BE625114A - - Google Patents

Description

       

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  "GAMHA-PYRONBS AND THEIR PREPARATION" .-

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 The invention relates to the preparation of compounds of the! ;; tfiL;) a-pyronet ut elle oonaeritcl, plua; Lrrt toul.ürerwnt a procodo for the preparation of a (jymwa-pyrone particularly interesting, lo ..taltol , ot of different novel compounds :( of this 1,, Iruttj) qà # and in particular of intermediate compounds * used during the preparation of said tiialtol.



  It is indeed no! Uiu that naltol, or J-l1YúxooJty-2-lUethyl ... t \ f, u '! I \ - "yrouo. (8t one of the most J: l1tÓreusmu; eo gam: ta.-pyronea . Its interest reduced by the fact that the evil you exult the flavor and aroma of various alitnontnireat products making them pliii3 attractive to the consotnatour. By: ni ulinonta which are remarkably U, 11! ÚJ, iorúll of this # u- mii-ro pure 1e alto1, we had 1: product output such as gainai ctoaux and i> ftt <5éj rlre preparations such as sweets and dos criz.tos t; lcé ... and onrto.il108 drink- /! Ions webs which the caf s ;.

   We also use the <ialtol 0011: 1: '10:!. nf, 'r': d L'1.! nt <1.1; \ 5 dos prfurns ot dos Nsanzncee, Until recently, we obtained! 1, lltol in limited quantity to uurtit 'of uaturol products by using difficult operating inodots and expensive * Industrial production of .altol has itd buat-e, nar exrrrmlo, 8ur la dis1o: i, 111t ...



  Hun t:. ', 5trtH, C.1, \, (., U'.1 woods and, cc-l IL- it is well cultivated these pyrolysis reactions provide [LSslt: ..' ": s. ; i.Ctt: 2t.bk the pro.1 \\ ;; "dîni.t * 6a with weak rarklu.:ixats. Also.} le .'rue / 'da c:' .I.801 ,. rltmt tend to be Units, quvmt \ their ca ', ucit6. à. auprovi- miozvr ..: total torxt in: .rGiar, a vrm'I1 \'. rc faciitlletzt dl1f \ 1oui1Jlo. In addition, on: a3.to1 obtained pure from such!, r ".c, J (.1: I from cii: aLilluti, destructive ort to tel1cJ,) .. 11Ce to contain certain il: 171'lri.t8 which adversely affect aon use 00: 1'.0 exultunt des aramea.

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  A known procedure for the synthesis of the malt cl 04t \> a.mi on the indications of Ii.A. Spîelnan and X * 1 "xeie, dox published * in 1! ' th | liperie n \ Jgh0iiifeat3L ei. king 69, pp. 9 (X9 * 7) This synthesis is studied in accordance with the following diagram
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 aôid * 2-pipri4ino- pyromec acid * 2% iquo xtaltol We now have d <open that it is possible to perform? 4yn, -i chemical teas of maltol from kojlqite acid, or 2-hydroX7-: # ethyl¯5hydrexy-e & mraa pyrone, a substance which can be easily obtained in large quantities * from process * (te economic fermentation and other compounds ut: LlilSablo. 09 = 43 ana1lih1 ".. prtmié. reno Qn has furthermore found that the maltol prepared by the process which is the subject of the invention is free from impw ot4o which has * find;

   
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 wind usually in Io maltol prepared by summer. Previously destructive distillation processes 1; known, mentto = 40 oi-detss.



  The invention a. the goal is to achieve a number of 4 * different operational #odss * for the preparation of maltol.



  A further object of the invention is to have 1% preparation of M * 1 * 01 from an economical and readily available raw material. kOj1qua.



  Yet another object of the invention is to prepare maltol 1
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  or * a form particularly free from impurities for use as <xa * .t <mt of flavor and arbue.
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 Another aim of the invention * and of producing interesting
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 intermediate product belonging to the group of gaweta-pyron., such as pyromeconic acid and hydroxyualtol from koj1quo acid.



  Other objects of the invention will be readily apparent to HD'sM
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 art in the course of the following description.

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 in one of its aspects, the invention relates to a process which
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 comprises r (1) the treatment of kojic acid with oxygen in the presence of a catalyst of the noble metal type at a pH of at least 10 pettr formzfde comenic acid, (2) -the decarboxylation of said acid eomenic to form pyramoonic acid, (3) treatment of pyrouseoonic ao14e with formaldehyde at a pH of at least about 9 to form hydroxyanltol, and, (4) reduction of hydroxy-maltol. under acidic to nearly neutral conditions to form ¯a1tol 1.



  Cuamte will be shown below in the example., The mine in
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 implementation of the procedure described oi-daesua makes it possible to obtain a maltol yield of approximately 50 i from the base of kojic acid, and constitutes the first industrial synthesis of maltol from kojic acid.
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  As regards the first stage (1) of the process specified here, it is known in the prior art that when attempting to prepare comenic acid by treating kojlue acid with oxygen by presence of catalyst * or by other oxidizing agents such as nitric acid or potassium permanganate, only traces of oomenic acid are formed., Since the acid is
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 kojique cannot usually be recovered from these reaction mixtures. These results are believed to be due to extensive destruction of the pyrono ring during these treatments *.
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 Moreover, as established by Heyne dama Chemische Borjohte, vol * 87. p.

   14 (1954), the use of alkaline conditions during the catalytic oxidation of kojic acid by oxygen and in the presence of a catalyst would not be possible due to the rapid destruction of the pyrone ring and, in fact, we cannot get
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 only traces of comenic acid even at pH 7.4.

   It could not therefore be expected that when acid / is treated with oxygen in the presence of a noble metal catalyst in solution at a pH greater than 10, it would not. no destruction of the cycle occurs
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 sa2nJl'l & -pyron., but a very clean oxidation of the 2-hydroxy-ssethyl group with formation of 2-olU "boxylate ootpaspondaïlt with back

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 yield. practically quantitative ** Before inventing the eeule known synthesis of coménlque acid from k4 acid, your industrially interesting yield included an oo.V..1'A of kojic acid as a derivative of.

   ether retithy type, 13.5ue erres during an oxidation of said ether to methyl ether of eateiftqur acid and a dimethylation of the latter ether to aoiJ, com4nique, The overall comenic acid content from ao1do koJ1que pu un * in 4 way also / direct * was of 1 order of 25% only, A critical feature of stage (1) describes Oi-4e "'*> you * in the fact that the oxidation is carried out in an alkaline medium at . \ pU of at least 10. It has been found that if one mowing to put in iluxx * this stage at lower pHs, for example at PU 9 and at PU 7 # obtains results substantially in agreement with the art *, ntisw that is to say that it forms only traces of com4xxîque acid The invention can moreover liter be implemented at pH much higher than batches one can, in fact, operate above of the measurable psi donation limit which is 14.

   In order to obtain the best yields and a particularly favorable rate of absorption 4 * oX1Kèn .., stage (1) will preferably be carried out at pHs of between approximately 11 and approximately 1.



  Or found that the technique used to maintain bdtt pH minimum is not critical. It is therefore possible to adjust the pH
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 at the minimum value at the start of the oxygenation reaction and
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 to add base during the reaction either by small ** f * t * lton4f or continuously or alternatively Oft can initiate * -, add ases of base in a single liver so that the ffflt
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 final mixture does not fall ** - below said minimum *
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 The means to maintain the minimum pH IU, w8péoiti4 11 ii 'pa * critical during stage (1) .. Any strongly alkaline r4a.'it capable of not dissolving * in the mixture can be used * 944 * ttd * n * 1 and which is inert to oxygen $ oatalysis $ r'ot other reaction intermediates.

   We can use *? ,, for example, hydroxide and alkali metals * such as lithium 4 * hydroxide,

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 of -
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 # sodium hydroxide, hydroxide / Pôta..ittm and the like, as well as * if only alkali metal carbonates such as sodium carbonate and potassium carbonate * Alkaline hydroxide can be used
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 earths such as calcium hydroxide and corn analogues are not given preference due to their low solubility in water and their tendency to chelate with the intermediates.

   Bases * noted ** organic wrong .. are not
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 preferred * because it * has a marked tendency to poison cataly- * sur *. Particular preference will be given to Ithydro1d. sodium, because this reagent is cheap and easy to
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 to get you it can be added either in its OO & J, 40, 6 * tt in solution * tail ** type or the amount of catalyst of the type ire t al noble used during stage (1) n ' is not critical.

   Thus, it is possible to use, for example, platinum and palladium, and the like., Either in finely divided states (what is commonly called
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 black people-). i are available in easily obtainable forms such as oxides, noble metals supported by solids can also be used such as, for example, as o "bont and vegetable charcoal * r, .a used, proportion of e <tttly m * / can vary over a wide range ea used, for example, 0.01, 0.1, 0.8, 1.0, 1.25 and $ 5 of catalyst by weight (calculated as metal) on the basis of kojic acid.

   It is particularly suitable to use about 1.0 of palladium on the .osaa * i <ï kojique mîl work, and to use! * said cataly- tower under the fort of a preparation sold from <Ut9 la oomraer 8., of palladium on carbon.
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  The oxygen used in the middle of the stadium (.j * can be found in the form of pure oxygen gas, or it can be very mixed from 8Ut ... fax. Xl, is also possible to use pure oxygen in the air (which contains about 2 'oxygen by weight), where to use mixtures of the two, or to use other gas mixtures containing oxygen in the condition that said other.

   go oc- * have inert towards products, intermediaries of faction st,

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 in particular, do not poison the at *, Iyoouro They are particularly convenient- to use oxygen-rich gas mixtures available as by-products of chemical manufacturing operations,
The reaction time and temperature for step (1) can vary within a wide range.

   However, it is desirable to
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 conduct the "ation at a temperature between approximately z and 'Aviron 60, $ Ce and at, <'pè "' ora preferably at ds te1lllP'rtll.t,! u Anfe- fr 4 & à erv3nan 0- * !.? discovered that U, 16 says working at temperatures above about 4000 tends to do slightly lower the yield and slightly alter the color of the product.



  It can be seen that the reaction time depends mainly on the temperature at which it is carried out. In addition, the proportion of catalyst and the rate of introduction of oxygen affect the time necessary to achieve complete consumption of kojic acid. In general, times of between about 4 and about 72 hours will be sufficient; longer times are usually needed at lower temperatures, lower catalyst concentrations and lower oxygen flow rates.
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  When preparing comenic acid directly in accordance with one embodiment of the invention, if the reaction is carried out at
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 a temperature between about 00 and about 4000 in the presence of about 1.0 kojic acid based catalyst at a minimum pH of about 11 and with an oxygen flow rate corresponding to about 1400 ml / minute oxygen per mole of kojic acid, said kojic acid is almost completely consumed at the end of
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 d'snviran ten linker *** Although it has been indicated that the process is modified.

   implemented using water as a solvent, it should not be forgotten that
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 It is possible to use, as mixed minor components of water, other inert solvents commonly used in oxidation reactions. However, it is preferred to carry out stage (1) of the reaction with water as the sole solvent.

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 It read 6 1 that in order to avoid the difficulties that one sometimes experiences in obtaining precise and sure mores * from the pit, the purity of kejic acid is not particularly critical,
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 However, it was found that crude kojic acid, of lower purity
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 at about 60 by weight, is. awning nélaag6 A certain substances
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 which are known to act as poisons with respect to the cataly-
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  ur,

   Although the effects of this * catalyst poisons may be
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 partially attenuated, for example eh using higher proportions
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 As a catalyst, it is argued that it is preferable to use an icojic acid having a purity of at least about 60%. The isolation of the oo-en1que acid ... reaction mixture. Therefore, after filtration to separate the catalyst, an 8utti amount of a strong acid is added to bring the pU below at least 295.
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 For this purpose, acids such as hydrochloric acids can be used.
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 sulfuric, nitric and similar driquee.

   It is however preferred s. '' adjust the pH below about 1 to avoid co-precipitation
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 possible derivatives of alkali metals * of the product which could
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 be observed at higher pH. Comenic acid can be separated
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 by filtration or centrifugation, and can be air dried or by any other means * normally used *
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 With regard to the second stage (2) specified above, it has been known that comenic acid can be decarboxylated to form a <pyroeteoonic ide.

   However, clause indicatesht the conditions
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 used by previous researchers *, one might expect
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 and that the industrially feasible production of pyroreioon3- acid to lose colic acid is difficult and expensive.
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 Oarkusha in Journal of General Chemistry, V.S.S.R .. vol * 16, p.



  2oz5 (1946) reported that only 50 per cent pyrmeoonic acid yield is obtained when heating equal amounts of eetenic acid and copper powder. It has since been discovered that the yield of pyromeonic acid is not improved
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 But ..'. in fact, lowered if one erases oat decarboxylation.



  .r rw .--: x under the conditions called "OlAssiques .. Aini..1 one

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 heating eomenic acid with copper, drunken bronze and copper salts in the presence or in Ilabuoi% eo 4 * e, e, isr "we end up with leobten> tlon 4'ao1d..pyrem'Qoniqu .. ... 4. yield from 15 to 50 i> * It was therefore surprising to find what if we heat comenic acid in the presence of a certain solvent * chosen It is gently decarboxylated into pyromeconic acid, and still find that 'a copper catalyst is useless for the reaction * and therefore against all expectations that we have d4o,> lzv * rt that we can <
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 to obtain pxamarrniquar acid from comenic ao1,1'1 * with a yield of 80 by heating the oollltép.1qu acid.

   in a solvent
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 selected from the group consisting of naphthalene and mono- and
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 di-alOOY1 (interior) naphthalene., said poor alkyl groups have up to 4 carbon atoms; t4traty4ronaphthalbue and mono- and di, alaayr (in: Cérieur) tetxahydranap'hta. to, ea, lendits
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 group * alkyls which may contain up to 4 carbon atoms
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 unsubstituted or mono- or di8Ub.titu 'diphenyl ether by
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 alkyl or alkoxy radicals containing up to 4 carbon atoms}
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 polyglycol diethers and monoether-monoeatera corresponding to the formula RO (CH 2 Cil 2 0) n Ri in which is an integer ne 9
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 to 6, R is selected from the group consisting of lower alkyl or
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 phenyl, and Ri- is selected from the group consisting of alooyl. interior.

   lower acyl and phenyl, said groups. aleoyle interior
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 and lower acyl containing up to 4 carbon atoms; phosphite and triphenyl phosphate and their mononuclear derivatives * substituted by
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 lower alkyl containing up to 4 carbon atoms;

   oy- T "'" ##' ii "'4 1" "i1! clique aliphatic amides having the formula CH2CU2CH200N-R in which
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 R is an alkyl containing 4 to 8 carbon atoms, open chain aliphatic saturated mono-) carboxylic acids (8 to 16 carbon atoms) and lower dialkyl esters of the acid! phthalic acid and its mononuclear derivatives substituted by an in-- alooyl
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 ter3suar, said alkyl groups comprising up to 4 carbon atoms, at a temperature at least equal to that at which carbon dioxide is given off, maintaining said temperature until the
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 release of CO has practically ceased, and collecting the acid
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 pyroe4ooniqu. that does not form.

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  Although it has been found that a catalyst is not tested ,. re to obtain improved roundness *, the addition of a copper ground such as 3'koitate tivr #, qae can be reoommandab, e dana
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 some cases when one wishes * to shorten the reaction time.
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  The temperature at which we can carry out the. decarboxylation varies over a wide range. However, at temperatures below 4. At about 170 * 0, the rate ** of decarboxylation * and too low for the * needs of practice, while at a temperature above * t about kOti3 there is a *. tendency to decrease the *. yield of pyrom4conic acid as a result of side reactions * It * and advantageous to carry out the riac.tîou deoarboxylation at a temperature between about 2150 and about 250 ° 0.



  It is believed at this stage of the synthesis, to use the suitable solvent $ one cannot use all the eolvanta bouillart in the same temperature range # <general. Through
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 example $ when glycerol, saturated hydrocarbons are used,
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 such as dlanline, mineral oil, N, N-di4thyltoltî "i. o-nitrochloroben3ènejl nitrobon2ene, quinoline and oaiibaxole de-ne and embodiment of the invention, one do not isolate
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 pyromeconic acid with little or no yield at all-
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 If, on the other hand, diaryl ethers, phoephitot and
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 triaryl phosphate *, di-lower alkyl phthalates,
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 glycol ethers such as thex, tetraethylene glycol di.rabthyl, of * H -alkylpyrro11done.

   such as N-cyclohoxylpyrrolide # aromatic hydrocarbons as well as A-mithylnapILbalene # organic acids such as i8odeoanotque acid, and di-lower alkyl phthalates such as dimethyl phthalate <ux <- 'marked libration of the yield of pyromeconic acid.



  It is desirable to choose a following which is not sensitive-
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 is more volatile than pyromeconic acid at the reaction temperature * For example, one can choose a solvent whose P.E. is relatively higher than that of pyromeconic acid and which will route
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 in the container while the pyromecodic acid is distilled
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 Alternatively, a significantly larger solvent can be used * vola, fil, and traction which with the pyrcaeoenic acid can be separated and reused.

