Patented Aug. 30, 1949 2,480,649 I, UNITED STATES PATENT orrica HOMOLOG OF VITAIWIN Be 7 Stanton A. Harris‘, West?eld, and Andrew N.'Wil S011, Colonia, N. .L, assignors to Merck & 00., Inc., Rahway, N. J ., a corporation of New Jersey No Drawing. Original application August 27, 1942, Serial No. 456,370. :Dividedsand this an ‘ ‘ plication July 20, 1946, Serial No. 685,239 ’ 5 Claims. I (chasm-297.5) t 1 - This invention relates generally to organic (whichvvcanybe obtained by condensing equimo chemicalcompounds and to methods of manu facturing the same; in'a more limited sense, it lecular proportions of methyl ethyl ketone and methyl methoxyacetate in the presence of sodium is ‘concerned with a growth-promoting factor re at a low temperature) are added with a small lated to pyridoxine (vitamin B6) and to proc- 5 amount of piperidine, to about 24.6 g. of cyano esses for producing the same. . The .present- application is a division of the co- acetamide dissolved in approximately 100 cc. of hot absolute ethanol. After cooling, the ‘precipi pending application by the same inventors, ‘Serial 't'ated solid massvlis removed and washed with No. 456,370, ?led August 27, 1942., "ethanol. The present invention involves the synthesis 10' Approximately 119 g. of the Z-ethyI-Il-meth of a novel organic chemical compound, 2—ethyl-' oxymetliylé5-cyano-6-hydroxypyridine thus 0b 3-hydroxy - 4,5-bis-(hydroxymethyl)-pyridine, a material which prevents or cures an acrodynia- tained is suspended in acetic anhydride and about 60.’? cc. of fuming nitric acid is added slow like dermatitis in young rats and which possesses 1y,‘ while the mixture is vigorously agitated and growth-promoting properties in the metabolism 15 maintained at a temperature of about 65-70“ C. of plants. Upon cooling a yellow crystalline solid appears. The process according to the present invention The solid and liquid are slowly poured into water includes the condensation of cyanoacetamide and the solid, which is the 3-nitro compound, with l-methoxy-ZA-hexadione (which can be ob~ is removed, washed and dried. tained by reacting methyl ethyl ketone and meth~ 30 About 76 g. of the 3-nitro-compound, 100 g. of yl methoxy acetate), treatment of the 2-ethyl- phosphorous pentachloride and approximately 3 - methoxymethyl - 5-cyano-6-hydroxypyridine 320 cc. of dry tetrachloroethane are mixed and thus obtained with nitric acid, phosphorous halide, and a reducing agent in succession to heated upon an oil bath. After the reaction has begun, as indicated by evolution of hydrogen produce 2-ethyl-3-amino - 4 - methoxymethyl-éS- 25 chloride, the bath temperature is maintained at‘‘ aminomethyl pyridine, diazotization followed by halogenation of the product, and hydrolysis of the halogen compound to yield 2-ethyl-3-hy- 140-145” C. for about two hours, after which the tetrachloroethane and phosphorous oxychloride formed are removed by distillation under reduced droxy - ‘L5 - bis- (hydroxymethyl) pyridine hydropressure at below 70° C. The residue is then dis halide. The reactions involved can be repre- 3n solved in benzene and poured on crushed ice and, sented as follows: after being maintained at appromixately 0° C. CNCHgONH-g CH2OCH3 Na I ON HNOs cHaoH2ooH3+ onloom?oom _-> cmon?cnu?‘omoom —» o o oHeocHa OzN CN CHaOCHa P015 OzN CN CH20CHs B: ——-v CHaCH2\N/OH -—-> CHsCHNN/OH HCLHzN CHzNHz-HCI HNO: ——p CH:CHz\N G1 I ——> CHaCHz N cmocm CHzBr HOOCHzOH OHaCH: N H3!‘ H0 OHzBr Hi0 -—> CHsCHa onion —\ .AgCl N HBr , HO cHlon CHaCH HO] I The following example illustrates a method of carrying out the present invention, but it is to 70 for one hour, a slight excess of ammonia is added. be understood that this example is given by way of illustration and not of limitation. Erample About 38.4 ‘g. of 1-methoxy~2,4-hexadione 75 The benzene layer is removed, concentrated under reduced pressure, extracted with petroleum ether and the extract is then cooled, yielding a yel low mass of 2-ethyl-3-nitro-4-methoxymethyl-5 cyano-G-chloropyridine. The (i-chloro compound thus obtained is re 2,480,649 1. 2-ethyl-3-hydroxy-4,5 -bis- (hydroxymethyl) - pyridine hydrohalide. chloride of 2-ethyl43-amino-é-methoxymethyl-B aminomethyl-pyridine. 4 We claim: duced in methanol, using palladium black on charcoal as a catalyst, yielding the dihydro 2. z-ethyl-3-hydroxy-4,5-bis- (hydroxymethyl) - About 10 g. of the re pyridine hydrochloride. U I duced compound are dissolved in hot water, and approximately 6.43 g. ofwsodium nitrite and 11.3 g. of hydrochloric acid (36%) are added. After 2éethyl-3-hydroxy-4,5-bis- (halogenmethyl) -pyri cooling and neutralizing, the mixture is concen- - » bis- (hydroxymethyl) -pyridine hydrohalide. 3. The process that i comprises lhydrolyzing dine ‘hydrohalide to form 2-ethyl-3-hydroxy-4,5 trated under reduced pressure, extracted. with 4; The process that comprises heating 2-ethy1 alcohol, dried and further concentrated. The :3-hydroxy-4,5-bis- (bromomethyl) -pyridine hy product so obtained is then mixed with about ' drobromide with water to form 2-ethyl-3-hy 50 cc. of hydrobromic acid (48%) and heated to droxy-4,5-bis- (hydroxymethyl) -pyridine, react boiling, causing evolution of. methyl bromide and hydrogen bromide. After concentration fol lowed by cooling, crystalline‘ 2-ethyl53-hydroxy- I 4,5-bis-(bromomethyl) pyridine hydrobromide is‘ _ obtained. About 1.04 g. of this material are dis; solved in approximately 100 cc. of water and ing the latter solution with silver chloride and recovering 2-‘ethyl-3-hydroXy-4,5-bis-(hydroxy ‘methyD -pyridine hydrochloride. 5. The process that comprises heating 2-ethyl 3-hydroxy-4,5-bis(halomethyl)pyridine hydro halide with water to form 2-ethyl-3-hydroxy-4,5 heated at about 95° C. for approximately 25 min .ibirs(lhydroxymethyl) pyridine hydrohalide. > 20 utes, then the solution is ?ltered, cooled, and shaken with about 2 g. of silver chloride. The STANTON A. HARRIS. ' .solution is then ?ltered, concentrated almost to ANDREW N. WILSON. dryness at a ‘low temperature, and diluted with acetone, yielding crystalline 2-ethyl-3-hyroxy 4.»,5-bis-(hydroxymethyl) pyridine hydrochloride, >melting at about 1914-192.a 0. 25 REFERENCES CITED ‘The following references are of record in the ?le of this patent: Modi?cations may be made in carrying out the present invention without departing from ‘the } Enzyrnologia. VII, 28QCII) 1939, pp. 385-386. spirit and scope thereof and the invention is to 30. be limited only by the appended claims.