Патент USA US2406774код для вставки
2,406,774 Patented Sept. 3, 1946 UNITED STATES PATENT OFFICE 2,406,774 SYNTHESIS OF RIBOFLAVIN AND INTERMEDIATES THEREFOR ' Jonas Kamlet, New York, N. Y., assignor to Miles . Laboratories,’ Inc., Eikhart, Ind, a corpora ' tion oi’ Indiana No Drawing. Application June 28, 1943, ' Serial No. 492,622 13 Claims. (Cl. 260—211) 1 2 condensed with d-ribose, reduced and then sapon i?ed to the free amine, 3,4-dimethyl, G-amino The present invention relates to a new‘ syn- ' thesis or riboflavin. More particularly it relates to a new process whereby 6,7-dime'thyl-9-(d-1' phenyl-d-ribarnine. (d) SA-dimethylaniline is condensed with d ribityl) isoalloxazine, which is identical with the naturally occurring ribo?avin, or vitamin B2, may 5 ribose and the resultant riboside is catalytically reduced to 3,4-dimethy1phenyl-d-ribamine. This be synthesized. It has for an object to provide compound is then coupled with an aryl diazonium a simpli?ed procedure for the synthesis of this salt to form the 3,4-dimethyl, ?-arylazophenyl-d vitamin, whereby some steps in the present syn ribamine and the latter compound is reduced to thesis may be eliminated. It has for a further object to provide a synthesis of ribo?avin which 10 the 3,4-dimethyl, G-aminophenyl - d - ribamine. does not require the use of the expensive and dif ‘ (Karrer et al., Helv. chim. Acta, 18, 1435 of 1935.) This method gives the best yields of all of those described. In 1933, Gyorgy, Kuhn and Wagner-Jauregg, It will be noted that all of the methods described isolated ribo?avin and recognized its identity with vitamin B2 (Naturwissenschaften, 21, 560-1 of 15 for the preparation of 3,4-dimethyl, 6-amino ?cultly-obtainable pentose sugar, d-ribose. 1933). Shortly afterward, the structure of this vitamin was established to be 6,7-dimethyl-9-(d 1'-ribityl) isoalloxazine (Compound A) : (Compound A) , ‘ $HZ-CHOH~CHOH.CHOE'CHZOH phenyl-d-ribamine require the use of d-ribose, or a derivative thereof. d-Ribose may be derived from natural sources, or prepared synthetically, but, under any circumstances, it is very di?icult 20 and expensive'to obtain. The major cost in’ the synthesis of ribo?avin may be attributed to the d-ribose required. In order to avoid the use of this expensive pentose, Weygand (Berichte, 73, 1264 of 1940) made novel use of a valuable or ganic reaction, the Amadori rearrangement. By this method, 3,4-dimethylaniline is condensed with d-arabinose. The resultant d-arabinoside, in the presence of a small amount of acid at an and it was synthesized by Karrer (Helv. chim. elevated temperature rearranges to form the 3,4 Acta, 18, 522-35 of 1935), and Kuhn (Berichte, 68, 1765—74 of 1935). .30 dimethylphenyl-d - isoarabinosamine, which is then reduced in alkaline solution to the 3,4-di The basis of both the Kuhn and‘ the Karrer methylphenyl-d-ribamine. This compound can processes is the condensation of 3,4-dimethyl-6 then be coupled with a diazonium salt and re duced, as described in paragraph (11) above. Al amino-phenyl-d-ribamine with alloxan to yield ribo?avin. Karrer carries this condensation out in acid solutions (U. S. Patents 2,155,555 and though the overall yield'of 3,4-dimethyl, ‘(i-amino phenyl-d-ribamine is low (9-10%), the raw ma 2,237,074), whereas Kuhn materially increases the yield of that condensation by e?ecting it in terials required for this synthesis are inexpensive. d-Arabinose can be prepared in good yield by glacial acetic acid solution with‘ the use of boric acid as a catalyst (U. S. Patent 2,238,874; Berichte, 68, 1282 