   The volatility of the brightener is not critical nor4 from the point of view of the invention, since one can vmyvélr to others. embodiments in which the pyrogenic acid remains in the reaction vessel and is separated from it, for example by selective extraction in a third solvent which does not lose power. aelvant with respect to said deeayboxylation solvent.

   The oomenic aold pttzt therefore be oh,% utt4 do-no a container in; presence of a solvent immiscible with water. 09 that it is almost completely converted to pyroMeconue acid, then pyTomeoonic acid can be separated from the solvent by extraction with water * Other considerations desirable, but not critical, in the choice of solvent for the mine implementation of this part 4 * the invention is that its initial price is low, that it is thermic and that it is relatively inert with regard to coméntque and pyrou4coniquo acids. either a liquid of low viscosity at ordinary temperature, that it has a low solvent power with respect to pyrameconic acid at ordinary temperature,

   he will not do
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 not toxic and has a weak odor or taste * In a particularly preferred embodiment of the process
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 The improved d4carboxylation used in this embodiment of the invention by filling a reaction vessel with a portion of the crystallized acid crystallized in about 1 to 3 volumes of solvent, followed by heating the mass. up to about J! 15 * Ct A vacuum of about 150 names of Mercury is applied to the system, and the pyroNeco "nic acid distils as it does not form * The major part of the carbon dioxide does not release in about three hours * at this temperature, and the heating is continued until the pyro! aeoohi acid <"
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 that elbow to distill.

   After about 6 hours, you get a '*
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 reiterated to pyromecon44um acid of about 80. We $ 4p% re la petititt! proportion of solvent which has bo-dJotill4t and this is recycled to the reaction vessel.

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   As an alternative, a suspension consisting of approximately equal parts of comenic acid and solvent) may be introduced into the fraction vessel in the vessel containing the initiator.
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 holding an equal volume of solvent heated up to about 25000, This operating speed allows a reduction in reaction time of up to 30% and has no significant effect on the overall yield or on the purity of the pyromeoonic acid produced. You ee which relates to stage (3) specifies where the conversion of pyromeconic acid into hydroxymaltol is obtained, a notable increase in yield is obtained by carrying out the procedure used in this embodiment of the invention.

   We know that the acid
 EMI12.2
 pyroaeae can be converted to hydroxymaltol with a yield of by treatment with dehydro form. These yields moderate, as indicated by Shemyakin and his collaborator in Doklady Akadg 2 [& Mkou V, .. 11;., vole 831 p 1301-4 ( 152), were obtained by carrying out the reaction in alcoholic solution in the presence of an excess of formaldehyde and with sodium acetate as catalyst at a pH of up to about 8.

   But given the instability
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 well-known gamraa-pyrone in alkaline media and the tendency of gamma-pyrones such as kojic acid to degrade to 696-bie- condensation product when treated with formaldehyde in the presence of a strong base, we discovered with surprise that the pyro-
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 Doonic in aqueous solution at a pH of at least about 8 is converted in high yields to hydroxymaltol by treatment with an alololar equivalent of formaldehyde.

   Neither would it be expected that there would be no decrease in hydroxymaltol in such conditions. However, it has been found that yields of at least 85% hydroxymaltol are obtained. by carrying out the improved stage of the process forming the subject of the invention, which stage consists essentially in adjusting the pH of a solution
 EMI12.5
 of pyromeoofic acid to at least about 8 before adding approximately one molecular equivalent of rormld'lyde.



  Surprisingly, it has been found surprisingly that the reaction is carried out in an alcohol containing from 1 to about 3 carbon atoms.

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 carbon, it is possible to obtain hydroxyo4altôl with * yields of up to 90 if the treatment with formal-
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 dehyde is carried out in the presence of a substantially stoeoh3omdtcique proportion, with respect to the pyrora46acradyiua acid, of a strong bar selected from the group consisting of alkali metal hydroxides. such as sodium hydroxide, hydK'jxyd * de pot assit ** <t analogues, and the.

   hydroxide * of aloalino earth metals such as calcium hydroxide and the like
 EMI13.3
 In aqueous media, the means for bringing the pH to at least 8 are not critical. Thus, 8 bases such as Noch, KOCH, x ,,: L0lt and the like can be used.



  The procedure for adjusting the pH of the aqueous solution
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 of pyromeconic acid up to at least 8 is not gold $ .tique. Thus the base can be dissolved in water and added to a solution of pyromeaonic acid or alternatively, pyroweee "nic acid can be added to a solution from there .. the two reagents
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 that can be introduced either as solids or as a solution
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 In view of,

   obtaining the best yields it is preferable to limit the proportion of totmalddhyde added. to a molar equivalent on the basis of pyrouoonic acid The use of an exe 2 s of formaldehyde can reduce the purity of the product if the we operate in an aqueous medium *
 EMI13.7
 As will be seen in the examples, a above pH 8 there are effects on the reaction rate) the yield and the purity which appear to be due to the pH at which the riactianls made. Thus, the reaction time necessary to get the highest
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 yield decreases as the pH increases from 8 to 109 the total yield increases and the product is purer.

     Since the yield and purity tend to decrease above pH 10, for example at
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 pu 13, the stage will preferably be carried out at pH 10. It is not critical to add the ferMaltehyde in any particular form. Thus, the usual aqueous qualities can be used.

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 EMI14.1
 j3t * 4 th P41dào Alcoholic Solutions do t..14'hydt of tt6t) Mtmra * t Êet eoetteu condensed from forMaildhyde them that lb teîô * imétitel4né bt 1 ... raror .... 16 tormald4hyd..onoM. àïëu # 4 Due to the greater ease of handling, said utilt.I. de peâtëeênbb there "f alà *** u * Here is an inodb of my favorite * bn work * of the operating modes.

   Pai <jfatm! ti <at Invention 1 we add abid 'p.méôbiqe & tnvïtou four times its potd * deoati èto or' 1. acts'. 6h. Jb '. a qutit..ultiâante of an 801utlob <KHt tme z% 0% * fi peiat) .'hy.r6yd8 of 8G4iU. for aeanet at 10 the pH of taéltttigi i-4iûlbâittt Ctt 01d. of caustic alutîon represents approximately half gü o4. dl * btdo, yro.éoon1que initial.mont Mio en ceuvréi A eeite tf6i <ajbut4 a ttolaife equivalent of r.a14'hy. ' .u8 fôittàè do .1 '* ldh MqU8U ..

   at 37 in weight ta tewpéfwtuice de 'Ót1h µ # pupil epoïitan 5hient from about 25 to about i 6 * 6 èt of time # keeps the mixture fttjLen) Htl clear for envitfbn tooib h <m] f <m a temperature of about 35 * 0 while fâlaânt ..1 of the water from ftfifoidiftoenxnt in lm ohet! i <tt * <i <fit) tt of the tomoitono eolplght The h1doxY $ .1ol is isolated by adjusting the pit of the 1'-tetmétionntl to 5 by the addition of a 12 # dtàetd4 oiillarh / dritlUe solution. <tUtp <m < <ion jüâqüfà envi * oh 5- <5 on Ilddtto '8ba, about 30 minutes, and the product is separated pti "t! 1t.t'.kj small further concentrate the filtrate Up to * twlebbi of urtqu' do .on #Olume for collected)! ' A further amount of hydebtytaltol4 U overall yield of hydroxyihaltol thus obtained is alternatively, as described in Oiw4t.

   in more detail, we can convert hydrojcymalttJl to waltel <t * at 3t'it6l <t! "of its solution. Since this latter mode is an elementary filtering operation, it is easily used in the preferred work of the prepay process. tiçn di ri4al * (l from kojiquoo acid
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 In od which 06.ûdoeAb the final stage (4) specified el-d '.. ū, in the * 6d * di eiàd eh work of the invention, it was surprisingly discovered. 'it #, k do convert directly with a high rendering

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 EMI15.1
  hydocyaia, ko. in maltol.

   Aatxer, sremi * "', put' 414V44t been pri.!. By * a @de, iydroxyncaltal. Que ea. #Ov> -S # ua * i # * # -4f * l? Ord the hy- dax 'y'a.c1 es' ahloroma7.tol, then On Ocgv * ttt4g4nb ie, 4 * 4 * p4 * chloromethyl of the latter compound in "Ou4 4i * yït #. ", 1 'y, also that * the help oj 3.9ue isemèra d I hy4 ffym% ** # l qut ,, @ Woto troupe y'fd;' x" 'A7It', '110t'l.j', , e 1li3 position 7r instead of d.-.

   Blle'iy., ', Ya111lF4! I pte to be' reduced to l.lo.t.1 with a good r * ndom n ', 9 "' r ikamasts" ne ,, ame,. 'A, aupérit, re â 9! $ Have ptti iiti 'aEen, 3 ", 5'.ozt di-
 EMI15.2
 recta of kojioyue acid da dei conditions t4 * DttqnOe J.lea 'which led to yields of 9C? 9 OR waltoj, from fl'UYdroxylmaltol% it is therefore included in the po! -T4 <do l | .nT ntiW W * precoid4 in single stage for the preparation of the maltal 4ut ii | pip n4 treatment, 'by a * Are reducer of a sumation dxno *** # !! # the gr * upo 3-hydroxyl of said 1-.ydroxymaltol w ro; rt prf4ttquemont ra. tterly in a non-ionigeot form
 EMI15.3
 : It is critical that the chemical species in the treated hydrexyMitel practically not entirely find * 0 "roast flax! 50'ioia < <.



  Ï3L is known that hydroxyM.tol ax.at ecuw tuaw '' 'a 41, tinot. according to the acA <ti <relative ten wl3.i tt dimp have dtgnouse Tros 4 ce- oopecon pemyont ettro W j 3ri Rii # **? *>? eor- mule * livening up \ ") <- ..
 EMI15.4
 



  BO "-". 1 - - (J noc Ro; 7, 1- Ho20, -, 0 moeu 2 -, - * $ "tp H2C, .. 119 HCOH (I) nyaOX1.tol anon ydroX1mnlto and <t <yyj., 3: 1 ux
 EMI15.5
 if itoupèoo qui pr4dol * Lne tn solution 00 1 * anise form 1'ox ^, 'maltol <), 1 send.ment in maltol is very low after txaiteamxt of the solution by the reducing agent * If, on the other hand. the predominant amount of hydrytol is that in which PPup 3-hydroxyl is practically completely non-...: \ ,. Qn1.e, we have9.c; t, by xâd;

  kct, a, 1 urs. single stage, yields> 0 to 90% On sua3.wtt.,

  <Desc / Clms Page number 16>

 
 EMI16.1
 In tail solution * $ 'dtt prove that 1 * hydroxynaltol 8 * found mainly under the required for ** (I) in the interval of ttri up to about 8 8 So I used one M. * <you <HMt, 11 * Ot newrrir, aâra en owuxre this mode of Jt.jt. <Kttio 'tt dom $% "rv & He of pH at * -ap4citi4o li * A # ejslï'e 1" lxu *: traction in other solvents appro- j) trt <twitt p) Mf lttrie, le, only alcohols, acids or the like, / iV * it dwidogit that one will have to take into account the effect of the acidity of the adilleu wW '1 tobd * not of Il = * particular forms of .'t''rxyynalid, predominate. It is easy to determine that
 EMI16.2
 fold interval is suitable for any solvent in setting. ## t Vr * the techniques usually used.

   A particularly advantageous technique consists of titrating a hydroxymaltol solution in the chosen solvent medium and determining, from the data * thus collected, the * points of dissociation of the respective species.
 EMI16.3
 The nature of the solvent to be used in the embodiment of
 EMI16.4
 "the invention biett not critical as long as this solvent is 1.nert. with regard to the reducing agent used * It is therefore possible to use, for example, water, alkanols . lower such as rwiba7üoi, l "thanol. isopropanol and the like, and aceti acid.
 EMI16.5
 either alone or in the form of a mixture. The temperature at which the reduction is carried out is not critical in this particular embodiment of the intention.

   So,
 EMI16.6
 A reduction to a single blast can be achieved between about 50 and about 12'-0. Since there is a certain tendency for the establishment of undesirable side reactions at temperatures
 EMI16.7
 extreme 40 is Interval in usually prefers to drive the
 EMI16.8
 reaction at a * temperature between about 250 and about 75 C,
 EMI16.9
 the interval considered to be more particularly advantageous being
 EMI16.10
 the one included 1lxlrï approximately bzz and 60 "C <The time required to obtain
 EMI16.11
 However, a planned reaction will vary with the type of reducing agent used and also with the reaction temperature.

   We found, by
 EMI16.12
 .:temple. which if the reduction is carried out with zino and an acid to a pI of about 1 t at a temperature of 53 to 60, the hydroxyaltal is almost completely consumed after about 4 hours.

  <Desc / Clms Page number 17>

 



  As previously indicated, the raw material can
 EMI17.1
 be hydroxymaltol isolated from the hydroxymethylation of pyromeoonic acid. This hydroxymaltol can be redieeoue including the solvent to be used for the elementary operation of reductions However, as a variant constituting moreover the preferred embodiment of this stage of the process in question, the hydroxymaltol is reduced directly and without l. 'isolate beforehand * Beén
 EMI17.2
 understood this method of mine implementation prefers to eliminate a filtration operation.



   In accordance with one embodiment of the invention ** the
 EMI17.3
 Clear solution of hydroxyraaltol prepared as described above by hydroxyTaethylation of pyromeonyl acid, * alternatively, formed by adding about one volume of hydroxyraaltol. 1 to about 5 volumes of water is treated with a sufficient amount
 EMI17.4
 of an aqueous acid at .0% by weight such as, for example, sulfuric acid or hydrochloric acid to bring the pH below about 5 * The suspension is then heated to about SO 5 * C and o add an amount of zinc powder equivalent to the weight of "xymaltol hydra" present * This equates to about 2 moles of sine powder per mole of hydroxymaltol, ie an excess of 100, well tala. In view of certain qualities of zinc powder, one may be sufficient.

   lesser quantity.- The raisor. a difference in effectiveness between different qualities of zinc powder is not currently clearly understood; it is still true that in some cases it has been found that
 EMI17.5
 It is sufficient to use about 193 moles of groin per mole of hytroxymaltole. The reaction mixture is then vigorously stirred and an aqueous solution of hydrochloric acid containing approximately ION is added.
 EMI17.6
 less a stoichiometric proportion of acid relative to the hydroxy maltol taken; this addition of acid makes you slowly and hard
 EMI17.7
 Approximatly one hour.

   Care must be taken to keep the temperature below about 60. otherwise the gas evolution in the reaction mixture tends to get carried away *
 EMI17.8
 When all the acid has been added, the reaction mixture is kept at about 0 ° -6 ° C. for about 3 to 5 hours.

  <Desc / Clms Page number 18>

 
 EMI18.1
 To determine the extent to which the reaction is complete, a paper chromatographic assay of the reaction mixture can be performed using pure hydroxymaltol as a standard.

   
 EMI18.2
 A suitable development medium for this assay is formed.
 EMI18.3
 by 2 parts of chloroform, 2 will start from fornic acid at 90 and
 EMI18.4
 1 part of diluted ethanol that is prepared by mixing 36 part *
 EMI18.5
 of specially denatured alcohol No 3A (standard quality in the
 EMI18.6
 Unin America) with 4 parts water.

   We examine the stains *
 EMI18.7
 dehyttroxymaltol in ultraviolet light emitted by a lamp giving a wavelength of 254 m3111m.aione, then sprayed with a 1 'solution of ferric chloride, when the spot of hydroxymaltol from the reaction mixture is weak or has disappeared, we consider-
 EMI18.8
 re that the reduction has been complete. 6 When the assay shows that the. reaction was complete, we can
 EMI18.9
 icolate the maltol using the following procedure a heated the mixture and then bring the fold to about 2 by adding a 30% by weight solution of sodium hydroxide * So that the i
 EMI18.10
 filtration you perform in the best conditions, it is good
 EMI18.11
 that the temperature reaches about? 0 -! '5 * C during this operation.

   Unreacted sine is cured by passing the reaotionol eea5latc ge through a filter which has preferably been pre-heated to minimize clogging, then the remaining zinc is washed through the filter with a quantity of hot water * representing approximately z of Ne- 'jtLnlr4,', C.1C1 45 1 total.

   The filtrate is then refolded to 4 <, 'irfm, 3-1 :) 0 burp precipitate zk tal it is best to cool the mixture slowly for about # *> at a hour or so as the maltol is in an easily filterable form, On. spar. by filtration the crystallized product and, after washing with an equal quantity
 EMI18.12
 with cold water, it is dried by ordinary techniques. A particularly advantageous technique consists in ¯.
 EMI18.13
 about 60 * C us a vacuum of about 100-200 ma Hg until it roofs practically free of solvent # * then to lower the temperature to about 400 to complete the drying.

   If all of the drying is carried out at 60, the maltol has a certain tendency to settle.
 EMI18.14
 - -Ul 4 --- r.

