VOl. 75
NOTES
4080
Oxime of 2-Ethyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine (VI).-2-Ethyl-3-hydroxy-4,5-bis-(hydroxymethy1)pyridine hydrochloride' (10.7 g:) was oxidized with manganese dioxide and sulfuric acid in a manner exactly analogous to the preparation of pyridoxal oxime.* The OCzHb yield of the oxime of 2-ethyl-3-hydroxy-4-formyl-5-hydroxyI methylpyridine was 4.8 g. (50%). After one recrystallizaH C -0 tion from water-alcohol and one from alcohol, the oxime CH=SOH melted a t 225-226". HO' \ --AH2 ITWq\ -CH201I .Inal. Calcd. for CgH12N203: C, 55.09; H , 6.17; S , 14.28. Found: C, 53.22; H , 6.00; N, 14.12. cI ~ J , ~ ~ c2tla\yq Monoethyl Acetal of 2-Ethyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine Hydrochloride (VI1j .-Conversion of VI \'I I Y .4 g. of the oxime of 2-ethyl-3-hydroxy-4-formyl-5-hytlroxpmethylpJ.ridine (\.I) to the corresponding monoethyl Experimental4 acetal u-as carried out in the manner previously described The reactions carried out for the preparations of 2 4 0 - for the conversion of pyridoxal oxime.3 The yield of the hutyl-3-hydroxy-4,5-bis-(h droxymethy1)-pyridine and 2non no ethyl acetal of 2-ethyl-3-hydroxy-4-formyl-5-hydrox~n-amyl-3-hydroxy-4,5-bis-rhydroxymethyl)-pyridine were methylpyridine hydrochloride was 1.66 g. (39%); m.p similar to reactions previously described.'f6 Only the physi- 137.,5-138.5'. After one recrystallization from alcoholcal properties of the intermediates and products are listed ether containing a little hydrogen chloride and another rehere. from alcohol containing a little hydrogen 2-Is0butyl-4-methoxymethy1-5-cyano-6-hydroxypyridinecrystallization chloride, the material melted at 132-133'. IIIA) was prepared from l-methoxp-7-methyl-2,4-heptane.incd. Calcd. for C1~HieS03C1:C, 53.77; H , fi56; I;, dione (IA) (b.p 113' (24 mm.), n Z 91.4596). ~ After one recrrstalliz,ition froin ethi 1 alcohol, the product melted at 5.70 Found: C, ,54.00; H, 6.29; S , 5 63. 204-205" RESEARCH LABORATORIES .Ind Calcd. for CILHI~NZO~: C, 65.43; H , 7.32; S, MERCKA N D Co., Isc. R A H K A Y , S E T V JERSEY 12 72. Found: C, 65.68; H, 7.25; N, 12.71. 2-Isobutyl-3-nitro4methoxymethyl-5-cyano-6-hydroxypyridine (IIIA) was purified by two recrystallizations from ethyl alcohol, accompanied by decolorization with Darco; Chemistry of Vitamin B6. XI. Homologs of 4I l l 1, 167-168" Desoxypyridoxine Ancil. Calcd. for C12H16X304: C, 54.33; H , 5.70; S, 1.7.83. Found: C, 64.62; H , 5.50; i S,15.83. BY DOROTHEA HEYL,EILEENLuz, STANTON A. HARRISAxD KARLFOLKERS 2-Isobutyl-3-nitro-4-methoxymethyl-5-cyano-6-chloropyridine (IVA) IWS recrystallized three tiyes from petroleum RECEIVED APRIL22, 1953 ither ( h . p . 30 I t melted at 42-43 . 4-Desoxypyridoxine was shown to be a potent Anal. Calcti. for C I Z H ~ ~ N ~ C, O ~50.80; C ~ : H, 4.96; S, 14.82. Found: C , 30.82; H , 5.12; S , 1S.08. vitamin RE inhibitor.' Because of the biological 2-Isobutyl-3-hydroxy-4,5-bis-( hydroxymethy1)-pyridine interest in this compound, the preparation of hydrochloride (VA) was recrystallized from hot water, with homologs for further biological study was underdecolorization with Darco; 1n.p. 21.'-214°. taken. Three homologs, represented by structure Anal. Calcd. for CliHl&OaC1: C, 53.33; H, 7.32; S, 111, in which the methyl group in position 2 of 45.66. Found: C, 53.35; H , 7.2B; N, 5.91). desoxypyridoxine has been replaced by ethyl, isol-Methoxy-2,4-nonanedione (IB).-Condensation of methyl methoxyacetate with methyl n-amyl ketone yielded butyl and n-amyl groups, have now been prepared l-methoxy-2,4-nonancdione; h .p. 138 O (28 mm .), n% by svnthesis through the intermediates I and 11. I .4fia.