of 1935). , The 3,4-dimethyl-6 submitting the low-cost and readily availablecal 40 cium-d-gluconate to a Ru?" degradation, i. e., oxi aminophenyl-d-ribamine required for this con densation with alloxan may be prepared by a number of methods as follows: (a) 4,5-Dinitro-o-Xylene is condensed with d ribamine and reduced catalytically in aqueous» a1 K15 coholic solution (Kuhn and Weygand, Berichte, . (b) 3,4-dimethyl, G-nitroaniline is condensed with d-ribose and reduced (Kuhn et al., Berichte, 68, 1765 of 1935; 70, 773 of 1937) . (0) 3,4 - dimethyl, 6 - carbethoxyaminoaniline Amer. 'Chem. Soc, 56, 1632 of 1934). t It is an object of the present invention to improve and simplify the procedure whereby the Amadori rearrangement may be used for the preparation of 3,4-dimethyl, 6-aminophenyl-d 68, 1001 of 1935). The yields by this method are too low to be practical. dation with hydrogen peroxide in the presence 01 ferric acetate (Hockett and Hudson, Journ. 59 ribamine, as well as to provide a novel synthesis of ribo?avin that avoids the direct use of.3,4 dimethyl, G-aminophenyl-d-ribamine, but em ploys rather av more easily obtained precursor thereof, the 3,4-dimethyl, G-aminophenyI-d isoarabinosarnine. » (Karrer et al., Helv. chim. Acta, 18, 69 of 1935; 18, According to Kuhn and Weygand (Berichte, 426 of 1935), or 3,4-dimethyl, G-acetylaminoani 70, 769 of 1937) , the Amadoriv rearrangement in line (Karrer et al., Berichte, 68, 216 of 1935) is 55 2,406,774 3 4 volves the conversion of arylamine-N-aldosides ylphenyl-d-isoarabinosamine (Compound D) is into the corresponding aryl-N-isoketosamines, in now dissolved in a suitable organic solvent (e. g., the presence of a small amount of acid at elevated 95% ethanol, glacial acetic acid), treated with a small amount of decolorized carbon and ?ltered. (b) The solution of 3,4-dimethylphenyl-d-iso arabinosamine (Compound D) is now coupled with a diazotized arylamine (Compound E), of which the aryl nucleus is eventually removed, temperatures. Thus, when the aldose is d arabinose, the rearrangement probably goes through the following stages, catalyzed by the acid present: ' ' K : while a N-atom 0f the diazo linkage is retained. 10 Although any arylamine may conveniently be used, I prefer to use an arylamine containing a water-solubilizing group on the ring, as in p aminobenzoic acid, and sulfanilic acid, and many others which are available. The rationale for 15 using an arylamine bearing a Water-solubilizing group on the ring will become evident as this process is elaborated. The reaction involved in this step is the fol lowing: - (Compound D) 25 The Schi?‘ base (I) ?rst formed is in equilibrium with the furanose amino-aldoside (II). The OH: (Compound F) CH3 oxygen-bridge of the latter readily breaks to form the -ol form (III) of the isoarabinosamine, which tautomerizes to the‘keto form (IV). When the original amine R.NI—I2 is 3,4-dimethylaniline, the ?nal isoketosamine is the 3,4-dimethylpheny1 d-isoarabinosamine. To eiTect this rearrange ment, 1 mole of the aldose, 1.1 to 1.4 moles of the aryl amine and 0.002 to 0.02 mole of acid are heated in the presence of 2 to 4 moles of water at 70-90” C. for a few minutes. (Wey gand; Berichte, 73, 1259—1276 of 1940.) The ?nal product is a mixture of the arylamino-N alcloside and the aryl-N-isoketosamine. ' In the speci?cation and claims of this inven —NHCH2COCHOHCHOHCH20H The mixture of the 3,4-dimethylphenyl-d-iso arabinosamine and the diazonium salt is agi tated vigorously at 5~10° C. for 0.5 to 1.0 hour to effect the condensation illustrated