  <Desc / Clms Page number 19>

 
 EMI19.1
 Different reducing means can be used for this reaction. For example, in addition to the zinc-hydrochloric acid couple described above, other metal-acid couples can be used or alternatively, as a variant. , chemical reducing agents,
 EMI19.2
 or hydrogen and a catalyst * It is not possible to use strongly basic reagents such as a mixture of sodium and al.

   eool to achieve the reduction, since these reagents are usually not or * in su. '? 4yury utils, it exia- ternizes in such a way as to its aniv * yue aspect (i' As regards the Using mdta, .aci ± pairs as a reducing agent, it has been found that zint, iron, aluminum, tin, magnesium and the like are effective in replacing hydrogen from acid.

   Preference will be given to sine as a stall because the mine $ besides its economic advantage tends to give a maltol of significantly higher purity and a lighter color. $ Can be used together with metals-;
 EMI19.3
 of the auadiv type, mineral acids or rrE, aliphatic menocarbox3pliques ausiquaa natures in open chain ceaportan from 1 to 10 atoms of arxbvne and soluble in the reaction system.

   Similarly, the mineral acids which are particularly effective are hydrochloric acid and sulfuric acid, and, among the organic acids, formic and acetic acids. In this particular reaction, preference will be given more particularly to hydrochloric acid, since it tends to give maltol in better yield * and at a higher degree of purity *.
This reaction makes it possible to obtain maltol if one uses a
 EMI19.4
 chemical reducing agent such as hydrofurous acid or one of its alkali or alkaline earth salts.

   For example, hydroeulfite of sodium, potassium, lithium, calcium, magnesium or the like can be used. Particular preference will be given to sodium hydroulfite, which is readily available, which is economical, and is a particularly powerful reducing agent.



    The use of this reagent for reduction in one, it stage of
 EMI19.5
 the hydroxymaltol in maltol will be described below in d4tbit in 14n examples *

  <Desc / Clms Page number 20>

 ua another effective reducing agent which can be used at this stage of the process.
 EMI20.1
 d4 produced in accordance with the invention "is hydrogen. It is neon * - mayor to use a catalyst of the noble metal type to achieve the
 EMI20.2
 Reduction using hydrogen $ and it has been found that the best yields * are obtained by operating in a pH range of between about 1 and about 3.
 EMI20.3
 



  Strong maltol concentrations are observed by chromatography on their paper after reductions in the mixture carried out respectively at p91 "" "!, t wt 34 after isolation, yields of maltol gas are obtained * It has been found, for this stage of the production In practice of the invention, the type and form of the noble metal catalysts. utility are not critical * Thus, platinum can be used.
 EMI20.4
 and palladium either in the form of finely divided metals or in the form supported on carbon or vegetable charcoal. Preference will more especially be given to the catalyst of the palladium on carbon type because of its high activity.

   The use of hydroene and of a catalyst for carrying out the direct reduction of hydromaltol to maltol will be described in detail below in the examples,
Of course, one embodiment of the invention can consider. ter to prepare maltol starting from unknown acid instead of
 EMI20.5
 kojic acid shot As will be shown below in the Jules examples, meoonic acid. who is the 2;

  6-dicarboxy-3-hydroxy-Camma-py- rone and is obtained as a derivative of opium, can be decarboxylated by carrying out steps (2a) and (2) of the synthesis which is the subject of the invention for forming pyromeconic acid can be converted into hydroxymaltol by carrying out step (3). and hydroxymaltol can be converted to maltol by mine by carrying out step (4) described above *
Another aspect of the invention relates to an improvement in the technique of Spielman and his collaborators, the reference of which was given above.

  <Desc / Clms Page number 21>

      
 EMI21.1
 



  In the article by Spielman et al. Cited ei-dexaue, it is: L71d: f ..-, that the yield of stage (1) of the above synthesis is 4 and the highest roundness reported gen le stage (2) above at that of 17. We only get an overall yield of 7.3 <in maltol from pyromeconic acid. It should be noted that this low
 EMI21.2
 yield could only be obtained after numerous tests and by driving * - reduction 8 <OU8 a very high pressure (100 atmospheres) and in the presence of an expensive catalyst based on noble metal (palladium
 EMI21.3
 on carbon '6tal).



  It has now been discovered that, through the application of the improved operative 8on4i- tions recently described by Ct's.en, and eew contributor * in Journal of-Organte CliemistrZ viol 3i, p. 86 "c, il4? In step (1) of the synthesis, and using pyro * 4ocni-que acid in place of the kojic acid used herein, the yield of 2di-nubatitui) amino-methyipyroaeaonic acid is increased to about 90% and that further, through the application of this improved operating technique in accordance with this aspect of the invention at the stage
 EMI21.4
 (), we see that the yield is increased to 53,

   4a therefore obtains an overall yield of 49 maltol from pyromeconic acid. An additional advantage lies in the fact that the reaction can be carried out under atmospheric pressure in ordinary equipment and without the need to use
 EMI21.5
 an expensive and easily poisoned catalyst.



  Therefore, the application of improvements 4 "OBri.



  3, i of these collaborators to increase the yield in * aid 1 2¯di- (eubatitué) -amino-methylpyroraeconique followed * by the application of the mine method of the invention relating to the stage of formation of maltol makes it possible to approximately four times the yield in
 EMI21.6
 maltol * the operating mode which can be carried out on an industrial scale and with substantial savings * on operating and equipment costs *
Another embodiment of the invention therefore consists in.
 EMI21.7
 Primarily for preparing maltol by treating a 2-dī (substituted) -amino-methylpyroreaonic acid with a reducing agent consisting of the combination of a metal and an acid.

   

  <Desc / Clms Page number 22>

 
 EMI22.1
 By the expression "2-di- (eubetitue) -amino-Nethylpyromeooni acid * 'as * as used in the present description, it should be understood the reaction products resulting from the
 EMI22.2
 treatment of pyt: OaldOLOlic acid with formaldehyde and a secondary Min *, produced well known in technology as Mannich's base. Besides the 2wpipdridü acid: oandthyipyromdaoniqu! noted by Speelman et al *, a number of other Mannieh bases can be used.

   2-DimethYlaminoIlIfSthYl-pyroateoonic acid, 2-di-n-batylaminopyromconic acid, and 2.¯orl pholinolltethylpyromecunic acid are examples of 2-di- (eubetic) - .. lnom4thylyromeconiqu .. especially more interesting
What about the expression? reducing agent consisting of the association of a metal and an acid * as used ioi. it is necessary to understand, which is moreover obvious for
 EMI22.3
 those skilled in the art, combinations of acids with metals suitably situated in the series of electrochemical tensions of the elements, these a8ool1one carrying out a reducing action on organic compounds.

   As we have said previously and as will be shown *. '- later in a detailed manner in the examples * the metals for these associations can be chosen from tele metals, for example, as zinc, iron, aluminum, tin, magnesium and the like, and acids among mineral acids strong as hydrochloric and sulfuric acids or among
 EMI22.4
 organic monooarboxyl acids <saturated aliphatic chain ..H.4, \ -. t1rt *. '^ .- x + xcr':. 1 to 10 tMt <a '!' 'carbon and solxtts3ea in the rFaatic eystise i:

   A.., '-'A te .. acids atc !. represented, not '11 \! '>';> 1 .., by formic acids. acetic, i8olUoano! que and analogues * Z-d1- (8ub.tltué) -1no'thYlpyrG.'00n4 ... acids can be prepared by reacting pyromeconic acid with a mixture of formaldehyde and d an organic lead such as, for example, dimethylamine, di-butylamine, pip4ridimoq morpholine or the like.

   Pyroweaanic acid can be obtained, for example, by decarboxylating comenic acid which is always obtained by oxidation of commercially available kojic acid.

  <Desc / Clms Page number 23>

 
 EMI23.1
 Suitable reaction conditions * for the formation of the piperidine-derived Meumieh base are described in the mentioned article of Sp3alman et al. * However, as 3 'pf 4-;

   as indicated, one will preferably have recourse, because of the better yields which it allows to obtain, to the procedure of * 0'Brien and collaborator * by replacing the kojic acid by pyro- acid. 1 m4oonilue in equivalent quantity As we will show it .oi.ugxirr in r, examples, we obtain the aeidat with in
 EMI23.2
 d "'4" encornent *' J: "I ',,, 4l> / ôs t i?," 8 f'aril \! \'> 1'atteirè :: - e 92 du rend -
 EMI23.3
 theoretically.
 EMI23.4
 With regard to the perfected stage of this mode of realization- j
 EMI23.5
 
 EMI23.6
 tion of the invention., 2-d, - (aubatitudj-aminc.mêthy7pyrcsrnd6onique acid can be dissolved in mu or in mixtures * of water and other *:

   solvents such as lower aloanola, aafque acid and the like.
 EMI23.7
 treats the mixture with a quantity of a metal such, for example, that
 EMI23.8
 lead, iron, aluminum, tin, magnesium and the like equivalent to from about 1.2 to about 295 a.va-grammea of metal per mole of 1itnnichx base the resulting suspension is treated with
 EMI23.9
 the acid forming part of the association constituting the reducing agent, '
 EMI23.10
 and the reaction mixture is maintained at a temperature of between about 50 and about 125 ** or preferably, to minimize side reactions, between about 254 and about -3 ° C or more preferably between 55 and 6500 until such time. that a paper chromatographic assay revealed that the itdi (ßubatitulSj-aaeiriamâtrlpx. romeconic aid was practically aottpltemonstrated ooneoiaml.

   We can isolate *. , the maltol of the reaction melanca by adjusting the pH to a value 'compressed entered about 1 and e. about 3 and extracting the solution '
 EMI23.11
 aoide by about 5 volumes of an organic solvent such as, for example,
 EMI23.12
 as chloroform, ether, ben2, ene or the like. By concentration .d the organic layer, precipitation of maltol 3ristailla4t is caused.
 EMI23.13
 This product can be separated by filtration *
 EMI23.14
 The metal to be used in this reaction must be suitably chosen from the series of elactrochemical stresses after which it is dried.

  <Desc / Clms Page number 24>

 
 EMI24.1
 with the acid to which it must be associated and provide the desired conditions. to cause the reduction of the base of Maes.n3.ah.

   Metals of particular interest for this purpose are zinc, iron, aluminum, tin and magnesium. Because of the convenience which cannot be obtained and its low cost, Bina should be used do prlt'ran08. The term under which 10 * al should be used is not critical. Thus, it can be used in the form of large voroles, granules or powder. However, it is particularly advantageous to use metallic zinc in powder form for this operation since the reaction
 EMI24.2
 rs continues to the end in a relatively shorter time than if the metal is used in other forms.



   The acid to be used can be any strong mineral acid.
 EMI24.3
 or an open chain satunated aliphatic monooarboxylic organic acid having from 1 to about 10 carbon atonies, soluble in the rational medium and capable of reacting with the metal under the conditions necessary for reduction. Although the exact degree of reduction is not fully understood, it is and possible that the interaction of the metal with the acid provides the necessary electrons or, alternatively, that the association of the metal and the aoida provides an active form of hydrogen capable of participating in reduction.

   Among mineral acids
 EMI24.4
 particularly effective are ohlorhydx ic and 8ultur: lqu't acids. and, among the organic acids, formic acid and aul- ± * '* # * acetic acid. For this reaction, either hydrochloric acid or acetic acid will be used, as the maltol will tend to be produced in a higher yield and at a higher purity.



   Of course * it is also included within the scope of the invention.
 EMI24.5
 It is also possible to reduce the 2-di- (orbatitué'-aminomethyl-pyrom6eoriic acids directly in solutions where they are not formed as a result of the treatment of pyromeconic acid with fcrnialdahyde in an amine.

  re added to the reaction mixture 1 = '* 1. the acid is added and the reaction is carried out as described

  <Desc / Clms Page number 25>

 
 EMI25.1
 above, and as hereinafter will be described in the Examples In another important embodiment of the invention
 EMI25.2
 dealing with the production of maltol, it was found that while at li <m to directly reduce .hydraxymaZto3, to maltol, by first reducing the aforesaid hydroxymaltol bzz to a halog4nomaltoZ such # for example, as 2-ohloro-, 2-bromo- or 2-iodomthyl-3¯Uydro'xy * f 4-pyrone (hereinafter respectively referred to.

   ohloromaltolx bromomaltol and iodomalto) and if we then convert .'hal, ag4naraaLtal ta mal toi, maltol can be obtained with very high yield * By reduction using salts of hydrasulurous acid or with aida of hydrogen activated by a catalyst of the noble metal type. The maltol which is thus obtained is not contaminated with the iron chelate being * in the reduction procedure based on the use of sjlno and hydrochloric acid because in this case it is not necessary.
 EMI25.3
 re, or even desirable, to use reducing means of the type
 EMI25.4
 of the metal-aCide association.

   As a result, the mal-tol is obtained in a form which can be used directly, without purification.
 EMI25.5
 later, in all food applications *
 EMI25.6
 It is well known in the art that one can prepare ku
 EMI25.7
 maltoi from hydroxymaltol via a
 EMI25.8
 halog'n0l8éJ: al.

   Thus, Stodola in Journal at 'the Amerioan Ohem att Society; flight. 73, p. 5912-3 (1,51) and Shemyakin et al in Chemical Abstracts vol. 47, p. 4292 (1953) 4would both debrit such a process. However, previously known processes involve the use of expensive products, thianyl chloride and chloroform, to prepare chloromaltol and flax * and # 3, #% *! {! #
 EMI25.9
 acetic as * reducing * means for p * 4p * r '# r maltol s or $ # neo reducing means. 8 $ itent an * operation * Ippnfllitui.9 4. fr.e cation and a view of obtaining a t'mUe krerrxebxe seen from i4ttltu 0,
 EMI25.10
 Food tions $$ The operating mode pf .. '1.nn' r4 & li 4 oort (or .... nt l the ...- ing * # distinguishes from those of Stodola and ShemyakÏn and 0011.

   We 00 that one uses a reagent 4rhalo 4n * tion relatively little oodt.ux,

  <Desc / Clms Page number 26>

 
 EMI26.1
 the hydrogen halide and that we resort to means * reduo-
 EMI26.2
 heifer perfected ensuring that the maltol finally obtained
 EMI26.3
 can be used directly as a power supply, by providing K * 1.

   
 EMI26.4
 thus eliminating a purification operation usually necessary
 EMI26.5
 to obtain a maltol free from clièlatés rer
 EMI26.6
 This operating mode of the process forming the subject of the invention
 EMI26.7
 essentially consists of treating hydroxymaltol with a reagent
 EMI26.8
 selected from the group consisting of hydrogen chloride,
 EMI26.9
 hydrogen bromide and hydrogen iodide to form a compound "having the following formula t
 EMI26.10
 
 EMI26.11
 in which X is chosen from the group consisting of the substitutes
 EMI26.12
 killing chloro, bromo and iodo, and to treat said compound with a reaction
 EMI26.13
 tif choice! from the group consisting of hydroeulfurous acid, the alkali metal salts of hydroau acid:

  , iurrux, alkaline earth metal salts of hydromulfurous acid, xinc hydroaulfite, Ithydro8ultit. ammonium, and hydrogen activated by a catalyst of the toble metal type, to form maltol Of course, as is well known in the art the abi of hydroeulfurous (H2S204 'hyposulfurous acid, dithionous acid) is
 EMI26.14
 a relatively unstable substance.

   This is the reason why we
 EMI26.15
 used dw pnt: t; '' '(fnC: 6 this reducing agent turns us into one of se *
 EMI26.16
 
 EMI26.17
 set of alkali metals *, al Al-earth metals, zino or other ... 1.- .. hydreryaialtol used as raw material can be easily prepared, for example, from acid kojic not found in
 EMI26.18
 trade,
 EMI26.19
 The preparation of haloénona.tsl by implementing this mode
 EMI26.20
 operating according to the invention can 'be carried out according to the following general operating mode:

   the hydroxymaltol is dissolved in approximately
 EMI26.21
 ucutique. "to 6 parts by weight of a solvent such as, for example, that of lt'eue

  <Desc / Clms Page number 27>

 
 EMI27.1
 glacial, chloroform or the like, and the solutian is treated with hydrogen halide gas. The reaction temperature has tended to
 EMI27.2
 this to rise spontaneously in a few minutes deputed from about 2500 to about 0 ° C. Although the reaction is complete * in about 8 hours if the mixture is kept at about. 6000 by the application of external heating means, the temperature will preferably be raised to about 100 to 1200, since thus the reaction is usually carried out for about 1 to 2 hours.



  The solvent to be used to form the product Ilha.og6nomaltol is not particularly critical; however, it should be relatively inert with respect to the hydrogen halocenide serving as a reagent, and auget with respect to the halosenomaltol produced; it is also appropriate that the halogéciomaltol is at least moderately soluble in the said solvent. Solvents * Particularly effective are acetic acid, formic acid and chloroform.

   Acetic acid oat utters because it is relati-
 EMI27.3
 vein inexpensive and because it can., rs heated to preferred temperatures under atmospheric pressure; Chloroform, having an internal boiling point, can be used in a vessel allowing work under pressure.