verted to the monoethyl acetal VII. These redctions are analogous to those previously described for the corresponding pyridoxal derivative^.^,^
7
2-n-Amyl-4-methoxymethyl-5-cyano-6-hydroxypyridine (IIB) waq recrvstallized twice from ab5olute alcohol; m.p 131-1:E0 I I1 Anal. Calcd. for C i ~ H I R S ~ C, O ~66.84; : H , 7.74; S, CH, 11 96. Found: C, 66.74; H, 7.64; N, 12.05. 2-~t-Amyl-3-nitro-4-methoxymethyl-5-cyano-6-hydroxypyridine (IIIB) n as recrystallized twice from alcohol and once from dilute alcohol. It melted a t 161-162'. Anal. Calcd. for C11HI,S30a: C, 55.90; H , 6 14; Y , I11 15.05. Found: C, 56.25; H, 5.79; 9,15-24. 2-n-Amyl-3-nitro-4-methoxymethyl-5-cyano-6-ch~oropyri2-Ethyl-3-hydroxy-4 methyl 5 hydroxymethylpydine (IVB) was recrystallized twice from petroleum ether ridine hydrochloride and 2-isobutyl-3-hydroxyi b p 30-60'1; m p 42-43'. 4 methyl 5 - hydroxymethylpyridine hydrochloAnal Calcd. for C I ~ H 1 ~ S 3 0 3 C C,l : 52.43; H, ,542; ride have also been prepared by the direct hyS ,14.11. Found: C, 52.16; H , 5.00; N, 14.20. 2-n-Amyl-3-hydroxy-4,S-bis-(hydroxymethy1)-pyridine hy- drogenolysis of the 2-ethyl-3-hydroxy-4,5-bis-(hydrochloride (VBj was recrystallized from alcohol containing droxymethy1)-pyridine hydrochloride2 and 2-isotrace of hydrogeri chloride. The product melted at 186- butyl - 3 - hydroxy - 4'5 - bis - (hydroxymethy1)-
-
-
187O.
A n a l . Calcd. for C ~ Z H Z O X O ~CC, ~!5.05; : S ,5.36. Found: C , 54.93; H , 7.82; N, 0.47,
H. 7 70;
'2) D Heyl, Ibld., 70,3434 (1948) (3) 6. A. Harris, 0 Heyl and K. Folkers, tbid , 86, 2088 (1044). (4) We w e indebted to Mr. Richard Boos and his associatea for the fnicroanal yses (6) 4 h Umls rnd Y. Falkers, THISJoaR*r!+,(2, IZ48, 3887
(lPlQ1,
- -
-
pyridine hydrochloride. Hydrogenolysis of pyridoxine hydrochloride to form 4-desoxypyridoxine hydrochloride was described previously. (1) W. H. Ott, Proc. SOC.Ex+. B i d . Med., 61, 125 (1946): W.W Qtovtes all6 B. €$. Sndl, Ibid., 'HI 73 (1948). (2) 6. A. # & i C und A. N. Wilson, THISl o u n ~ ~ LI S. ,, 2626 (1841). (a) r). H@Yl,B, LUL. 9. A. Harris and K. Folkerr, Cbid , 78, 4078 {igsa). (4) R. A, #M",4bId.i Ofif #POL) (1940).