above. The reaction mixture is then made alkaline and a deep reddish-brown solution and/or vsuspension of the 3,4-dimethyl, 6-arylazophenyl-d-isoarabi nosamine (Compound F) is obtained. (0) The 3,4-dimethyl, G-arylazophenyl-d-iso arabinosamine (Compound F) is now reduced in alkaline solution. In general, two types of reduc tion, the term “isoaribity ” (see Compound M) ing agents may be employed; namely: (q. v. Weygand) refers either to the Z-keto-d 1. Reducing agents that will reduce both the aribityl or to the Z-keto-d-ribityl group, or to 45 azo-linkage (to the amine) and the keto group both. The only di?erence between d-arabinose in the isoarabinosamine side-chain forming the and d-ribose resides in the optical con?guration corresponding secondary alcohol (Compound H). of the asymmetric carbon in position 2. When These agents (Compound G) include sodium this center of asymmetry is eliminated (e. g., by amalgam in the presence of a stream of CO2 conversion to a keto group) both cl-arabinose and 50 (to neutralize the NaOH evolved), hydrogen in d-ribose give the same Z-ketopentose. Thus, 2 the presence of Fancy nickel, and hydrogen in keto-d-ribityl is the same group as Z-keto-d the presence of a reduced platinum catalyst. As aribityl, and is here referred to as d-isoaribityl. Weygand has postulated, reduction of the d-iso The present invention is based on the follow arabinosamine side chain in alkaline solution ing sequence of reactions: 55 leads only to the desired d-ribamin (Compound (at) 3,4-dimethy1aniline (Compound B) and d H) (Berichte, 73, 1262 of 1940), thus: arabinose (Compound C) are submitted to an Amadori rearrangement. The resultant mixture (Compound F) of 3.4-dimethylphenyl~d-isoarabinosamine (Com pound D) and 3,4-dimethylaniline-d-arabinoside 60 OH3(Compound D’) is then distilled with steam. CH3 The isoarabinosamine (Compound D) is not af fected by this treatment, but ‘the arbinoside (Compound D’) readily hydrolyzes to give back the original BA-dimethylaniline and d-arabinose. 65 The BA-dimethylaniline distills over with the steam and the major portion of the amine origi nally started with may thus be recovered for re use. The residue after the steam distillation com ‘ prises an oily layer of impure 3,4-dimethylphenyl ~—NH.OHB.CO.OH0H.CHOH.CH2OH —-N=N—R reduction ——-> (Compound G) (Compound H) CH CH3 —-NH.CH2CHOH.CHOH.CHOH.CH2OH NHQ + R.NH2 d-isoarabinosamine (Compound D) and an aqueous phase from which the major portion of The reaction mixture, after reduction, is evap the d-arabinose originally started With may be orated in vacuo to dryness. The residue is dis recovered for re-use. This impure BA-dimeth 75 solved in a minimum amount of hot absolute 72,406,774 of 6,7-dimethyl, 9-(d-1'-ribityl) (Compound P) :1 ethanol, and ?ltered from insoluble material. If the original amine used for obtaining the di azotized arylamine contained a solubilizing group, isoalloxazine (Compound M) 0112.0 O.CHOH.CHOH.OH:OH i. e., if it was p-aminobenzoic acid, for example, it exists in the dried residue as the alkali-metal l salt which is soluble in water but insoluble in the absolute alcohol. Thus, a convenient method is provided for the separation of the 3,4-dimethyl, ?