   The hydrogen halides can be introduced in the form of a gas into the reaction mixture by resorting to proper means! known in the art. It is particularly suitable, for mid
 EMI27.4
 nimize the reagent doors *, especially during large scale operations, to introduce the hydrogen halide into the reactor under low to moderate pressure and to add the hydrogen halide gene as and when as the care to replace the one who reacted.

   
It has been found that adding a small proportion of a strong acid such as sulfuric or phosphoric acid to the reaction mixture
 EMI27.5
 tends to promote higher yields of chloroNaltol when hydrogen chloride is used to treat hydrexy-maltol. Proportions of acid between about 0.1 and about 0.5 by weight of hydroxymaltol are sufficient to

  <Desc / Clms Page number 28>

 
 EMI28.1
 att * 44r * ..... ut.t, -4 # n * 44, e 1.oa is not well qlflttoltiled.

   Such an effect was not observed when using * lM ' <Mttmf # of hydrogen or iodide of hydrogen, we obtain 4ooo40 "in quantitative halogenomaltols corroup" - 4% after 1 to t hours of reaction in the absence of added acid. you i.,. lacomaltol by cooling the reaction mixture, 1Ia.a .... partdLMI "40, to the reaction temperature, which is usually. nrO11Q} JL.O .. to about 15 to 250C. halogenomaltcl eiftttjttlli ** then starting from the solution. The product is separated by
 EMI28.2
 filtration, then we hide it in the air.



  As a result of the reduction of halogenomaltol to maltol, this operation can be carried out with good efficiency by treating a solution of halogenomaltol with an alkali metal hydronultite such as sodium potassium hydrosulfite or the like. , or by an alealino-earth metal hydroaulphite such as 1 ibaloium or magnesium hydrosulphite or the like or by ft3, pi hydroeulfite! As an alternative, hydrogen gas can be used in the presence of a noble metal catalyst such as hydrogen gas.
 EMI28.3
 finely divided platinum, palladium and platinum oxide,

   or platinum or palladium suspended on supports such as oarbo-
 EMI28.4
 1961 Harben Vegetal or analog $ * The solvent used in reductions using alkaline hydrosulphites is not critical, it is sufficient that it is relatively inert with respect to the reagents * -It is particularly effective. . b, you use the water as a solvent. When hydrogen gas is used as a reducing agent in the presence of a metal-type catalyst
 EMI28.5
 Molli can be used solvents commonly used in
 EMI28.6
 / technique of catalytic hydrogenation or moderate pressure.

   Of
 EMI28.7
 particularly suitable solvents in this case are acetic acid
 EMI28.8
 and indoor aloanolas such as methanol and the like. Acetic acid is considered to be more particularly advantageous because it
 EMI28.9
 allows to obtain the highest yields in this environment.

  <Desc / Clms Page number 29>

 
 EMI29.1
 



  The general procedure for the reduction of a ha.c, in1 * lta. by alkaline hydroaulfites by implementation of this aspect of the invention is the following one dissolves or one. ment suspended about 1.6 moles of alkaline hydrosulphite in about 1C volumes of water, and is added thereto about one equivalent of halce4nomaltal in about 30 minutes. During this addition, a sufficient amount of an ION sodium hydroxide solution is added to maintain the so-called pH of the reaction mixture 15.55 * At the end of the addition of ha.agi * 3. '1 "
 EMI29.2
 the reaction mixture is stirred for about 30 minutes then
 EMI29.3
 heat to about 90 ° C, and a small amount of insoluble material is removed by filtration. The maltol is collected in a vtjPHiM which dies the filtrate to about 13 ° C # ee which precipitates the product.

   The crystals are separated by filtration and they are removed by air. As regards the reduction of ha, lo, nauaalta.1 by hydrogen activated by a catalyst of the noble metal type, it is possible to
 EMI29.4
 implement the following operating mode
 EMI29.5
 Halogenomaltol is suspended in about 50 to ZOO
 EMI29.6
 parts by weight of a solvent such as, for example, acid
 EMI29.7
 glacial acetic or methanol, and to this mixture is added envirbi 2.5 by weight, based on the weight of haloginomaltol and calculated in
 EMI29.8
 Noble metal, a catalyst of the noble metal type such, for example,
 EMI29.9
 a catalyst to $ 5 of palladium on carbon * Then added ') a quantity of a base such as triethylamine or ammonium acetate representing the equivalent of halogenomaltol,

   and introduces hydrogen into the slurry until it 4 $ 4t * - initially creates an overpressure of about a111Pe *! *! ' Xé73 A, t approximately? kg / cm2. The suspension is shaken and the hydrogen pressure drops to a somewhat predictable k value corresponding approximately to the number of equivalents. <Jt'haJ, o < <do not introduce maltol, and this in about 15 to z minutes. 04, Collect the maltol by filtering the reaction mixture to separate the ea4Ja <* reading and evaporating the solvent from the filtrate.

   XI remains a maltol residue which can be further purified by rear.x ^ k, i, sal.at -
 EMI29.10
 in water.

  <Desc / Clms Page number 30>

 
 EMI30.1
 x.7n another aspect of the invention that relates to them interesting *
 EMI30.2
 intermediate product))) usable. in view * of the preparation of maltol, and original procedures using these products.
 EMI30.3
 intermediate in eu * of .ynth8 .: maltol. Thanks to this embodiment of the invention, we have avoided, during
 EMI30.4
 of the final stage, an additional distillation operation because this
 EMI30.5
 distillation is associated with a decarboxylationp operation which makes it possible to obtain more economically a maltol of excellent purity and color.

   These new syntheses of maltol from iridescent intermediates in this embodiment of the invan4
 EMI30.6
 tion comprise, During their later stages., the decarboxylation
 EMI30.7
 acid * 6-mdthylodn, qtia or derivative 2, '.. dihydt "o ... of this acid * According to another aspect dr,' invontion, it was discovered that we prepare malta, i from 1 * 6- 'tethylooB acid <eniquet two interesting new gamma-pyrones obtained by said implementation of the invention, the choice of * solvents for the stage of deabt xylation during the preparation of the desired product is very extensive due to the high solubility of the 6-mtbYleoenic acid.



  The invention also relates to the preparation of new and interesting substances from the gamma-pyrone group which include 6-methylcoméniquo acid, 6-.éthyDtejlqulu acid and 2;, - dihydro- acid. 6- * ethTlcomenic.



  6 "II'tby! Colrtenic acid has the following formula t
 EMI30.8
 
 EMI30.9
 C - .. t an ori.ftl11 Bolide. from P.F. 37twx3l '
 EMI30.10
 
 EMI30.11
 6..ethylkjiqu acid. pO.8ôd. the following formula
 EMI30.12
 
 EMI30.13
 - ei a solid arara7..rrô of P. ', 145-145.5-0

  <Desc / Clms Page number 31>

 
 EMI31.1
 Z, dhydro-6ât & ycéniue acid possesses the formula.
 EMI31.2
 
 EMI31.3
 



  It is a crystallized solid of P * P- 156157 C. the invention also relates to the preparation of nomirollop gamma-pyroues posiédant the following formula i
 EMI31.4
 
 EMI31.5
 wherein 1> is selected from the group consisting of hydroxyl, the lower alkyl groups (can contain from one to four cubent atoms), pip4ridieo, lI1orphol: 1.no, chloro, bromo and iodine. still another Interesting gaUt1Ua.-pYX'01'1e that bears ** of p1 "for the invention have di - buhylaminoctthylkojic acid <.



  The interesting intermediate produced mentioned * Qi-d-s # U8 and the evil you can be easily obtained 4 F'prt :. kojic acid according to the synthetic routes outlined in the diagram ciapr..t by implementing other reactions which will be described in detail
 EMI31.6
 

  <Desc / Clms Page number 32>

 
 EMI32.1
 
 EMI32.2
 6-methylcomenic acid Malt 01 where X is chlorine, bromo or Iodine,
The first stage of the synthesis is carried out by adding oxygen to an aqueous solution of ko, jic acid at a pH of at least about 10 in the presence of a noble metal catalyst.



   The second stage of synthesis, acid conversion
 EMI32.3
 comenic to a new compound, 6..hydroxymphylcoményue acid, can be made by suspending the comic acid in about 3 to 10 parts by weight of water, adjusting the pH to about 10 by addition of a 0% by weight aqueous base such as, for example, .0d1 \ I hydroxide, to add to the mixture a molar equivalent of formaldehyde, and to maintain the resulting solution at a temperature.
 EMI32.4
 temperature between about 15 and about 6o * C for about 3C 1l1uto. about 5 hours. Hydroxymethylomonic acid can be isolated by adjusting the pH of the reaction mixture to below about 5 by adding an aqueous acid, for example 12N hydrochloric acid.

   The pH is preferably lowered below about 1 to minimize the tendency of the corresponding sodium salt to oopre-
 EMI32.5
 o1pitr. <The resulting suspension can be cooled to about 5 ° C, and the precipitated product can be filtered off. By concentrating the filtrate to within one fifth of the volume, a second crystallization stream of 6-hydroxyetbthyloomenic acid can be collected. The overall yield of this acid is of the order of 90 to 95 * 6 of the theoretical yield.



   Although it is within the scope of the invention to effect the direct conversion of 6-hydroxymethylcomenic acid to
 EMI32.6
 6 "') aethyloom <5nique by treatment with fine hydrogen in the presence of a catalyst of the noble metal type in glacial acetic acid or by causing chemical reducing agents, such as, for example, sodium hydrosulphite, to act. higher acid yields

  <Desc / Clms Page number 33>

 
 EMI33.1
 6-Mithylcomenic if one first converts the hydroxym4thylcomenic acid to the corresponding halomethylomenic acid and then this intermediate compound is reduced.

   For the direct conversion of 6-hydroxymethylcomenic acid to 6-methrlcownic acid, cata. Suitable nobla metal type lyseura are, for example, palla. dium and platinum used in the form of finely divided toebaux or in suspension on supports such as carbon, vegetable carbon or the like. The solvent for the reduction is somewhat. Critically in this case, glacial acetic acid gives the highest yields, methanol gives significantly lower yields, and by working in solution in water pH 11 no reduction takes place at all.



   Regarding stage (3) of the synthesis which we have just d
 EMI33.2
 present the diagram above, the acid 6-haloenoméhY1COmn1q. can be prepared by treating 6-hydroxym'thy1comiqu acid. with a halogenating agent such as, for example, hydrogen bromide, hydrogen chloride or hydrogen iodide * A particularly suitable procedure for the preparation of the acid
 EMI33.3
 6-Brotaomethyloomenique consists essentially of treating a * skirt ** of hydroxym6thy7.comenic acid in about 3 to 10 parts by weight of glacial acetic acid with dry hydrobromic gas. The gas is quickly dressed in the suspension; it follows that the
 EMI33.4
 mixture heats up spontaneously to about 55-600C in about 15 minutes.

   Sufficient heat is then applied externally to raise the temperature to 90 to 110 ° C. while gas is introduced. The reaction is maintained under these conditions for a further 1.5 to 2 hours, then cooled to approximately
 EMI33.5
 25 * Co A small amount of sodium bromide formed as a by-product is filtered off, then the solvent is concentrated to remove under a pressure of about 20 mm Hg until the volume of the mixture is 3. / 4 of the initial volume.

   The product,
 EMI33.6
 6-bromomethylcomenic acid, can be isolated by filtration and can be further purified by recrystallization from a

  <Desc / Clms Page number 34>

 solvent organizes such as, for example, ethyl acetate, acetic acid or the like. With yields of up to 90% of theory, 6-bromo acid is obtained.
 EMI34.1
 mÓtbY'lcom6nique, P.J. ". 197" 197t5'C <t The preparation of 6-chloromethyloomenic acid is carried out in the same way by replacing the hydrogen bromide with hydrogen chloride gas.

     It can be seen, however, that in this case the yield tends to be lower unless we add approximately
 EMI34.2
 5 by weight, based on the weight "of hydraxymethyloasninic acid, of a strong mineral acid such as sulfuric or phosphoric acid * With respect to Stage (4), reduction of the acid
 EMI34.3
 b-halognom6tnylocmlnique in aoide 6-.ethylcom, niqu., this reaction can be effected for example, in the presence of chemical reducing agents as from sodium, potassium, lithium, naloittihb magnesium, zinc or ammonium hydroaulfitee , or by hydrogen activated by catalysts of the noble metal type such, for example, that.

   
 EMI34.4
 platinum and palladium form finely divided lethals or supported on carbon, charcoal or. the like, or with a combination of a metal and an acid acting as a reducing agent. It is especially preferred to use sodium hydroeulfite since this reagent is economical and readily available. For example, by adding a small amount of 1N hydrochloric acid, a solution of sodium hydroeulfite in 10 part is adjusted to a pit of about $ .0-5.5. by weight of water.

   To this solution is added in small pulls, over about 15 minutes, about 0.66 equivalent
 EMI34.5
 molar of 6-bromomethylcomenic acid at the bottom * of sodium hyùro8ultite, and a sufficient quantity of 1 IN hydroxide solution
 EMI34.6
 of aoditra to maintain the pH, which tends to drop, at 5 O-5.5. the temperature of the mixture tends not to rise spontaneously to about 40 ° C. To complete the reaction, the mixture is stirred for about an hour, then heated to about 60 ° C. and on. shakes it during daht. two more hours.

   A romatographic analysis on paper indicates almost complete reduction of the acid.

  <Desc / Clms Page number 35>

 
 EMI35.1
 ! .. bxomoraéthy3, csomén3que at the end of this time. We can isolate the acid. 6-methylcomenique by adjusting the fold of the mixture sâaat.oszr, el to about j 1 by adding concentrated hydrochloric acid, and, after that. A small amount of sulfur precipitated from the mixture by filtration, the filtrate was cooled to about 5 ° C. to precipitate crystals of the acid. After filtration, we obtain
 EMI35.2
 6 "methyloorenic acid with excellent yield.



  Another clod o, -, 'ato3.:e to achieve the reduction of 6-bï'omotBothylcoa'ni'Tt * oc .. s ste% sentieiie> " <or! i dissolve the compound * in about 10 volumes of glacial acetic acid, adding a 5'6 hydrogenation analyzer of palladium on carbon in an amount corresponding to about 1% by weight of palladium on the bottom * of.
 EMI35.3
 weight of 6-bromomethylomonic acid, and treated with hydrogen in an apparatus operating under pressure until the theoretical quantity of hydrogen has been absorbed.

     It is quite convenient and convenient to carry out this reaction under an overpressure of hydrogen.
 EMI35.4
 of about 3.5 k / am2. The product can be isolated by separating the catalyst by filtration, evaporating the solvent and recirculating;
 EMI35.5
 Tallise the residue in ethyl acetate. By this procedure 6-methylcomenite acid is obtained with a yield of up to about 90.6% of theory.



  Although 6-iodo- and 6ct.à.orom6thy.aoxcniqa.r, s can both be reduced to 6-methylootaenic acid by the use of the procedures described above, the yields tend to be low. lower and the product tends to be significantly more difficult to isolate than when using the compound 6-brja! 0 (therefore the 6-browo- count which will preferably be used). (5), decarboxylation of 6-methylcomenic acid to maltol, this is accomplished by suspending 6-methylcomeniquo acid in about 2 to 5 parts by weight of a decarboxylation solvent such as, for example, as , ', dimethyl talute, dibuty, .'.- earbitol,: - mSthy: Lnatal4no et analcciien. Then the suspension is stirred and heated;

   we see "that- the acid

  <Desc / Clms Page number 36>

 6-Methylcomenoqque is almost completely dissolved when the temperature reaches about 150 C. Vigorous evolution of carbon dioxide is observed when the temperature reaches about 220 C. The temperature gradually drops to 250 C in about 20 to 25 minutes , during which the evolution of CO2 ceases almost completely * To isolate the product, the reaction mixture can be cooled to 100 C, a vacuum corresponding to about 15 mm Hg applied, then the reaction mixture heated to temperature between about 150 and 250, whereupon the maltol distils out of the vessel at a vapor temperature of about 14-150.

   The distillate, which usually contains some decarboxylation solvent, is cooled, and the maltol which crystallizes is filtered off and can be freed of solvent by washing with about 5 volumes of cold ethyl acetate.



  The maltol thus obtained, with a yield corresponding to approximately 75% of theory. 157-160 C is eminently suitable for use as a flavor and aroma enhancer,
As a variant, when 6-hydroxymethylcoménque acid is treated with a reducing agent consisting of a metal-acid association, maltol is also obtained by oxidative decarboxylation of the new intermediate product thus formed. This intermediate, 2,3-dihydro-6-methyloomenic acid, is a novel compound also included within the scope of the invention.



   A suitable procedure is essentially to treat a mixture of hydroxyethylcomenic acid with about 2 molar equivalents of sino suspended in about 5 parts by weight, based on the weight of the acid, of water with about 4 molar equivalents. concentrated hydrochloric acid. The mixture is stirred for approximately one hour at approximately 60 ° C. then the unreacted zinc is separated by filtration. A quantity of dissolved oxalic acid equivalent to approximately 0.9 molar equivalent of the zinc initially used is added, and the precipitated zinz oxalate is filtered off.