Aug. 20, 1953
NOTES Experimental6
4081
A mixture of 6.7 g. of this material, 1.5 g. of 10% palla-
2-Ethyl-3-hydroxy-4-methyl-5-hydroqmethylpyridine Hy- dium on Darco and 125 ml. of water was shaken with hydrochloride ( 111).-2-Ethyl-3-nitro4-methoxymethyl-5-cy- drogen under 2-3 atmospheres of pressure. One mole of
ano-6-chloropyridine (I, 25.6 g.) was shaken with palladium- hydrogen was consumed in several minutes. After removal Darco and hydrogen in a solution containing hydrochloric of the catalyst, the solution was concentrated to dryness acid under 2-3 atmospheres of pressure until 6 moles of hy- under reduced pressure. The white, crystalline residue drogen had been absorbed. The reduction was finished in was slurried with alcohol and collected on a filter. Two 21 hours. After removal of the catalyst, the solution was fractions, totaling 4.8 g., of 2-isobutyl-3-amino-4-methyl-5concentrated under reduced pressure to a thick oil. This aminomethylpyridine dihydrobromide were obtained. A oil was heated with 400 ml. of 40-42% hydrobromic acid, solution of this material in 78 ml. of water was heated to and about 250 ml. distilled a t atmospheric pressure. The 85" and treated simultaneously with 5.2 ml. of 6 N hydroblack color was removed with Darco. The solution, after chloric acid, and 1.95 g. of sodium nitrite dissolved in 26 ml. further concentration under reduced pressure, was diluted of water. The additions required 10 minutes and were with alcohol, which caused crystallization of 27.1 g. of crude followed by 10 minutes of stirring at 85". After decolori2-ethyl-3-amino-4-bromomethyl-5-aminomethylpyridine di- zation with Darco, the solution was concentrated to dryness hydrobromide (11); m.p. 217-220' dec. Concentration of under reduced pressure. The residue, dissolved in a small the filtrate left a n oil which was again subjected to the hy- amount of water, was treated with an excess of sodium bidrobromic acid treatment. Another 3.8 g. of product carbonate and extracted continuously with chloroform for 19 hours. The product, 2-isobutyl-3-hydroxy-4-methyl-5brought the yield to 76%. A solution of 18.0 g. of this material in 600 ml. of water hydroxymethylpyridine hydrochloride, was isolated and was shaken with 3 g. of 5% palladium chloride on Darco purified as described above for the ethyl homolog; yield 1.OO catalyst under 2-3 atmospheres of hydrogen. There was g. (28%, based on 6.7 g. of 2-isobutyl-3-amino-4-bromoalmost no hydrogen uptake for about an hour; then one methyl-5-aminomethylpyridine dihydrobromide); m.p. 163mole was rapidly absorbed. The catalyst was removed by 165'. filtering, and the solution, combined with the reduction Anal. Calcd. for CllH18N02Cl: C, 57.01; H, 7.83; N, product of another 12 g. of bromomethyl compound 11, was 6.05. Found: C,56.85; H,7.79; N,6.13. concentrated under reduced pressure to about 100 ml., and 2-Isobutyl3-hydroxy-4-methyl-5-hydroxymethylpyridine then shaken with 48 g. of silver chloride for several hours. Hydrochloride by Hydrogenolysis of 2-Isobutyl-3-hydroxyThe solid material was removed by filtering. The resulting C,J-bis-(hydroxymethy1)-pyridine Hydrochloride.-The hysolution containing 2-ethyl-3-amino-4-methyl-5-aminometh-drogenolysis was carried out on 3.0 g. of material exactly ylpyridine dihydrochloride was diluted to 450 ml. and heated as described for the ethyl homolog, with the exception that to 85'. A solution of 11.2 g. of sodium nitrite in 150 ml. the mixture was shaken with hydrogen for 2.5 hours. 2of water, and 15 ml. of 12 N hydrochloric acid were added Isobutyl-3-hydroxy4-methyl-5-hydroxymethylpyridine hysimultaneously over a period of 20 minutes. After an addi- drochloride, m.p. 160-162", was obtained in a yield of 0.77 tional 10 minutes of stirring at 85', the solution contained g. (27%) after isolation as described for the ethyl homolog. no nitrous acid, and was decolorized with Darco and con2-n-Amyl-3-hydrory4methyl-5-hydroxymethy1pyridine centrated to dryness under reduced pressure. Hydrochloride (III).