-aminophenyl-d-ribamine (Compound H) and the original coupling amine that was regenerated by the reduction. CHz- GE's- I . N-—C 17 a //N\00 l . N=\ CO/NH ~ Pt + 2112 —---r catalyst (CompoundN) (Compound 1?) . CHZ-CHOH.CHOH.CHOH'GHBOH The 3,4-dimethyl, G-aminophenyl-d-ribamine (Compound H) thus obtained may now be con \ )‘3 verted to ribo?avin by condensation with alloxan, as described by Karrar and Kuhn (q. v. supra) 15 . (Compound L). (I10 NH O/ 2. Reducing agents (Compound J) that will reduce only the diazo linkage. These agents in which rapidly reverts to ribo?avin (Compound A) clude sodium hydrosul?te (Na2SzO4) in alkaline onshaking with air (Compound Q). The cat solution, andlnascent hydrogen in acid solution 20 alyst is, ?ltered oif and the ribo?avin isrecov as produced by’ zinc dust in acid solution. The ered from the alcoholic ?ltrate by evaporating 3,4 - dimethyl, 6 .. arylazophenyl - d - isoara 'to dryness in vacuo. It is obvious, of course, that in this condensation, the use of boric acid as a catalyst is optional, and the use of alloxan, as binosamine (Compound F) will thus be reduced to a new compound, 3,4-dimethyl, G-aminophen yl-d-isoarabinosamine. (Compound K) : mentioned in this speci?cation and claims like wise refers to its functional equivalents, such as dialuric acid, isodialuric acid and alloxantine. The following examples are’ given in order to (Compound F) CH —NH.CH:CO.CHOH.CHOH.CH2OH a CH; de?ne and illustrate this invention but in no way to limit it to reagents, proportions or con reduction N=N—R -_--> (Compound J) , ditions described therein. CHz- Numerous modi?ca tions will occur to any person skilled in the art. (Compound K) EXAMPLE I —'NH.CH2.00.0HOH.CHOH-CHIOH Step 1.-Preparati0n of 3,4-dimethyl, 6-(p-car CHr- . NH: + 3.1m, boxyphenylaeo) ' phenyl - d - isoarabinosamine (Compound F) and (a, species of 3,4-dimethyl, ' Where the used and regenerated amine is water soluble,_ the new compound may likewise be sep arated from the concomitant regenerated cou pling‘amine by evaporating the reaction mixture to dryness and extracting with hot absolute al cohol. > 6-arylaeophenyl-d-isoarabinosamine) _ A mixture of 20.0 grams of d-arabinose, 16.0 grams of 3,4-dimethylaniline (Compound B), 1.0 gram of benzoic acid and 6.0 cc. of water is heat ed on the boiling water bath for six minutes. A homogeneous melt is soon obtained which is a ' (Id) The 3,4-dimethyl, ?-aminophenyl-d-iso mixture of, 3,4-dimethylphenyl-d-isoarabinos arabinosamine (Compound K), obtainedas de 45 ‘amine (Compound D) and 3,4-dimethylaniline scribed in the paragraph immediately above, is d-arabinoside (Compound D’). 100 cc. of hot now condensed (Compound L) in glacial acetic ’ acid with alloxan in the presence of boric acid 95% alcohol is now added, and the solution is submitted to steam distillation until the distil as a catalyst, to yield a new compound 6,7-di late is substantially iree of 3,4-dimethylaniline. methyl, 9-(d-l’-isoaribityl isoalloxazine (Com 50 The residue in. the distilling flask soon sepa pound M) :. ‘ (CompoundK) CH3v NH.CH'2.CO.CHOH.CHOH.CH2OH + CH NH: (Compound L) (Compound M) CH2.CO.CHOH.CHOH.CH2OH --NH 00 I 00 0 CH? / N\ C /N\ CO co -__' ([30 llTH ~ I CH@— ‘ /C\ )NH - C., then adding dropwise with constant stirring, ‘l / N so CO rates into two phases. The aqueous phase (con taining the major portion of the d-arabinose originally used) is decanted and preserved. The dark brown oily residue is dissolved in 500 cc, of 95% ethanol, 2.0 grams of decolorizing carbon is added, the mixture is heated on the water-bath under re?ux for 30 minutes and then ?ltered. Simultaneously, a diazo solution is prepared by dissolving 2.75 grams of p-aminobenzoic acid and 4.0 cc. of concentrated hydrochloric acid in 50 cc. of ice water, chilling the solution to 5°~l0° 14.0 cc. of 10% sodium nitrite solution. 