   The filtrate is adjusted to a pH of about 1 by the addition of a 50% aqueous solution of sodium hydroxide, and the mixture is evaporated.

  <Desc / Clms Page number 37>

 solvent empties you. The product can be isolated by extracting the residue with a small volume of glacial acetic acid, separation by
 EMI37.1
 filtration of organic salts to Insolubles after which the acetic acid is evaporated, empties us and is re-crystallized 1 <residue in ethyl roetate * "acido, 2,

  g..dihdra6.rxéthy3.aamln.qur is decarboxylated with oxidation to form maltol by dissolving the crystalline product obtained in about 30 parts by weight
 EMI37.2
 of glacial attoidoacetic and adding a 4quiraolai * e proportion of lead tetraacetate.

   The temperature of the mixture rises <poA taneously to about 0 'g and, after 95 ">) 409 * Chromatography on paper indicates the presence of Mltl in the reaction mixture. The reaction is carried out to a good fix by heating the mixture. mix for one hour at 40 ° C, then another hour at 16 ° C to 0 # and finally another hour at reflux temperature * The maltol is isolated with a yield of 70% by cooling the reaction mixture to 25 C, and diluting it with an equal volume of water and extracting it once with an equal volume
 EMI37.3
 of chloroform and once with an equal volume of ether,

   after which the combined organic extracts evaporate. The product can be purified by re-installation from hot water.



  Another aspect of the invention relates to the preparation of
 EMI37.4
 interesting -gamma-pyroues in question using sum product * intermediates of Mannich bases. Thus, one can prepare 'maltol from kojic acid by passing through another das
 EMI37.5
 new produced intermediates already eiK))) above tt pptoftMt in the troop of acids 6-N-, N-di.ub8t1tu'.aNtno.'thc .. '. tqu ...

   operating mode can ae present by the 8uoo ... i.n reactions schematized below t

  <Desc / Clms Page number 38>

 
 EMI38.1
 
 EMI38.2
 kcjic acid comenic acid 6-N, N-dïnubatitu4, amlnomethylomynic acid
 EMI38.3
 
 EMI38.4
 6-methylovmenic acid maltol
 EMI38.5
 wherein ZN is selected from the group consisting of di-alk * Yl (inferiority) amino, said * alkyl * group having up to about 4 carbon atoms, piperidino and morpholino.



   Stage (1) of this synthesis, the oxidation of kojic acid to comenic acid, is carried out in the manner already described above.



   Step (2), conversion of cominic acid to the corresponding Mannich derivative, can easily be carried out by employing techniques which will be described in detail hereinafter in the examples. For example, a solution of a secondary amine, such as morpholine,
 EMI38.6
 piperidine # fimétTa3'.amine, di-n-butylamine the like, in about ten volumes of ethanol or water can be treated at 25 C with an equimolar proPÓ.1 tion of aqueous tormaldehyde at? 7 '6 and after to have acted.



  15 minutes the mixture, oh add to it, preferably all at once,
 EMI38.7
 a quantity of comenic acid representing approximately bye 6qll: iVA1 "" ': <3ïfiiï # of the initially sfnînus ItIj <6 in work. After oh- i vistm 5 minutes of stirring at about 'gold., All the acid ti 1.Q.U. dissolved and after another ten minutes the 6 N acid, y <dlubstitu, - .. 1nomethylcomenic. corresponding crystallized precipitated.



  If the reaction is not completed, the reaction mixture can be stirred for an additional hour. To isolate the product, it is preferable to leave the water mixture standing at 25 ° C. for about 16 hours, then to collect the crystals on a filter. After drying in air, the product results in a yield corresponding to approximately 80 to 95% according to theory *

  <Desc / Clms Page number 39>

 
 EMI39.1
 In this way, stage (3), reduction of 6-tf.N-diaubatit-aainomethylcoNenic acid to raétkylcoér.iqus acid
 EMI39.2
 corresponding, it can be carried out using reducing agents.
 EMI39.3
 chemical agents such as, for example, sodium hydrosulfites of lithium, potassium, calcium, magnesium, alcohol or
 EMI39.4
 ammonium.

   Since we encounter certain difficulties
 EMI39.5
 IHh1X 'Isolate ie "" :: 1:' -: -. It if other reducing agents are used 14,80 for example which ' <4 <" <m. ;; Ítal-acid associations or such as. i JI, '- * 3gèn * on prasnrta dl]) ..... tal.1aur of type I! 1c1't ", l not: fJtt o4; is preferably addressed to hydro8ult1tes for this purpose, Lr reduction by sodium hydroaulfite can be carried out by using
 EMI39.6
 the procedure described above for the reduction of the acid
 EMI39.7
 Corresponding 6-hydroxywethylomenic, this operation being garlic
 EMI39.8
 described in detail below in the examples.
 EMI39.9
 



  Raaltol can be prepared by deo3.rbox'la.tiQn 6-methy3 comnic acid by carrying out the procedure described above. The interesting new gamma.5vrnea in question can also be prepared by using an S) ' nNl'3e passing through 6-eétitylkojtqua acid, one of the interesting -new product.
 EMI39.10
 intermediaries in question.

   This synthesis is carried out in accordance with
 EMI39.11
 au achema auivant t r¯¯ '
 EMI39.12
 
 EMI39.13
 kojic acid 6-hydroxyathylkQj1qu acid. 6-m Sthylkojlque acid
 EMI39.14
 
 EMI39.15
 aolde 6-dthycb: nnique maltol
 EMI39.16
 Regarding the stadium (!) <hydroxyNthyla.tton of the acid 'k0jiqu t 6-iycü8xyrathyzkcsi acid can be obtained. <;, ua with r.d.mant8 reaching up to 90 by blocking the general operating mode according to 1 we put in supllns1Dn the aci ', kojir'nr

  <Desc / Clms Page number 40>

 in about 4 parts by weight of water, and a sufficient amount of a 50% by weight aqueous sodium hydroxide solution is added to the suspension to bring the pH of the mixture to at least about 8.



  To the resulting mixture is added 1 equivalent, calculated on kojic acid, of formaldehyde in the form of a 37% aqueous solution; and the reaction mixture is left to stand for two hours at about 25 ° C. The reaction mixture is then acidified to a pH of about 1 by the addition of a 50% by weight acid such as: example; than sulfuric, hydrochloric or analgesic acid. After cooling the suspension to about 5 ° C. the product can be collected by filtration.

   We can obtain an additional quantity by concentrating the filtrate we empty up to the neighborhood of a fifth of its volume. Or can purify the product by re-installation in methanol to obtain 6-hydroxy, methgylkojic acid, m.p. 148-1500C.



   L reduction of 6-hydroxymethylkojic acid to 6-methyl acid. kojic, a new compound, can be carried out easily to constitute stage (2) of the synthesis by carrying out the following procedure A supensioon of 6-hydroxymethylkojic acid in approximately 5 to 10 volumes of water and containing approximately 2 equivalents molars of metallic zinc powder, calculated on the acid, is processed by addi. A dropwise drop of about 4 molar equivalents of concentrated hydrochloric acid. Such an addition is suitably carried out at such a rate that the temperature of the mixture does not rise above about 65 ° C. the time required is about 15 minutes.

   In order for the reaction to be complete, the mixture can then be heated to about 60-70 ° 0 with stirring for an hour and a half. The product can be isolated by heating the suspension to about 90 ° C. while filtering it to remove. zinc metal which did not react, adjusting the pH of the filtrate to about 2 by adding 12N sodium hydroxide solution and allowing the suspension to stand at 5 ° C. crystallization is conspiracy it takes about 16 hours. The crystallized product can be collected on a filter and then air dried at about 25 c.

   We can get a

  <Desc / Clms Page number 41>

 
 EMI41.1
 
 EMI41.2
 a small additional amount of product by entering the filtrate up to the fifth of in vo1 \ P11, then preceding to a 4x # regation with an oil such as chloroform, evaporating the organic layer, and making 1 " ..ri.'a111.8r the residue in a 410001, .1. for example # that of i.opropano1.



  Zn which oonoerne stage (3) 0 oxidation of autde -w4l * hyXk * Jiqu. gti * nic acid '# the operating mode in uivrt i # 1f owa "3. <tMe the same as ..lui dierit * ± -above pçbur! ' <t <tli n 'Itoiredatton of the Reid # hejiqMO <m. ". ù .., M6niqu .. Par .x .., I, .. 1Ii ..if t * u pt - * Ilaet ion of k * d" 40 6 M4thyik0jj, qut doM about 4 to 10 v 4uUitf of water on .40ui..approximate,! vlm.ni. 4uiY''A "... r .. i'Hy *! * -1 xide of IOdi" 8 .YES form of an aqueous solution% # XM9 $ i * mixture) * <taotiC! mw3. is oomplbtomont homogeneous # by adding 4wpt <wa * about 1% u8qutà envirost 1% palladium, Q & 1ou14..ur ttÁ.1d.1 6-mèthylkojiqueg us the fe! " <Mw of a 5 µm palladium on carbon catalyst suspended in 50% by weight of water * The reaction mixture is kept overnight at about 3000 at temperature. u- remento and we blow air into the M41ages r4 * 0t:

  tongel at the rate of about 5 ml per minute per gram dfactdo 6 "methylkojiqu * for about 16 hours. The product 1A * 4p4zant is isolated from the oatalyst by filtration and acidifying the filter." .. . do. 1 'I, Q14. hydrochloric acid concentrate Up to a level of 1nté1. At about 1% Pee, the light color separated and after cooling to 5 ° C the product was filtered off and dried in air at about 25 ° C. 6- acid <5tbyloem * niqu * r? * C a yield which can reach up to about 00% of the theoretical r8nd. Altol is prepared by decarboxylateon 40 4-methyloomenic acid by proceeding in the manner already described OÎ-40 * suap and who serves,. also described hereinafter. in the examples ..- Another epertolic drug for the preparation of the acid, ..jth11. eoaenique includes the preparation;

  * 4t,, J ,. low at * Mann4.eh eorvsspondant from acid kojiueeite cyntïteee can. .o; ma1.4. of
 EMI41.3
 
 EMI41.4
 the following way t '

  <Desc / Clms Page number 42>

 
 EMI42.1
 
 EMI42.2
 half kojil1U 'goido e.M' ... db ,, "n,: Uu4 .... id. 6, t, 'ka, wY #wincmtS thy iko j iqu
 EMI42.3
 - # # eu XX .... Hol.1 paelui le grouteu een t ± tu4 by di.al .., l (int '. loadtte troops & 100.1 ..

    carrying ", .q, l.1i" about 4 atoms * do GArbon '. piperidin # * morpholitiot and which 1Í'lejrf \ 1 10 ..adt (1) 'of this ynth6g,' Ol \ yt "tI de, 1 t ltc1cht kojiqutf -1 \ Io derived from Nnnaieh sotte .8iI: t.'n Polit êted brrtebutà oâ implementing the rlftdral operating procedure described ei "0nomt liropos liropos of the preparation of the derivative of HahtUch or1 '* ï'ftpot 1'sidtf COM'ftiu ..' nr:, x8 = 1'11. a * solution of a secondary Amthâ such <bill 11101 "\ 1110111 \., p: i.pilr: t.d1ne, diNëthyletmiMt CU." lilbulii tYl: l.nlit1 or & A & ltK in about 5 volumon of water or alcohol '-3d pat- eXimpl;

   than 1146thanole * and thit '. by a proportion whichM * "laie, $ of appropriately used we fo.-mo of a..01u" tien aqueui at 37 1> t and one agitates i our.u8.ment the .'tan, - " U1tArtt during the minute, We add * then 0 quickly no amount of ddido ko1qù. OO.jp4ndant to about 0.75 molar equivalent of friendship 4w con4.1 'mi)!' * 6n worked. After about 5 minutes , the added Jiartié 66 the acid kojîqù4 b44 t dissolved, and after about 10 minutes the dêl4t-6 v <of M1h eoatmcttttt to crystallize and not to separate from the m61sne réaôm U.oMe1. The reaction mixture is stirred for a further 4? utîhutabs then on ', ft \ band (\ r'.;,! J \ at rest, .-, "tW'.fl '.. 1 ,,, at 4 p.m.

   We collect the l't'odult by (: titr4tiou by suction, and dry it at 1. 'Ih:'; * n, 41ïwo ron 25 * do @il thus obtain, with yields included., Ntr ... n't "iN:! t \ 75 * t 95. alde amihomethylkOJ1qU. 6-N, .N'-dî ubatituée tn gé which concerns stage (2) reduction of the Kattnich derivative in step 6 of the Kojic acid to 6-methylkôjiqueg atïide It is the node of the implementation of this reaction in the presence of agents jM4âudi * e type of .. '6oiattofi etal-acid.

   For example, we pre par. a disturbing .u.n8iG, acid. aminometbylkojique 6-NtN-disubstituted dâhi. \ JX'a1rotl 3 to 10 parts by weight of water, - and there is added approximately 2

  <Desc / Clms Page number 43>

 
 EMI43.1
 . # amea, ammea 4th laying of zinc asbta ,,., a ° .g1 '.. we'laagfc and we add approximately 2.5 to 3 eq ".. 1.va, hn11 4'" '111. , 10tf! L: "q, u. Con.,. Counteracts an aHure such that the temp '!. (\, 1at, e Il *'. '.'T ..

   Q \ t, J1.u. between 50 and 55'C <this requires around 30 midnight, * <H $ # 9H t '' - fiil4itioa 4th
 EMI43.2
 the acid one finishes in reaction in ahatx''1ç tu in aet4nt & ât. â "0 for another hour and a half, 0 i J, e 9 P" 1J "tt one filtering out 1 metallic zinc having pftq x4 *, y # $ ** t11 * tion t years a'ustxae p0 ", ## * a year 4ju ta.nK aa pU du f: r.; lttPtf. '\ I" axr, ss 2,0 by e4attion eÀ4ur. * - <,, '... tion M, ""'. l $ 6. s ,, d'3'dodr 4 ", vaw; .n had fn cooling the auspolision * u # p. '# 1 5? Çf Ot then eloglinizes up to about pU. 10 by additive d.'qn4t n mv # 44f 41t . '$ of aqueous .olu1o of Ne4H, it is eliminated by fcrutiufv! # p, S, pt *' 'hy- d1'lof <l. of xino formed, and the pi; lu fU t1 ".t is readjusted to about, 2 $ '? pure addition of hydrochloric ars3 ror, dnsx4, On .'r-Q.", 1r.' 18, aolut;

  f, .ox *, q ,, m * or empty until oi.ina 'of inHAÎinn * 4 oo, ro.uaa, we cool the (1aftcantrat to 50ce Aprba a'. "hnd1VI''1a <njmp <n- ion at the meal weighing about 48 eu.s ** at '' 0 Of '). rtqU¯: 1J.ff 1. crystalline product which precipitated. On oh ':!. Êrrq ": l..fl.I': I., 1 q. '. 1 !. W good' # # * nt, fie \ 'ac4. 6" yuèthylkojiquoo On r4par l'atoide 6mi hy ... ,, w4iipA JH \ 'o? ty <J * fton do J. ' 4- help 6 ... JtSthylkt.tJique by implementing 10 jttfd *? P <5rfttetiy 44 rit ct ... d ... u. and also 01-1% near in loq.; CIIIi.1. "Çn pirépetre le! # tel par dÓ08.1" b <utylatio: .1, from Ilaolde 6, aab, xerl "drilling in the previously deorUed manner, and" s ,, "" -. en, 1I 4 e & "4prbo in the
 EMI43.3
 example**
 EMI43.4
 After August I gave different 8! IC, mpb ,. '9101% 8f1t,' A4 "1? # L; 1, state: t, t '.., do put" n put the xin, rrc.r.



  Ejca 1 - In a r cipiaxt oi a.pi9P inaanydftfelf of 8 1: t'rw. equipped with a stirrer and a tube for y f.4. "; r '\. vot; from the air * we place a 550 in suspension d \ 8idt't 1 <Qj tfUf! dantt 3500 III 10% uo The gT 11.1 is adjusted by addition of 6 ml of an elution containing 50% N'AOH. then we add 14th g (7, Ir d *! t \ 't "') (('a 5 # ote.xrexrr of palladium on charcoal * We do p.

   ej !! ' 4th air r! "

  <Desc / Clms Page number 44>

 
 EMI44.1
 The reaction, which is slightly exothermic, is maintained at a temperature of about 20 * 22 * C by cooling externally when the beaain makes you feel it. After 11 hours, we filter the reaction mixture to separate
 EMI44.2
 
 EMI44.3
 this catalyst, and the filtrate is treated with 600 ml of hydrochloric acid.
 EMI44.4
 
 EMI44.5
 Dric Concentrate * The crystals of comnic acid which precipitate
 EMI44.6
 *
 EMI44.7
 from the p13 0.5 mt mixture collected by filtration, washed with a small amount of cold water, air-sprayed.

   We obtain inai; 328 t of product, which corresponds to 8.3 of the theoretical yield. A titration shows that the purity of the product is 99.2% and the yield expressed as pure comenic acid is therefore 84.6 '6.