-Zn-Amyl3-nitro-4-methoxymethylThe residue, dissolved in a minimum amount of warm 5-cyano-6-chloropyridine (I, 29.8 g.) was hydrogenated and water, was treated with a n excess of sodium bicarbonate and heated with hydrobromic acid as described for the ethyl extracted continuously with chloroform for two days. After homolog. 2-n-Amyl-3-amino-4-bromomethyl-5-aminomethremoval of the chloroform under reduced pressure, the resi- ylpyridine dihydrobromide (II), m.p. 215-218", was obdue was dissolved in alcohol and treated with an excess of tained in a yield of 5.0 g. Concentration of the filtrate and alcoholic hydrogen chloride. 2-Ethyl-3-hydroxy4methylfurther treatment with hydrobromic acid yielded another 5-hydroxymethylpyridine hydrochloride (111) was obtained 11.4 g. raising the yield to 37%. in a yield of 5.2 g. (35%, based on 30 g. of crude %ethylThis material (5.0 g.) was subjected to hydrogenation and 3-amino-4-bromomethy1-5-aminomethylpyridine dihydro- diazotization as described for the ethyl homolog, and the bromide); after two recrystallizations from alcohol the m.p. product was isolated in the Same manner. 2-n-Amyl-3was 174-176'. hydroxy-4-methyl-5-hydroxymethylpyridinehydrochloride Anal. Calcd. for G H I ~ N O ~ C IC, : 53.07; H, 6.93; N, was obtained in a yield of 1.46 g. (53%, based on 5.0 g. of 6.88. Found: C, 52.81; H, 6.64; N, 7.13. 2-n-amyl-3-amino-4- bromomethyl-5-aminomethylpyridine 2-Ethyl-3-hydroxy-4-methyl-5-hydroxymethylpyridineHy- dihydrobromide). After one recrystallization from alcohol, drochloride (111) by Hydrogenolysis of 2-Ethyl-3-hydroxy- the material had a m.p. of 125.0-126.5". 4,5-bis-(hydroxymethyl)-pyridine Hydrochloride.-A mixAnal. Calcd. for C12HloN02Cl: C, 58.64; H, 8.20; N, ture of 1.O g. of 2-ethyl-3-hydroxy-4,5-bis-(hydroxymethyl)- 5.70. Found: C, 58.72; H, 8.13; N, 5.95. pyridine hydrochloride,a 1ml. of 6 AT hydrochloric acid, 1g. LABORATORIES of 5% palladium on Darco catalyst and 125 ml. of water RESEARCH was shaken under 2-3 atmospheres of hydrogen for one MERCK& Co., INC. NEW JERSEY hour. Approximately one mole of hydrogen was absorbed. RAHWAY, After removal of the catalyst, the solution was concentrated to 3 ml., treated with a n excess of sodium bicarbonate. and extracted continuously with chloroform for 17 hours: 2Chloro-substituted Akenyl Dithiocarbamates Ethyl-3-hydroxy-4-methyl-5-hydroxymethylpyridinehydrochloride (0.19 g., 21%) was isolated as described in the ureBY MARIONW. HARMAN AND TOHN T. D'AMICO ._ ceding experiment; the m.p., 17&179", was not lowered RECEIVED APRIL 13, 1953 when this material was mixed with a sample prepared by the method described above. Although a number of alkyl esters of substituted
2-Isobutyl-3-hydroxy-4-methyl-5-hydroxymethylpyridine
Hydrochloride (III).-2-I~Obutyl-3-nitro-4-methoxymethyldithiocarbamic acids have been prepared, no refer5-cyano-6-chloropyridinea(I, 13.4 g.) was hydrogenated in ence to the preparation of chloro-substituted althe manner described for the ethyl homolog. The reductioa kenyl dithiocarbamates has been found.'-? The required 5 hours. The gummy residue, after concentration purpose of this investigation was the synthesis of of the filtrate, was treated with 200 ml. of 40-42% hydrobromic acid. After removal of one third of the solution by compounds Of this type* The compounds were prepared by treating either distillation at atmospheric pressure, the dark color was removed by treatment with Darco, and the resulting solution sodium dhethyldithiockbirnate, sodium diethylconcentrated under reduced pressure to 25 ml. Crystalline 2-isobutyl-3-amino-4- bromomethyl-5-aminomethylpyridine (1) R. Conrad and F. Salomon, J . 9rakl. Chen., 10, 28 (1874). (2) S. M. Delepine, Buff.SOC. chim. France, 47, 588 (1902). dihydrobromide (II), m.p. 211-213° dec., was obtained in a (3) M. T.Bogert, TSISJOURNAL, 45, 290 (1903). yield of 6.73 g. The yield was increased to 14.3 8. (69%) (4) J. V. Braun, BY,, 66, 1573 (1928). after further concentration of the filtrate. (6) W e are indebt& ta Mr. Ricbsrd BWDaed hi. MuOllIatea for th. mierosnslyna.
(6) W. H. Davics and W. A. Sexton, Blochem. J . . 40, I81 WW3). ( 6 ) P. Briesley, F l O l l ~ t sExchange, 108, 13 (1947). ( 7 ) M. w. Herman, U. 8 . P a t a t a,418,~aw,