65 The ?ltered alcoholic solution of 3,4-dimethyl phenyl-d-isoarabinosamine (Compound D) is cooled, with constant stirring, to 10°-15° C., and ‘ The acetic acid (Compound M) is distilled oif in vacuo, the yellow residue of impure, 6,7-dimethy1, 9-(d-1'~iscaribityl) isoalloxazine is dissolved in the freshly prepared diazo solution (Compound herein designated Compound N for convenience). The 6,7-dimethyl, 9-(d—1'-isoaribityl) isoalloxa zine (Compound M) is reduced vto the leuco form sodium salt of 3,4-dimethyl, G-(p-carboxyphenyl E) 'is added slowly. Stirring is continued for a 0.2N sodium hydroxide solution in ethanol and 70 an hour, and the solution is then made alkaline by the cautious addition of concentrated alco the solution is hydrogenerated in the presence of holic NaOH solution. There is thus obtained a a reduced platinum catalyst (the agent being dark reddish-brown solution-suspension of the azo) phenyl-d-isoarabinosamine (Compound F). 2,406,774 7 8 The free acid may be obtained by diluting the alcoholic solution with three volumes of water and acidifying with acetic acid. A gummy red dish brown material separates out which rapidly solution. The reaction mixture is ?ltered while hot and the ?ltrate is evaporated to dryness in Vacuo. The dry residue is taken up in 100 cc. of hot absolute ethanol, ?ltered from insoluble ma solidi?es and may be comminuted to amorphous terial and evaporated to dryness. brown particles, In. pt. 83°—8<l° (decomp.). For There is thus obtained 4.1 grams of orange-colored crystals, 3,4-dimethyl, 6-(p-carboxyphenylazo) phenyl-d m. pt. 119°-121° C. For 3,4-dimethyl, G-amino isoarabinosamine (Compound F): N (calcu lated) =10.5%; N (-found)=10.7%. The yield is N (calcul-ated)=10.4%, N (found)=10.3%. 5.1 grams. phenyl - d - i-soarabinosamine 10 Step 2.—Pre1vamtion of 3,4-dimethyl, 6-amino phenyZ-d-ribamine (Compound H) (Compound K) : Step 3.-Preparation of ribo?avin 1.05 grams of 3,4-dimethyl, G-aminophenyl-d isoarabinosamine (Compound K) is dissolved in The alcoholic solution-suspensionof the sodi 60 cc. of glacial acetic acid and added to a solu um salt of 3,4-dimethyl, 6-(p1carboxyphenylazo) 15 tion of 0.95 gram of alloxan tetrahydrate (Com phenyl-d-isoarabinosamine (Compound F), (pre pound L) and 1.80 grams of boric acid in 60 cc. pared in step 1) is made 0.2N with respect to of boiling glacial acetic acid. The mixture is free sodium hydroxide, and a catalyst prepared from 3.0 grams ‘of chlorplatinic acid according to gently re?uxed in the dark for 15 minutes and the acetic acid is then distilled ed in vacuo. the method of Adams in J our. Amer. Chem. Soc. 20 The crude residue of GII-dimethyl, 9-(d-l’ isoaribityl) isoalloxazine (Compound M) thus ob 44, 1937 (1922); 415, 2171 (1923) suspended in alcohol, is added. Hydrogen gas (Compound G) tained is dissolved in 200 cc. of 0.2N NaOH in 95% ethanol and ?ltered from insoluble mate is now passed through the vigorously agitated so lution at 25°-80° C. until the reduction is com rial. The Adams catalyst prepared from 1.5 grams of chlorplatinic acid, suspended in alcohol, is added and hydrogen gas is passed through the vigorously agitated solution at 25°—30° C. until the reduction is complete and no more hydrogen is absorbed. The catalyst is ?ltered o? and the ?ltrate, comprising an alcoholic solution of leuco plete and no more hydrogen is ‘absorbed. The catalyst, as well as other insoluble material, is now ?ltered off and the alcoholic ?ltrate is evap orated to dryness in vacuo. The dry residue is taken up in 100 cc. of hot absolute ethanol, ?l tered from insoluble material and evaporated to dryness. There are thus obtained 4.0 grams of light orange colored crystals, in. pt. 123°—124° C. 6,7-dimethyl-9-(d-1’—ribityl) isoalloxazine (Com pound P) is neutralized with acetic acid. It is then aerated for an hour to oxidize the leuco base For 3,4-dimethyl, S-aminophenyl-d-ribamine (Compound H): N (calculated)=l0.4%; N (Compound P) by the oxygen (Compound Q) of (found) =10.4%. 