the excess of barium hy droxide is precipitated from the resulting solu N-(d-ribityD-p-toluidine separates in colourless needles, which, after recrystallisation from alco hol. has a melting point 140-141” C. 3:4-dimethyl-ani1ine separates 4. Preparation of N-(d-ribityl)-3:4 in colourless , 15 plates, melting point 141-143’ C., which is identi dimethylaniline (a) d-Ribonic _ tion by the passage of carbon dioxide and ?ltered hot. In both cases, on cooling, the N-(d-ribityl) - cal in every respect with the same compound acid-3:4-dimethylganilide prepared in any convenient manner. synthesised by P. Karrer (Helvetica Chimica is For ex Acta, 1935, 18, 1130). » ample, a mixture of 5 parts of d-ribonic acid We claim: lactone and 5 parts of 3:4-dimethylaniline is 20 1. A process for the manufacture of N-(poly hydroxyalkyl) arylamines, which comprises heated on the water bath overnight. A solid is acetylating an anilide of a sugar acid of the gen formed, which is triturated with hot butyl alco hol. After cooling, the product which is d-ribonic’ eral formula ‘ ' acid-3:4-dimethylanilide is ?ltered off. It crys tallises from butyl alcohol in colourless needles, melting point 162-163° C. I , RI (b) 10 parts of the above d-ribonic acid-3:4 dimethylanilide are acetylated by adding the wherein a: is selected from the integers 3 and 4 same to 4 parts of zinc chloride in 65 parts of and R and R,’ each represent a radical selected acetic anhydride, which is cooled in ice. After so from the group consisting of hydrogen. and a being kept at 0° C. for 1 hour, the mixture is lower alkyl radical, to form the corresponding allowed to stand at room temperature for 24 acetate, chlorinating the acetate with phos hours and poured into water, precipitating tetra phorous pentachloride to form the correspond acetyl-d-rioonic acid-3:4-himethylanilide, which ing N-(polyacyloxyalkyl)-arylamine, and hy crystallises Irom alcohol in colourless needles,w as drolyzing this compound with a non-oxidizing melting point 114—115“ C. hydrolyzing agent to form the N-(polyhydroxy (c) A suspension of 10 parts of ?nely pow alkyl) -arylamine. dered tetra-acetyled-ribonic acid-3:4-dimethyl 2. A process for the manufacture of NF-(d aniiide and 5.5 parts of powdered phosphorus ribityl) -p-toluidine which comprises acetylating pentachloride in 50 parts of dry toluene is heated 40 d-ribonic acid-p~toluidide with acetic anhydride on the water bath at about 50° C. for 1 hour. in the presence of zinc chloride to form the cor The toluene and phosphorus oxychloride are re responding acetate, chlorinating the acetate moved under reduced pressure, a i'urtner 50 parts with phosphorous pentachloride to form the of toluene added and the evaporation repeated. The residue is taken up in 50 parts of hot pe troleum ether (boning point IOU-120° 0.), the solution is ?ltered, and the orgamc solvent re moved under reduced pressure. The chloro imine remains as an oil winch solidi?es on cooling and may be crystallised irom a mixture or‘ ether and petroleum ether, from which it separates in colourless needles, melting point 62“ C. (a) Catalytic hydrogenation of the above corresponding chloroimine, hydrogenating the 45 chloroimine with hydrogen in the presence of palladized charcoal and platinum oxide as cat alysts, and hydrolyzing the resulting compound in an aqueous solution of barium hydroxide to form the N-(d-ribityl) -p-toluidine. to acetylating d-ribonic acid-3:4-dimethyl-anillne 3. A process for the manufacture of N-(d ribityl) -3 : 4 - dimethylaniline which comprises with acetic anhydride in the presence of zinc crude chloroimine is carried out by shaking a chloride to form the corresponding acetate, chlo solution or 9.3 parts 01' the chloroimine in 150 rinating the acetate with phosphorous penta parts of dry ethyl acetate with hydrogen in the as _ chloride to form the corresponding chloroimine, presence 01' 0.8 part 01 25% paiiadised charcoal hydrogenating the chloroimine with hydrogen in or 1.5 parts 01 10% paliadised charcoal and 5 the presence of palladized charcoal as catalyst parts or anhydrous sodium acetate. The hy and hydrolyzing the resulting compound with arogenation can be accelerated if desired by the, so aqueous solution of barium hydroxide to form addition or more my ethyl acetate. when the the corresponding N-(d-ribityl)-3:4-dimethyl hydrogen uptake is complete, the solution is hl aniline. tered, evaporated to dryness, the residue taken , 4. A process which comprises acetylating d up in dilute hydrochloric acid and non-basic ma ribonic acid~3:4-dimethylaniline with acetic an terial removed by extraction with ether. The cs hydride to form the corresponding acetate, chlo aqueous solution is made aikaline with sodium( carbonate solution, when the N-ltetra-acetyl-d ribityl) -3:4-aiinetnyl-aniiine separates as an oil, rinating the acetate with phosphorous penta chloride to form the corresponding chloroimine and hydrogenating the chloroimine with hydro which quickly soiidi?es. This is extracted with gen in the presence of a noble metal hydrogena ether the extract washed with water, and dried. 70 tion catalyst, to form the corresponding N The solvent is removed and the residue on cool (tetra-acetyl-d-ribityl) -3 : 4-dimethylaniline. ing lorms a solid crystalline mass, which after recrystallisation irom methyl alcohol has a melt ing point 98-99‘ C. This product is N-(tetra acetyl-d-ribityl) - 3 :4-dimethylanilide. 5. 3.4-dimethyl-N-tetraacylribonyl~aniline. FRANZ BERGEL. AARON COHEN. 76 JOHN WYNNE HAWORTH.