  ] Deenglo II # The procedure of Example 1 is repeated, operating at temperatures of 10 * 30, 400 and 55 * 0 with substantially the same yield (from 70 to 85 z) at temperatures of 10, 30 and 4000; for the reaction carried out at 5500, obtains some, with a lower yield,
 EMI44.8
 a darker crude colored product *
 EMI44.9
 Syemtsi 13; The procedure of Example 1 is repeated using, in place of palladium, on vegetable charcoal, the following catalysts o trampling black, palladium black, platinum oxide, and
 EMI44.10
 platinum on charcoal. In all cases, una quan is used. tity of catalyst corresponding to 7 * 1 of metal.

   We get meaning! -
 EMI44.11
 blemont the same * results.
 EMI44.12
 sLxenm.e I1f m The operating mode of example 1 is repeated, replacing
 EMI44.13
 placing the air with oxygen and adjusting the water flow to a quarter
 EMI44.14
 of 1 * | i specified value. Substantially the same results are obtained x, .s ,,; =, a, l "w, '", yl .. A reaction mixture filtrate prepared in the manner * described in Example 1 is adjusted to a lower pH. to 1 per additon of sulfuric acid; we thus obtain, with a high efficiency, a
 EMI44.15
 
 EMI44.16
 domenic acid of high purity.

   The procedure is repeated, replacing the hydrochloric acid with nitric acid, and the ntemea results are obtained substantially, FXeY, - The procedure of Example 1 is repeated using, instead of sodium hydroxide aolutioa * 250 g of potassium hydroxide (added forms a 50 * 6 aqueous solution) <

  <Desc / Clms Page number 45>

 
 EMI45.1
 The same results are obtained substantially.
 EMI45.2
 The procedure of Example 1 is repeated using 110 g of lithium hydroxide (in the form of an aqueous solution h 10 z) 3 "
 EMI45.3
 in place of the corresponding solution of sodium hydroxide.

   We ob-
 EMI45.4
 keeps appreciably lea aStaes * ltxem] 21 * VT, 1; - In a 150 Ml Pyrex balloon equipped with acting. With the mechanical aid of a thermometer and connected to the receiver by a distillation head, 10.0 5 comenic acid prepared as described in Example 1 and 30 ml of diphenyl ether are placed. The reaction mixture is stirred and heated by applying a
 EMI45.5
 heating jacket. After about 20 minutes *, the temperature reaches
 EMI45.6
 22500 and one. observes that pan gas * in the receiver, When the temperature reaches a4 t5üt! "we observe a vigorous release of carbon dioxide * After another ka Minutes at 243-25000, OR dietillt the pyromeonic acid until more nothing passes at an internal tsrpistuxa of 25500 in the flask and for a temperature of 20 * 0 of the steam.

   A further 30 µl fraction of diphe-ether is added! nylic acid in the flask ot a new quantity of pro
 EMI45.7
 after distillation for another hour 10 minutes of Main-
 EMI45.8
 maintain an interior temperature of 253 "C <The product is dissolved in about 5 volumes of hexane, then it is separated by ttitra-1 tion, and it is reoristallized in 4 volumes of toluene. 5.71 g of pyroxi4coniquo # r PF 11w1.i! Ir C. are thus obtained. By concentration of valuén3 mother liquors, qu.ee up to the vicinity of the "fine tieme of their volume, a further 0.7 g of a significantly less pure pyron4cin4ctuoi acid is obtained.

   All of the resulting pyromeconic acid produced represents a conversion rate of 80 ± # The procedure is repeated, replacing the diphenyl ether with triesyl phosphate, and the pyromylic acid is obtained with. a yield of 80 # &# If we replace the diphenyl ether by dimethyl phthalate and we obtain substantially the same results *

  <Desc / Clms Page number 46>

 
 EMI46.1
 M !! î4à ** On "4pbto - .. ud. Operatmirs of 1 ...... 1- vzw fla t'Ather d.1}, h6nyl1I \ u. PAr 1 ... olvnnh xittttt tv <o $ 4nolio
 EMI46.2
 bl!) t. ttfltW * y $ 3.taw AthyMphtho '4x% tyapht!) t <3.dw <thyln <tph'me a.s,; sxxys, 8thtatfttt} titttln, <t 3., 4 * 'diMthit <tfthydf <tphtaI.w
 EMI46.3
 6.4 awl
 EMI46.4
 t8fth;

  eïtyMt <'! thydï * onmphthal <in 'ethr 26-Methyl, pl.aqur 4thole 3 * tSthyi diph4nyliqu éth0t lwtltty3. diph4hyii.que itUit kt-mithyt dipt.xiyliqcre r tliriG '4t4' * aiHthyi diphnyliqu * ithéi "l2,4 * dia, <Jthyi, p '. ± xy ^, t.que 4th î- <ttltyltKt du txrttyl: ne glycol thé * èxph & yli% u0 ûn tithyU-nc glycol 4th * r il.t ^ èty ,, Aki du têtr & 4thylene glycol dthoe àiati!, l, rtr of ihrxa6thylens glycol trioopenphryl triophryl ph 4, , 4 ',! T' tyinthyltfiph <ny phetphitw! d 1È 9 "tx * ittdthy.t ^ iphdri ', e phoaphite of 3-i -butyiphnyI photpktâkte de î, 2' i2" -trim Sthylt;

  riph <'' nyl pliosphate d * tiAr r4 "wtx.adthr, t.phlSrxy, e pïï4> * ph t # il * 3-butyIphônyl - diphnyt. <t

  <Desc / Clms Page number 47>

 
 EMI47.1
 X "butyl pyrrolidone N-eyolohoxyl pyrrolidone N-2- (Sthylhexyl-pyrrolldon *
 EMI47.2
 caprlic acid
 EMI47.3
 lauric acid,
 EMI47.4
 palmitic acid
 EMI47.5
 f nîee 180dérftOlra .r; x: .yxst fir Itt4i, - v - rv ^ ï: qse u '' thy! gly <-9 * tiaVi..t9. "'Pd; O de l' ti" G.i IUChh ',' S ".3,, ü du> '1; çhy1..'," ".'-" 'J.
 EMI47.6
 rorPacéttte of the monoethyl ether of Illiexaethyléite g.y'ca;

  , mono-state diethylene glycol mcnobutyl ether acetate. eaonophenyl ether triethyl ester glyr, ol monobenzoate of the monomethyl ether of diethyl glycol Qhtaltte diethyl phthal, dibutyl ate dlmethyl t4r4phtatate dim4thyl 1NOphate, dimethyl dimethyl 2NOphate, dimethyl 2-dimethyl phthalate 2 ". .
 EMI47.7
 rg3ontiple In a. reaction vessel in 4c, '. * r stainless 19 liter * equipped with a mechanical stirrer, a ttarmafrra and a receiver for distillation, 1750 9 of pr4pztrt comenic acid is placed in the manner described in 1 sxsrsplo 1 and 2675 ml of dimthyJL-ttrtL-ethyliztne glco3, (* Anaul Ether 2-181 ").

   We apply to the aysthma a lives of 130-160 tra,;. ? 'g and one ehreuffe the m4lanC * reactiozzrzetl Until 210-215 * pendam. j ## Irsi 1 haur <) Uîo the heating is continued for a further 8 hours x ..: ar, q, .e the temperature of the mixture re..ec 3 onns reaches 2.Oi, one observes tïn vicelut4eux release of carvonic gas, and the aaido pyz * orxeconic begins to distill out of the vessel * A. end of the reaction pyromeconloite acid - & eqr4,% é Ue iat112vrr. Praying there. reaction, the solvent which aeriiy: 'I.Iic Fivec is rarely recyolated in the foipioni. We collect! '.- # iio pycM' '. that and one the word in tt ') apomtio! t in approximately 5 volume? T '9lrarrxnr p>

  <Desc / Clms Page number 48>

 form a suspension from which the product is separated by filtration.

   After
 EMI48.1
 drying, pyronéooni4ue acid is obtained with a yield of 766.



  The procedure is repeated and% decreasing the amount of solvent
 EMI48.2
 juoque at 2 days, 7 ml and adding the acidocomenic fractionally * to the hot mixture over 2.7 hours, a vacuum is not applied to the system.
 EMI48.3
 Pyromécontque acid is obtained in an amount corresponding to 80 of the theoretical yield.
 EMI48.4
 Example In a 2-liter Pyrex balloon, we place 1000 rai!
 EMI48.5
 1'8 absolute uethftnol and 100 g {$ 0.8 Mol <') of pyr ornée oniqu acid prepared as described in Example IX. To this solution was slowly added 90 g of a 30% by weight aqueous solution of sodium hydroxide, the resulting solution fold * was about 10.

   The reaction mixture, which spontaneously reached a temperature of about 35 ° C. during this addition, is treated with 154 ml of an aqueous solution.
 EMI48.6
 37% formaldehyde The functional mixture is stirred for about 16 hours at a time during which the solid phase changes appearance, then treated with a solution of 35 ml of concentrated sulfuric acid in 65 ml of water . The reaction mixture is then evaporated off *
 EMI48.7
 eeo has a temperature of about 50 ° C and a pressure of about 15 mm, and the solids are extracted with two 750 ml portions of iaopropanol heated to. about 90 C.

   The concentration, up to about 1000 ml. of the collected extracts causes the precipitation of a
 EMI48.8
 first jet of hydroxyntaltol, which is separated by filtration * A: or high concentration of the filtrate up to about 500 ml causes the precipitation of a second jet of hydroxymaltol1J A third jet of product is obtained by concentration of inopropanolic solution to about 250 ml. A total of 197b4 g of hydroxymaltol is obtained, owing to a yield of 84.6%.
 EMI48.9
 



  The procedure is repeated using a reactive solvent for iaopropanol in place of teothanol4. The same results are generally obtained *
The procedure is repeated, replacing the sodium hydroxide
 EMI48.10
 by atoeohlomdtxS, uemeai equivalent amounts of the following baama t hyrb; l11; Yde of lithium, hydroxide of potassium, and hydroxide of

  <Desc / Clms Page number 49>

 
 EMI49.1
 calcium. Substantially the same r4oultates are obtained. Example XX - In a stainless steel bowl, 1000 g of pyromoonic acid (8.92 moles), prepared as described in Example Six, are dissolved in 4.9 liters of water * The pH is adjusted to 10.0 by adding 447 ml (8.47 moles) of an 18.9N solution of sodium hydroxide.

   669 ml (8.92 moles) of formaldehyde in an aqueous solution at 37% by weight are then added. The temperature does not rise spontaneously;
 EMI49.2
 to 4 ° C, then gradually decreases to 2900 over a 2 hour shaking period. Libydroxyr, 4% ltol, is precipitated from the clear solution, adjusting the pH to 5 by adding 705 ml of 12N hydrochloric acid. The suspension is cooled to.
 EMI49.3
 5 ° C., stirred for 0 minutes and filtered. We wash the hydroX) 'maltol with) .1 liters of ice water, and we dry empty. The first jet of hy-
 EMI49.4
 droxymaltol, P. '. 15-155 C, weighs 949 g, which represents bzz of the theoretical yield.

   By concentrating the 9.5 liters of mother liquor to about 2 liters created a vacuum of about 20 or hg. a second spray of 152 g is obtained. The total yield of hydroxymaltol therefore represents 88% of the theoretical yield.



   The procedure is repeated using the appropriate amounts of 18.9N aqueous sodium hydroxide solution in place of the 47 ml previously used, to adjust to the respective pHs specified below. It can be seen that when the pH increases in the range between 6 and 13, the reaction rate increases as shown.
 EMI49.5
 yield as a function of time.

   The results are very good for optimum reaction times *
 EMI49.6
 plI tompa optimum Returns, eme1'1t - (in hdrOxîmdtol.. f -, 6 24 hours J Total .. ...- '2..t1' greater than lQO t "
 EMI49.7
 
 <tb> 24 <SEP> hours <SEP> 53
 <tb>
 <tb> 7 <SEP> 24 <SEP> 67 <SEP> 66
 <tb>
 <tb> 8 <SEP> 10 <SEP> 77 <SEP> 70
 <tb>
 <tb> 9 <SEP> 86 <SEP> 78
 <tb>
 <tb> 10 <SEP> 1.5 <SEP> 85 <SEP> 82
 <tb>
 <tb> 13 <SEP> 1.5 <SEP> 73 <SEP> 68
 <tb>
 

  <Desc / Clms Page number 50>

 
 EMI50.1
 "t:. '" - t - nt' f chI} 'ruL.uit. fnnd: 'nt. an ::.-.- .. "df 130 * z '(,! 0J1t1 tt1 Ur1 (! qlY" "(7t' i ''! r., t;. '¯r'l \ t' l" onF11 ... 4ur'nt "on t;: tll'etY tjttti., FE rt'odlttt; tiU1C rtt" .. 'I' "'Ir: 1' 1 pnviro! 1 il il iL% nP att; mAntntl 5n a In f * i end f <'ndtm <* nt "1., '.. la, rrt .: (II" 1' hnf! r'o " <Yt ": \ 1t. ,,) It.

   I1ttC 'tH ") inntioh titi t (' I! \ '1! I tie ratite- ci- ohR <-) r'vn f \ n'd 111 '"1" tnc1l'n ("", à rit 33 ttN' "tH.'i1tltttlon dt '1: t' If '' '' l './. f -1 ('I rrnt'inAtrt.' D. !! "" '1' "'' ln t: fiina de rtM: t '.!. (1n optimum ne Y .-. R <--tA tir rIi de> 5, rln 1, '. 4 "' n '.' ff" "nd" '' '' '' nt an hydro "yr.1a) 'tot t5ri" hl ""' N1t i nf r: r 0.



  '..... 1 ,. \ T -D: 111 "t.rs t, ti '(7Y: t y r ,;"; "; (l'tir; t # 9l.: D'tt.rttr lt1a.



  1 j ':' I ", IJ't.t \ r,", 'fr, ": AJ'l1nt - (' ondprt!: L" 'Hr ... t. Uni' ..,:, (}., 1 ... trfllj tI (! I: C'14 "1 rll1tlie 1 (0 '* (#', t'7 r: ol (') d'hyc1J'ox'; 'r: ltlltoJ t4ar ' <! <"1", t'l \ td '>' t4 1ntliq'I6.t 'in Il, ..., .... 1 XLlt () ,. i "(03b: tt (1 (! 1A> r 'rcnt) rr., nntIn (the!' nf0 t! 11 tiltkalk rot 5f) "0.011.,". <II ,. ", Sf1 ': li: jhri' 1! 'Tv.Mf'h 1 1 t: f! -' ri ..: it. ('Hfi.YitltiNt <i! '1 11.'W l, "'11" 1'T "Lf :, j; itttor-] r> t on 1", rlttt (' r \ rt, rlltx, r '! i., e (it1 njrl1t't "'/ l" n ft!' * fit'fiti 1 lmtt'r r1:

   htttïtt '" <mttc3-t ml d'nfidt 'f'h1ot'h'dt'tl'l' "antiet-.ti- ty'.Ar ''" 'rotr-w df * rh .-' nff-t? t rf 'fl', x, on f'i11.ta> 1t Myar¯A ftttCt.ihllar r "1 rh xi t ('1' ,,," / '' r1 "" '"1, ..: rine' r4tii . n'n 1'n8 t "n: hr3'nr, 1 ton ttj \ t" 't. (i \) 0)., l! I ttlf tît1' ". : "1 'ati..2t: .iDf1 ti'n' *" o1..t.icm.: O ': ""'. '!'! '"Dlhdt'o''c1" dl' !! 'o (! IIIM 2 () ". {' J1. l '' '? 1> f: 1tr, tio" Î (i5rjrr7'KSCr' eitir It "tjr'Îtaj on,. 1vf *>" PC "0" d't'an .. 1t0 C v Qn rttlî 1f !; fi ltr '"ttt' ' <01'1 tt.; FUi'lto .4: 'H, 4 v "., R' '1'" \ ('t (:

   ('h1orhydr' (, I \ "..." ,,,,,. ,,: '0 20;,; l't't'I "f'rî'MdMBe' '' ri-rrt; tr :(; li tn \! rn r,> ' <r, on rrrti> i 11e pir f: t1i.rntion te 17 \ n.ltol t '! u1 1 \ rital1.0 ""' 0 Glnljr'it 'i "i 3, Q7 lr.F.15A158'C .LlptPctinn Ci1 (f "i.1tJ't t'l1r frnction- d! '50wy dr- C" hlororor:' 1 "/ r't1 twn; orrtirn de ' <* 'y <* 'tfr'it.t vttl t -'-' tmr donnp "'" (' os' '' '2,12 cl f, t': \ 1 '01 .01 "1 gets!' .1f! é '' 1-1. T .. "" '.3 ar! DF! 8' te "'() i 1 5rç. T'" 'HtH'tH "'.," N1 rif f141 ', r * "" "* - '." 1, ..; 5.! "' 11 '}' f F ..., <'".' "'n'i, -. c "'' '* fn!" ; i2 '1 t i oh cw ".s, t.ttli.'. ICtt1 .1 .., .. '",' r, .i'î, ..C de ia; 'l' <'aoL1 b3S..C!' ..-. "sih1 '* Mf!' j> l! i, 3'1.'i; .t;, lt: 4ü Cn âf '' t't¯ 1 ,. ' . '.' ''; r.1011 \. ' (- '"' rtoi)" '' "! 'I" r "';": 1: 'I "' t? f'h! it, "h (i: 1." "'> ;. â" d1 "T! antt' '- at (terilitt!' t: 1 r1 rfW> ltnt 'Td" ,, 1 "" nt, ..:

   d '"-" (' n't '! "' livtlnt! 11: -" 1t'r ff'I ',: 11U1:! in: f.'tl "l, lt': 1i.n, .t . fn'Mr't.'t.f'.n fshf trit <; "'0" 1 "1"' r; "nt. TE" 1 "7rt: r: ', 1tl \ i, .lIti Cn> <w%; t.r. l '' ':: r'1t'Jde o "'! r: oto1r. ' r "r" 'M', 1f \ f ": lnt 1 ', 1 <': I. (\ E V41nrhygh dt'il'J.l1 ".if (P.-'; 11: 1nt: i (é, ..t.orl'hio .... t1" (I'J .Itt'r \ r'nt, 1I'J., Tiv, '1 "nt, ..... d" I a' '' ide ' <or "': \" I1j'1'If) Ìd ,,;'! nts t'ot'r:! i'1 "p., rrtll> t1r" ', .1'. if-, ocl., ("'tt1o \' '1't, .. A" .. c

  <Desc / Clms Page number 51>

 
 EMI51.1
 0 acid it is desirable to add an appropriate amount ** of a 00-nolVant to the system in which water is predominant, to obtain
 EMI51.2
 a dissolution. We obtain substantially the same result $.
 EMI51.3
 



  Exemole XIII - 10 g of hydroxymaltol are dissolved in bzz.0 ax3, water! and we adjust the pl ±. of the solution to 1 by adding a solution of 1 of 10% hydrochloric acid * To this reaction mixture. 1.0 g of a. 10 palladium on carbon contmarco catalyst V4-
 EMI51.4
 1 -;, ta 1 j3tY.,. Xl ',:, n ..' H 'uSj'3? Njb.l1 .J'An "tJ11 device d'l'tydrog.na1: 1.on,' tal, well .'tt suspnNioM <.t ' <j: T <ujr 'device. d'Rydron & tl.on f i # 25er and a ..1 tl !; ' 'le.,.: 4 r, 1 L.- i',. "v'lTt4 '; fit." F of' <. ! 1..lj:. "T2 s
 EMI51.5
 when a quantity of hydrog- <E.rum, ara A 1 mole per hydro- isola? xymaltol was absorbed, the reaction was stopped, the reaction mixture was filtered, and the solvent evaporated from the filtrate.

   We do î. recrystallize the residue by dissolving it in 100 ml of water at 95 # C, then cooling the solution to: 1. VS; we obtain 2.1 g of Mal. you of high purity. Ceoi corresponds to 30 of the theoretical rsndMfM; The same operating mode is repeated, ma.la, replacing te palliai dium on vegetable charcoal by lee ca, tz.l-zer; sui.v: anta, Covered for the same weight of metal neble: pljttin black, palladium black, platinic oxide, and platinum on eFxaro,: xa, véta3 ,. We obey
 EMI51.6
 noticeably holds the mmea results.
 EMI51.7
 



  Example XIV - H80 g of hydrosulphite is dissolved in 1.1.4 liters of water in a 22-liter Pyrex glass flask. The pu of the solution is 5 ps * A, this solution at 250c, 575 g of hy'aroxymaltol are added over 20 minutes at the same time as fractions of the aqueous solution of sodium hydroxide in the desired quantity to maintain the p 5t0 "5 <5 <We do the rerotional for 30 minutes, then we if: rre jexqquttt 909C for another 30 minutes.

   Small amounts of solid impurities are filtered off by filtrating the hot solution, then the filtrate is cooled to 15 ° C Aprl, the filtrate is stirred for a further 30 minutes at 15 ° C. The maltol is filtered off and the mixture is stirred. lavo with 1.4 liter of ice cold water. Extraction of the filtrate by four fractions of 6 liters here ,, - chlorose r-
 EMI51.8
 kills and 14-eapoi-atol dfqs cl.lorai'rmic-ues finnII vi .q = xxië ..- extracts of maltoa. 173 g of rit-Ltol are thus obtained, ie 33 'lu xsr; at. ,
 EMI51.9
 theoretical.

  <Desc / Clms Page number 52>

 
 EMI52.1
 



  The procedure is repeated, replacing the 10-, 4iu.a hydrosilfite, in the following directions: lithium hydrosulphite, hydrosulfite # <calcium hydrosulphite potassium, and magnesium hydroaulphite.



  'The same results are noticeably absent. kojic acid is converted to comenic acid lire! a yield of 85 by the procedure described in Example X Ooml4nic acid and decarboxylated to pyrom6conic acid with a yield of 16 by carrying out the procedure described in Example XX * In a reactor with a single capacity about 380 lit. In the glass interior, 168 liters of water and 34 kg (0.305 per-kilograram) of pyromeconic acid are introduced. The mixture is stirred and 15.14 liters of a aqueous solution to
 EMI52.2
 8oddum hydroxide 0; the final pH is equal to 10. During the addi. With sodium hydroxide remaining, the temperature rises and the device is cooled to prevent the temperature from exceeding 40 C.

   We add
 EMI52.3
 22, '' liter. of a 37% aqueous solution of formaldebyde and, after a few minutes, the temperature tends to rise. It is kept at 35-40 C by applying cooling water for about 3 hours.
 EMI52.4
 res. To the clear reaction mixture is added 21.95 liters of an alution of 50 sulfuric acid, the resulting mixture is heated to 50-55 ° C, and 9.7 kg of sulfuric acid is added. zina powder. The suspension is vigorously stirred and 122.3 liters * of an ION hydrochloric acid solution are added slowly over 45 minutes, while maintaining the temperature.
 EMI52.5
 temperature to 55 * -6o * by circulation of cooling water.

   After in. Wrong 4 new at 55-60 0, a chromate paper assay reveals that the hydroxymaltol has fully reacted. The mixture is heated and, at the same time, it is neutralized to pH 2 with 22.7 liters of a
 EMI52.6
 Sodium hydroxide solution at 50, the final temperature being 90-95 ° C. The zinc is filtered through a porcelain filter preheated to.
 EMI52.7
 60 08, and washed with 11.35 liters of water at 8O-9O C. The filtrates are combined and cooled slowly, over 3 to 4 hours, to 5-10 (': the maltol crystallizes which precipitates is collected on a 60 cm porcelain filter.

   The filter cake was washed with about 38 l of very cold water, then the crystals were dried under a vacuum of 100 mm;

  <Desc / Clms Page number 53>

 
 EMI53.1
 from Hc first to 6000 until they are roughly. free 4 # 04u, then at 400C until they are completely dry * 0 & thus obtain 2 ', L kg of maltol, P, P'. 19-1.b04C, with an ash (sulfate) content of less than 0.5, 3 and whose titration shows that it is. a degree of purity of 98-100%.

   Extraction of the filtrate by 5 frace
 EMI53.2
 tions of chloroform representing 1/12 of its volume, pui. The poration of the chloroformic extracts provides an unaltered yield of 2% of a significantly less potent maltol. "", L. r.nd.m.J1.I; lQb "
 EMI53.3
 in maltol, from pyroraecortic acid, represeiMt '!.'. * # .- # duly theoretical. The maltol yield from kojic acid is therefore 59%
 EMI53.4
 Exomp, le-XVI - We repeat the procedure of 17ot, a or replacing the comenic acid by 10 g of mechanical acid, obtained by extraction from opium.

   The ddoarboxyulticity of this acid is carried out under the same conditions as in this operating mode pom? abou-1 shot to obtain pyromdconic acid, We convert pyrotae- acid! conical in hydroxymaltol by carrying out the procedure of Example Xi up to the point immediately preceding precipitation
 EMI53.5
 with 12N hydrochloric acid.

   The hydxoxyasaltcl, contained in the clear t4 lution is treated with two equivalents (in atomsrtramxrG, ea of zinc powder and 2 moles of hydrochloric acid per gram atom of zinc, in the manner described in Example XII, and the maltol thus formed in situ is collected in the manner described in the same example. A very high quality maltol is thus obtained.
 EMI53.6
 



  W-, X "m] 21st Xlnl - A mixture of 35 jf of mar, phO11he, 32 O gr * formaldehyde in aqueous solution at 3'j 96 and 400 ml of ethanol is left to stand for 15 minutes, then is vigorously added while adding 33.6 d of pyromeconic acid over 5 minutes Stirring is continued for a further 16 hours, then the reaction vessel is cooled in an ice bath, and the mixture is stirred. collects the product by filtration to obtain, with a yield of 84%. of il *, -
 EMI53.7
 2.morpholirtam & thplpyxor eeanic cide, Po? * 150 1r'leC.

   We also obtain * 8 the * of the same product, and of equal purity, after concertyratiozv,

  <Desc / Clms Page number 54>

 
 EMI54.1
 of the filtrate to a quarter of its volume, cooling to 5e0 and filtration of the crystals. The total yield is 92% of the yield. ment t3uo3qdd.



  Has an ausponnton negit6. 21.1 g of 2 .. "acid, Qrphélinom'thYlpyt <c: I "" m6; ::: oniquo, 23 g of zinc powder and 180 ml of water, 56 ml of concentrated hydrochloric acid are added at a rate such that the temperature is maintained between 60 and 65 ° C ; it takes about 15 minutes if the mixture is stirred onaultd for another hour and a half at 65 ° O while maintaining *: r11 \ nt the reaction temperature by external heaters IIi this is necessary. and filtered hot to remove the metal lead which could not r4agi) The filtrate is cooled to 3060 and the fold is adjusted to 2 by adding an aqueous solution of sodium hydroxide at 50%.

   The solution is extracted with six chloroform fractions each representing the ci <t <*! less than its volume, we combine the chloroform extracts, we
 EMI54.2
 concentrate up to a quarter of their volume, and the concentrate is cooled!
 EMI54.3
 1, .., crystallized maltol which the citite is filtered off, weighed 4.44 g, yield 15%, m.p. 160-1610. Concentration of the filtrate to a third of no volume allows. to collect a further 2.3 of p # o duit, yield 17.7 in maltol, h.lr '. 159-l61eO This represents a total yield of 53 ± # We repeat the procedure * iL replacing the morpho line by quantities * I! Itochiolluhriq \ 1rnent equivalent of the following bases t pipe *
 EMI54.4
 rdlx ;, r3, tzgir., and <3! Mr. ¯butyl i * tlr f we get eecla.taïrmeri4 1 3 Kfj.

   J! '' * '' * '' PJi:? J2iSj * U7¯L.¯ rep, t.te the taode .s.t = to3re of Il XVI
 EMI54.5
 
 EMI54.6
 replacing the zinc powder with sto chiom quantities <5triqu l * nt; equivalents of the following metals t ier, aluminum, 'tain, et agné.1
 EMI54.7
 We obtain substantially the same results *.
 EMI54.8
 Example XIX - The procedure of Example XVII is repeated if%
 EMI54.9
 replacing hydrochloric acid with quantities
 EMI54.10
 equivalents of the following acids ttcidee sulfuric, phomphoriquo, fomtqut acetic et imed4c, notquoà With organic acid a 0.0 it is desirable to add an appropriate amount of isopropanol

  <Desc / Clms Page number 55>

 
 EMI55.1
 as a flux to obtain the solubility in the dominated system, eu. We obtain substantially the same result.



  Example XX - A mixture of 15 g of morplacline, 4 of formaldehyde in a 37 'aqueous solution, and tao ml of ethanol is left for 15 minutes at rest, then is stirred vigorously while adding thereto over 5 minutes * 336 th of pyromeconic acid. We then bed the mea. lanee laying another 16 hours. To this suspension agit4o acid
 EMI55.2
 'iI1orpholiÍ. <: tm (Ít.h: 1-, "omÓccn1qne. we add 0.6 aton: e'-GT '" jn':. c of powder t; 113 ziJ ({": a / .t, <, 2Iifi'ï 'Ou .vï r. t,!:,. then or add to the concentration of rhi-hydrochloric acid at a rate such that the temperature is maintained between 60 and 65 C; it takes about 15 minutes. We then shake the
 EMI55.3
 mixing for another hour and a half 65001 penda ... t this time, the reaction temperature is maintained by external heating.

   The suspension is then heated to 90 C and then filtered hot
 EMI55.4
 to separate the metallic zino which laughed not resgi. The filtrate is cooled to 30 C, adjusted to pH 2 by adding a solution
 EMI55.5
 50 μs of aqueous sodium hydroxide, the maltol is extracted therefrom by mime using the procedure of Example XVII. We obtain substantially the same results
The procedure of Example XX illustrates the mode of carrying out the invention in which the improved method is applied to the reaction medium in which the base d. Mannich has been prepared.
 EMI55.6
 Example XX2;

   ¯ 11 ruz g of hydroxymaltol (0.08 mol) are added to 25 ml of glacial acetic acid contained in a 30 ml flask fitted with a stirrer, a thermometer, a gas inlet tube ,   and a
 EMI55.7
 cond.J \ seur-refirnnt to reflux. Anhydrous gaseous hydrogen chloride is introduced into the stirred mixture, and the temperature is observed to rise from 25 ° C. to 60 ° C. for 2 minutes.
 EMI55.8
 to bring the temperature to 1-loach, and this temperature is maintained for a further two hours while maintaining the introduction of gas. The mixture is allowed to cool to 25 c and we collect
 EMI55.9
 by filtration the finely divided solid product which precipitates.

   Chloromaltol is extracted from the solid product by about 10 parts.

  <Desc / Clms Page number 56>

 weight of boiling acetone. Evaporation of the extract gives chlorine
 EMI56.1
 romaltol which is purified by reorisiallization in chloroform. 2.46 s is thus obtained, P.1f. 146-.4'JeC, yield 19 of theory.)
We repeat the same procedure, but this time adding drops of concentrated sulfuric acid to the reaction mixture 1. We
 EMI56.2
 finally obtains 9.31 g of chloromaltol, M.p. 149-149.2 C, yield) 74% of the theoretical yield
 EMI56.3
 Example 7ClCIZ - 28.4 g (0.2 mol) of 62.5% hydroxymaltol are added. ml of acetic acid.

   The heated mixture is stirred in a can of adile, and hydrogen bromide gas is introduced. The mixture becomes homogeneous when the temperature reaches 100 ° C., and when it reaches 117 ° C., it is kept for another hour at this temperature. We ! turn off the arrival of Cas, we heat, and the mixture is allowed to cool to 23 * Ce The solid product is collected by filtration.
 EMI56.4
 which precipitates, and it is dried in a deeaioatour. Broaromaltol 32.3 is thus obtained.? *. 150 C.

   By concentrating the filtrate to a third of its volume and filtering off the crystallized precipitate, a further 6.0 g of product is collected. 147-i4gec. We bring together the no. lidos and recrystallized from about 25 parts by weight of acetic acid. A total of 34.7 g of bromomaltol is thus obtained, ie 84.6% of the theoretical yield, '.1'. 170 C. xem 1. x The operating mode of example JOCI is repeated, but by replacing the hydrogen chloride with hydrogen iodide 'The reaction is carried out in the absence of sulfuric acid as a preomotor. of iodomaltol with good yield.
 EMI56.5
 



  .Cerixes C "lC: t" 1i - 1180 g of sodium hydroisultite are dissolved in 1104 liters of water, then 728 g of water are added gradually over a period of time.
 EMI56.6
 of chloromaltol and in total 408 ml of NaCH ION to maintain a fold 0.0 5 "5 5 The temperature * 'gradually increases from 24 to 3800 * At the end of the addition of chloromaltol, another 100 g of hydfosul is added. The mixture was stirred for 3 minutes, the suspension was then heated to 91 ° C. and filtered to remove a small amount of insoluble substance. The solution was cooled to
 EMI56.7
 1> * Ct the maltol crystallizes, and. collect it by filtration and it is

  <Desc / Clms Page number 57>

   vacuum stain.

   Maltol is still collected by extracting the yarn.



   aqueous rat by four fractions of 3.5 liters of chloroform * On
 EMI57.1
 The chloroform extracts are combined and concentrated in vacuo. rowing 200 mm of Hg to obtain an additional jet of crystals'
 EMI57.2
 of maltol, which is collected. All of the maltol collected represents 70.3% of the theoretical yield. The first jet product melts at 0.1 ° C, and assay by ultraviolet spectrophotometrically reveals that: is 99% pure. The procedure is repeated, replacing the hydrulfite head (diuM). Ar the hydroxides: a.tea of the following metals or cations: lithium, potassium, calcium, zinc, * ± # *. &: ## eium and ammonium. The same results are never obtained.