35 the air and evaporated to dryness in vacuo. From This 3,4-dimethyl, G-aminophenyl-d-ribamine the crude residue, riboflavin (Compound A) may (Compound I-l) may noW be converted to ribo ?avin by the methods of Karrer or Kuhn. be recovered on crystallization. It is to be observed that in Example 2 the re EXAMPLE II ducing agent (Compound J) is employed which reduces only the —N=N-- group but not the —-CO-- group of Compound F, thus producing Compound K, which couples with the alloxan or equivalent Compound L to form Compound M; Step 1.——Preparation of 3,4-dz‘methyl, d-(p-c'ar bomyphenylazo) :0henyZ-d-isoambmosamine This step is eifected as described in Example I. While in Example 1, a reducing agent (Compound By acidifying the steam-distillate with hydro chloric acid and distilling on" the solvent, 10 45 G) is used which reduces both of said groups —-N=N— and —CO— forming Compound H, grams of 3,4-dimethylaniline (Compound B) may which then coupled with a Compound L provides be recovered (as the hydrochloride), and re Compound M’ which is similar to Compound M in turned to the process. Similarly, from the aque_ all respects except that the -CO-- group of Com ous phase of the distillation residue 12 grams of d-arabinose (Compound C) may be precipitated 50 pound M is a —CHOH—- group in Compound M’. The reducing agent Compound N reacts with as the 2,4-dinitrophenylhydrazone. By adding either Compound M or Compound M’ to give the this aqueous phase to the crude solution of d leuco product (Compound P), which is oxidizable arabinose obtained by following the procedure of Hockett and Hudson, immediately prior to the ' ?rst decolorization with carbon by air to ribo?avin (Compound 1A) . Having described my invention, what I claim and desire to protect by Letters Patent is: 1. In the process of making ribo?avin the steps (Jour. Amer. Chem. Soc. 56, pg. 1633, column 1, line '7, of July, 1934), there may be recovered 10 grams of d arabinose in addition .to the normal yield of 55 to 65 grams. Thus, the ?nal yield of 5.1 grams of 3,4-dimethyl, 6-(carboxyphenylazo) phenyl of reacting d-arabinose with 3,4-dimethylaniline and thereby forming the compound 3,4-dimethyl 60 phenyl-d-isoarabinosamine, reacting the latter d-isoarabinosamine (Compound F) is obtained compound with a salt of a diazotized arylamine from an overall consumption of 6.0 grams of 3,4 dimethylaniline and 10.0 grams of d-arabinose. and thereby forming the compound 3,4-climethyl, 6-arylazophenyl-d-isoarabinosamine, and reduc Step 2.--Preparation of 3,4-dz‘methyl, z’i-amz'no phenyl-d-isoarabinosamine (Compound K) ing the latter compound by the action of a re» 65 ducing agent selected from the group consisting The alcoholic solution-suspension of the so dium salt of 3,4-dimethyl, G-(carboxyphenylazo) phenyl-d-isoarabinosamine (Compound F) (pre pared in step 1) is heated under re?ux on the 70 boiling water-bath and a saturated aqueous solu tion of sodium hydrosul?te (Compound J) is added slowly until the dark reddish-brown solu tion has been discharged to a dark orange color, and there is an excess of free reducing agent in 75 of alkali metal hydrosul?tes in neutral solution and in alkaline solution and nascent hydrogen in acid solution thereby forming 3,4-dimethyl, 6~ aminophenyl-d-isoarabinosamine of the formula: CH3— —-NH.CH2.CO.CHOH.CHOH.CH:OH 2. In the process of making riboflavin the steps 2,406,774 -~ . 10$ > of reacting, d-ar'abinose‘with ‘3,4-dimethylaniline i 6-aminophenyl-d-isoarabinosamine with alloxan and thereby forming the compound 3,4-dimethyl phenyl-d-isoarabinosamine, reacting the latter in acid solution. l ‘ v , .,9.‘;In .a process "for the synthesis of ribo?avin, compound with a salt of a diazotized arylamine the; step which‘ comprises condensing 3,4-dimeth and thereby forming the compound 3,4-dimethyl, jyl, 6_eaminophenyl-d-isoarabinosamine‘ with al- - 6 - arylazophenyl - d - isoarabinosamine, reducing loxanjin acetic acid solution. the latter compound by the action of a reducing agent selectedfrom the group consisting of alkali metal hydrosul?tes in‘ neutral solution and in _, alkaline solution and nascent hydrogen in acid the step which comprises reducing 6,7-dimethyl 9-(d¢1"-is0aribityl) isoalloxazine by the action of 1,0; lira, process for the synthesis of. ribo?avin, hydrogen acting in the presence of a hydrogena- , tion catalyst, anddehydrogenating the resulting leuco-BJTV-dimethyl, 9-(d—1’-,ribityl) 'isoalloxazine thereby forming ribo?avin. solution thereby forming the compound ISA-‘die methyl,‘ 6-aminophenyl-d-isoarabinosamine, and condensing the latter compound with alloxan 11. The process of producing ribo?avin which thereby forming 6,7-dimethyl, 9- (d-l’-isoaribityl) comprises reacting 3,4-dimethylaniline and d isoalloxazine of the formula: arabinose by an Amadori rearrangement while forming thereby 3,4-dimethyl-phenyl-d—isoara= N binosamine, coupling the latter with a diazonium salt of a diazotized aromatic amine thereby form N \O// \('30 CH CH: onlooononononomon 20 ing 3,4-dimethyl, 6-arylazophenyl-d-isoarabinos amine, reducing the latter by the action of a re \N¢ \ 00/NH ducing agent selected from the group consisting of (1) sodium amalgam, and (2) hydrogen acting 3. A process for the synthesis of ribo?avin which comprises submitting 3,4-dimethy1aniline and d-arabinose to an Amadori rearrangement, in the presence of a hydrogenation catalyst thereby forming 3,4-dimethyl, 6-aminopheny1 25 d-ribamine, and condensing the latter with an coupling the resultant 3A-dimethylphenyl-d agent selected from the'group consisting of a1 loxan, dialuric acid, isodia'luric acid and alloxan isoarabinosamine with a diazonium salt of a, di azotized aromatic amine to form the correspond tine. ing 3,4-dimethyl, 6-arylazophenyl-d-isoarabinos . 12. The process of producing ribo?avin which comprises reacting 3,4-dimethylaniline and d arabinose by an Amadori rearrangement while amine, reducing the latter by the action of a re ducing agent selected from the group consisting of alkali metal hydrosullites in neutral solution forming thereby 3,4-dimethylphenyl-d-isoara and an alkaline solution and nascent hydrogen in binosamine, coupling the latter With a diazonium Y salt of a diazotized aromatic amine thereby form acid solution to form 3,4-dimethyl, 6-amino phenyl-d-isoarabinosamine, condensing the latter with, alloxan in acid solution to form 6,7-di ing 3,4-dimethyl, ,6-arylazophenyl-d-isoarabi nosamine, the latter containing a benzene nu methyl, 9-(d-1’-isoaribityl) isoalloxavzine, reduc cleus having attached thereto the linkage —N=N—-, reducing the —N=N— group by the ing the latter in alkaline solution to theleuco form of ribo?avin by the action of hydrogen act ing in the presence of ahydrogenation catalyst, and oxidizing said leuco form to ribo?avin. 4. In a process for the synthesis of ribo?avin, the step which comprises reducing 3,4-dimethyl, action of a reducing agent selected from the group consisting of (1) sodium amalgam, (2) hy drogen in the presence of a hydrogenation cata lyst, (3) alkali metal hydrosuliites in neutral solu tion and in alkaline solution, and (4) nascent hydrogen in acid solution, thereby forming a compound having the resulting group 6-arylazophenyl-d-isoarablnosamine to 3,4-di methyl, U-aminopnenyl-ci-rioamine by the action of a reducing agentselected from the group con sisting or (1) 500111111 amalgam, and (2) hydrogen acting in the presence of a hydrogenation catalyst. 5. In a process for the synthesis of ribo?avin, on the step which comprises reducing 3,4-dlmethyl, 50 CH:- N: —NH2 ?-ip-carboxyphenylazo) phenyl-cl-isoarabinos2i (2) hydrogen acting in the presence of a hydrog condensing the said resulting compound with a compound selected from the group consisting of alloxan, dialuric acid, isodialuric acid and allox antine, While thereby forming the essential group enation catalyst. ing mine to 3,4-almethyl, 6-aminophenyl-d—ribamine by the action of a reducing agent selected from the group consisting of (1) sodium amalgam, and k - p 6. In a process for the synthesis of ribo?avin, the step which comprises reducing 3,4-dimethyl, ?-arylazophenyl-d-isoarabinosamine to 3,4-di methyl, '6-aminophenyl-d-isoarabinosamine by the action of a reducing agent selected from the group consisting of alkali metal hydrosul?tes in neutral solution and in alkaline solution and nescent hydrogen in acid solution. '7. In a process for the synthesis of ribo?avin, the step which comprises reducing 3,4-dimethyl, 6-(p-carboxyphenylazo) phenyl-d-isoarabinosa 60 CH3 I and reducing the resulting compound by the ac tion of hydrogen and a hydrogenation catalyst - thereby forming the leuco base of ribo?avin from which ribo?avin is obtained by oxidation. 13. .The process of producing ribo?avin which comprises reacting 3,4-dimethylaniline and d arabinose by an Amadori rearrangement while binosamine by the action of a reducing agent se 70 forming thereby 3,4-dimethylphenyl-d-isoara binosamine, coupling the latter with a diazonium lected from the group consisting of alkali metal salt of a diazotized aromatic amine thereby form hydrosul?tes in neutral solution and'in alkaline mine to 3,4-dimethyl, G-aminophenyl-d-isoara-g solution and nascent hydrogen inacid solution. 8. In a process for the synthesis of ribo?avin, ing 3,4-dimethyl, 6-arylazophenyl-d-isoarabinos amine, the latter containing a benzene nucleus the step which comprises condensing 3A-dimethy1, 15 having attached thereto the linkage —-N=N-, Q,406,774 ' 11 ‘ subjecting the resulting 3,4-dimethyl, 6-arylazo loxan, dialuric acid, isodialuric acid and alloxan phenyl-d-isoarabinosamine to reduction by the tine thereby forming the essential grouping action of a reducing agent selected from the group consisting of (1) sodium amalgam, (2) hy drogen in the presence of a hydrogenation cata lyst, (3) alkali metal hydrosul?tes in neutral solution and in alkaline solution, and (4) nascent hydrogen in acid solution thereby at least reduc ing the —N=N—- group to one —-NH2 group in an aryl amino compound, subjecting the said aryl amino compound to condensation with a com pound selected from the group consisting of al reducing the said essential grouping by vthe ac tion of hydrogen in the presence of a hydrogena 10 tion catalyst to the leuco base of ribo?avin from which ribo?avin is obtained by oxidation. 7 JONAS KAMLET.