  Example XXV - 1.61 g (0.01 ntoïc) d> ohloromaltol is zus- pensioned in 200 ml of ethanol and 3.0 g - a catalyst as 5! of palladium on arbcne (in the e-lurl form suspended at 50% in water) and 1.01 g or 1.38 ml (0.01 mole) of triethylamine. The suspension is shaken in a hydrôgé'na # apparatus. tion under an initial hydrogen pressure of 3.5 kg / cm2. The pressure drops to 2 kg / cm2 within 30 seconds, then the pressure stops dropping and no further pressure drop is observed over the next 5 minutes.

   The reaction mixture is filtered, evaporated
 EMI57.3
 After the filtrate is dry, the residue is suspended in 10 ml of water, heated until dissolved, then the solution is allowed to cool to 5 ° C for 12 hours. The crystals which precipitated were filtered off, and the filtrate was extracted with 3 volumes of chloroform. The chloroform extracts are evaporated, and the crystalline residue is combined with the first precipitate. This gives 0.862 g of mal-
 EMI57.4
 you, or 68.5% of the theoretical yield, m.p. 5g-L60 C.



   The same procedure is repeated, replacing the methanol with acetic acid. The hydrogen pressure drops and stabilizes a constant value within 2 minutes. A total of 1.00 g of mal- is obtained.
 EMI57.5
 tel, PeP. 158-160, yield: 79.4% of theory.

  <Desc / Clms Page number 58>

 
 EMI58.1
 x "mp1". X \. 'V'T .... We put 2 # 05 ù (0.01 mol) of b: f'olttt'! I! IIÜto1. suspended from 50 ml of glacial acetic acid, then 1.2 ml (triethylamine and 2.05 g of a catalyst b. 5% palladium on carbon (so having the form of a 50% suspension in water).



  The suspension is shaken under an atmosphere of hydrogen under a pros-
 EMI58.2
 initial ion of 3.5 kg / om2t after 43 minutes * the pressure has dropped to about 0.5 kg / cm2 and remains constant The mixture is filtered to remove the catalyst, and the sclvant is evaporated from the filtrate under a pressure of about 15 mm Hg. The residue is dissolved in 10 ml
 EMI58.3
 hot water, and filtered. The ± lteat is allowed to crystallize at 5 ° C. and the crystals are collected by filtration. We thus obtain
 EMI58.4
 0.581 g of maltol, P-F- 157-1600C.

   Extraction of the filtrate by volumes of chloroform and evaporation of the chloroform parmetttent to obtain "uc 1) 1.0 0.2184 uo 411 ... 1 t01 P.l '. 157-105 O. First-run tealtol is 46% of theoretical yield.



   The same procedure is repeated, replacing the palladium-on-carbon catalyst with the following catalysts, of which an amount is used still representing the same weight of noble metal t
 EMI58.5
 platinum black, palladium black, platinum oxide; and platinum out carbon The r6au1tafau is substantially obtained. Example XXVII - The procedure of Example XXlV is repeated, replacing the chloromaltol with an equimolar amount of doiomal * i tol.

   Maltol is isolated with a good yield
Example XXVIII - In an 8-liter stainless steel container
 EMI58.6
 very equipped with a .if; it.tor Qt of a device for bubbling 1 '* Ir, a suspension of 3')! J g of kojic acid is placed in 1300 tal of water. The pH is adjusted to 11.1 by audition, 256 ml of a. 50% solution of sodium hydroxide then 142 (7 * 1% of metal) of a 5% palladiua catalyst on charcoal is added to <' <g <5tal.

   Air is passed through the suspension at the rate of 6 ml per minute per gram of kojic acid. The reaction, which is slightly exo-
 EMI58.7
 thermal, e8t '! 1 maintained at a * temperature of approximately .20 ... 22 0 by refrd1 {diaaant externally as required. After 11 o'clock *, we filter
 EMI58.8
 the reaction mixture to remove. the catalyst, and the

  <Desc / Clms Page number 59>

 
 EMI59.1
 filtrate by 600 ml of hydrochloric acid concentrate The cria rate
 EMI59.2
 of oom6nic acid which precipitate from the mixture. pH 0.5, are
 EMI59.3
 separated by filtration, washed with a small amount of cold water,
 EMI59.4
 and secliés z Il'air.

   128 g of product are obtained, i.e. $ 5.3 g of the yield
 EMI59.5
 theoretically. A titration indicates that the product is at. a degree of
 EMI59.6
 purity of 9th, Z 1 ,; the yield of comenic acid. \ e puer is therefore 8496 <f> ..S m? l. 156 g of comenic acid are mixed with 550 l of water * * and the pU is adjusted to 10 with a 50% solution of sodium hydroxide. The mixture is treated with 3.3 H of aqueous formai) dehyde at 37 4, and the mixture is stirred for one and a half hours at 20O. The pH is then just reduced to 0.8 by the addition of concentrated chlorine acid)! 100 ml of water are added, the suspension is cooled to 500, and the
 EMI59.7
 
 EMI59.8
 filtered.

   We obtain 209 g of product, which rep: ret "0, nte vm, ronder.1ent:
 EMI59.9
 
 EMI59.10
 almost quantitative, analysis of the product r4vZe or * 6-hydroxymethyloomonic acid is partially present under the: rcmo de. ! its sodium salt.



  Crude and completely converted 6hydroxymethylooméniCJ.ue acid,
 EMI59.11
 
 EMI59.12
 in free acid and dissolving 7t88 g da) ta 175 Mt of boiling acetic acid and treating the hot mixture with a solution of 1 g
 EMI59.13
 
 EMI59.14
 of sulfuric acid will be concentrated in 20 ml of antiqua * L pre-precipitated mineral salt which is removed by filtration, and the fil-
 EMI59.15
 trat is evaporated to half of its volume, then crin-
 EMI59.16
 talliaer the product, at 2! 5 C .. Is collected ,, by filtration, 2 # 5 g: of crystallized product, t, 1 evaporation of the filtrate until half of its volume perltlt't to collect Otl $ g 4'wt second spray of product.
 EMI59.17
 
 EMI59.18
 



  The rOQ1: 'istallitH "t, t", n ten first spray of criotaux in hot water gives a substance pOflr, étfant; uxt Por of 178-1.790C and an equivalent: of neutralization of 187 and 94, lt the values calculated for the acid 6..hydroxymethylco! n (.nic so'at i86 and 93- Analysis Calcula for C 7 11606 1 C 45, ill H.) t 2 'Found r C 45, h:.!; 11 3.41!: -. 16 3 02

  <Desc / Clms Page number 60>

   Example XXX- A series of reactions are carried out for each mine using the procedure of Example XXIX, with the exception of the fact
 EMI60.1
 that the pHs of the reaction mixtures have respectively 3, 5s 7 and 9 'No product can be detected rare chrouatograpYio on paper after the reactions at fold 3 and 5.

   After the reaction at pH 7, the presence of a small amount of product can be detected after a reaction time of 45 minutes. After the reaction at pH 9, acid forms;
 EMI60.2
 6 hydroxyjaethylcoraenic in moderate yield, but a considerable proportion of comenic acid is still not found in the reaction mclse after 2 hours. On the other hand, the operating mode of the exem '
 EMI60.3
 pie XXIX implemented at fold 10 leads to a conversion practically! complete from comenic acid to 6-hydroxymethylcomonic acid after about an hour and a half.
 EMI60.4
 



  Racemnle, XXXI - 1.97 g of 6-hyctroxymethylcoraenic acid prepared as indicated in Example XXIX are mixed with 0.5 g of 5 L cataf i lyser of palladium on carbon ¯ (50% of water), 200 uil of glacial acetic acid and 0.25 ml of concentrated sulfuric acid The mixture is stirred in an atmosphere of hydrogen under high pressure
 EMI60.5
 initial bzz k, g / ca2 and after 41 minutes, a pressure drop of about 0.9 kg / cm2, equivalent to 0.01 mol of hydrogen, is observed.



    The mixture is evaporated in a vacuum corresponding to about 1 mm Hg to a small volume, and allowed to crystallize. About 0.7 g of crystals are collected by filtration. chromatography on paper
 EMI60.6
 reveals that they are composed of 6-hydroxymethyloame :: ic acid and Yddt3iy.camâni.que aci-1 in approximately equal amounts.



   The same operating procedure is repeated, replacing the catalyst with; palladiun on carbon with equivalent amounts, by weight of noble metal, of the following catalysts platinum black, palladiun black, platinum oxide, and platinum on carbon. The same results are obtained appreciably.



   Example XXXTI - Hydrogen bromide is passed rapidly
 EMI60.7
 gaseous-eeo in a stirred mixture consisting of 35 g (0.18 mol) of 6-hydroxymethylcomenic ac- and 210 ml of glacial acetic acid.

  <Desc / Clms Page number 61>

 
 EMI61.1
 



  I The temperature 8 "rises up to. 60 G in 15 minutes then, the mixture is heated to 901, C C and maintained for 2 hours at this temperature.
 EMI61.2
 
 EMI61.3
 rature, then cooled to 30 ° C. The reaction mixture is filtered. * | tional, we concentrate the filtrate to a vacuum corresponding to ik rowing mm do Hic up to the sixth of its volume, and we, .'pa. by,: tx, r. , tion the ori tux which precipitate. Atnoï,> etl g.digotdo 6-bromor4èthylcomdniquet is obtained which corresponds to 90 of the yield .r: 1 that. A small amount of the product is still obtained web, ppesxe, t, W the filtrate up to half of its volume. By converting the crude product into ethyl acetate, M 1'.Q4t is obtained. ,.



   # '' ## # -,.; I} \.,; bromomethylcomene, F.5P1, 197-lp7t5 "Ct Analysis Calcula for C 7 it 5 0 5 Br t C 33ri 2t0 &',.; 1' 1 ',, i' #, 'Found s C 33s7 $; H 1.94 The same procedure is repeated, replacing the 4thy-drogenated bromide with hydrogen chloride, and 20% of 6-hydroxymethylcomenic acid is thus converted to 14.4 of 6ahaxamtthyl acid, ca-
 EMI61.4
 mnique.
 EMI61.5
 



  The same operating mode is repeated, replacing the hydrogen bromide with hydrogen iodide * 6 -ioda acid is obtained. <¯ 'thyloomcnic.



  Example XXXIIt - 1.2 # g of 6-braeoraethylacsnigus # acid are mixed with 100 ml of glacial acetic diacid, 0.5 g of a 1% palladium on carbon catalyst (at. 0; in water) and 0.385 g of ammonium acetate, and the mixture is shaken in an atmosphere of 2 C hydrdgèuo and an initial pressure of 3t3 1cg / sx2. <tal- <hydrogen abutment is * absorbed in 15 minutes. The reaction is stopped * the mixture is filtered, and the filtrate is evaporated in vacuo.

   1.18 g of crystallized residue are thus obtained. Recrystallization of the residue from a mixture of acetone and water gives 5-methyloomenic acid, P.II. 237 "238 * C (decomposition) The same procedure is repeated, but starting from 4.1 c of 6-ehloromethylcomenic acid prepared as in the previous example t 80 * 6 of the theoretical amount of hydrogen are absorbed in 75 µs. Evaporation of the filtered reaction mixture gives a product

  <Desc / Clms Page number 62>

 
 EMI62.1
 oily which can be riacaj1jaer in acetone to obtain 1.8 (î of fcubetattco <l P-. 228-232 * Ca m: \ ft1 ') 4i> On rli> tc the / procedure by replacing the 6..bromollt'thyl .. comcnic acid by 6-iodontethylcoMenic acid, We obtain sensitive-
 EMI62.2
 ment the atoms result.
 EMI62.3
 



  * Ey <> tanJ.e ,,, X% XTV - 5.0 main) acid 6 ... bromomethyluoménitu. are added in fractions of 15 rait.oles to a stirred mixture consisting of -5 :: 11 of water and 5.22 g (0.0 mol) of sodium hydrochloride taud !!! ! that we maintain 10 PII i -u 1'T ,, lnnG {'onh' .. 5 and 5.5 by adding! () 11 small amounts of IN sodium hydroxide. The mixture, which spontaneously heats up to 400 ° C., has been stirred for a further hour and is then cooled to 58 ... 6) OC and: 8.e, lt for a further 2. 5 hours * It is then acidified with Conèetitrô hydrochloric acid to plI 0.9. the white prl-oiplté which forms is separated by filtration, the filtrate is cooled down to 5 ° C and crystals are formed there.



  Filtration yielded 1.462 C # yield 46 '6, 6-methyl-comenic diacid, P.E., 2J7 .... 2B, ooC .. A small amount of additional product can be isolated from the filtrate by concentrating this filtrate to to half of its volume, then cooling the concentrate and 14
 EMI62.4
 filtering
 EMI62.5
 The same procedure is deemed to be the same, replacing sodium hydrosulfite with each of the following other hydroaulfites of lithium,) potassium, calcium, magnesium, zinc, and ammonium. Substantially the same results are obtained. The procedure is carried out in r>; # ï. <jm aetda 6-br.) \ tIo "l'juthj'lcomn1, u '! par1 each of the following !! other acids" C!': è '6 ... cblo- roftthyleotanique and acid 6-1odom' tylc1mJn1qu.

   We obtain ften.1-
 EMI62.6
 blame the same results *
 EMI62.7
 #) g.emipAeii.nXt? C We put 3.0 (0.012 mole) of 6-m acid <5thylcoméni 'that suspended in 12 ml of dimethyl phthalate in a 25 ml round 3-necked flask fitted with a mechanical stirrer. dun thetmométre and a short distillation head el1, M3me connected to a round bottom flask serving .de receiver. We stir and heat 16 mèlande, ut we see that the major part of 1 t has (ide

  <Desc / Clms Page number 63>

 
 EMI63.1
 Eethylcomenique has dissolved when the temperature reaches 150OCo. When the temperature reaches about 215 C, a vigorous evolution of CO 2 occurs which continues for about 15 minutes.



  The outside temperature is then allowed to rise to 250 C, then
 EMI63.2
 the mixture is cooled to about 1000th and a vi is applied. The reaction mixture is distilled at about 80 ° -250 ° C. at an outside temperature of about 20 tnm, and the cistillation is continued until there is no remaining Fln '! : q \ .1 "" very little substance: dani le balivii. A major part of the distillation offends one. <t steam temperature of 140-1500C. We retrcklit the juaQIh distillate! 15 C and the crystalline product which precipitates and is collected by filtration with suction. The product is washed with 5 ml of acetate.
 EMI63.3
 thyle and dry Xfr.

   Thus obtaining, with a good yield, a maltol of m.p. 157-16000, The same procedure is repeated using 10.0 g of acid.
 EMI63.4
 6-methylcomene and 40 mil of dibutyl eaititol. We get the mixture <j go reaction between 230 and 245 ° C for 45 minutes, then it is distilled by proceeding as described below. <iss> U3 The distillate is cooled to 25 ° C., the maltol is collected on a filter, then it is dissolved in 30 ml of hot water, the solution is filtered.
 EMI63.5
 hot, we cool it down to 10 ° C and we let the evil crystallize. The maltol is collected on a filter and dried in air.



  A new concentration of the filtrate to a third of the volume,
 EMI63.6
 then a fl1trati, n to separate the crystallized precipitate per # m.t.n; to collect a small additional amount of product.



  We repeat 1 "" '! R.1.!, Me, & operating, but replacing the 40 ml of dibutyl c ± 1rb1 t.::.1 nar 2 ml of., (-Methylnaphthalên.e. with a good yield of mp 160-161.50 C. p10, XXXVL- A medium of 46.8 p (0 53J * mule) of morpholine, 42.8 g (0.534 mole) of forr, -tld6llYde aqueous to 37%, and 534 ml of anhydrous ethanol is stirred for 15 minutes.
 EMI63.7
 times 62.4 g (Ot4 mole) of comniue acid, and we have,; 3.tr the tnôinntfe one hour in ordinary tarnish, then we xfxoa: â. juriquà 10 C and in the: .. "t1.tr, '" (' It collects t.t "1.8: f 0 c acid 6" morp'l '.' <'-

  <Desc / Clms Page number 64>

 
 EMI64.1
 methylcomenic. A recrystallized sample, P, 'Fd 173-1740C, peece from the following analysis C 48,611 il 5t51? No. 5123.

   Calculated for OIIH13Na6'H20 t C ** 8.35H 5.5:) 1 kt 5.13. Calculating as a monohydrate, the yield of crude product is 91%.



   We use the same operating mode, but replacing the morpho-
 EMI64.2
 lino with an equivalent molar quantity of piperidine, We obtain! 6-piperidinomthylcomnic acid.



  The same procedure is repeated, but replacing the death, holine with an equivalent molar amount of dim thylaminf. r'u obtains 6 diathylaminorabthylcoménigue acid.



  The same procedure is repeated, but replacing the morpholine with an equivalent molar amount of di-n-butylamtite. 6..di.-n-buty.aminomethylcomenic acid is obtained.



  Example XXXVII - Add 3 # 1 g (0.02 mole) of 6-morpholi-nomethylçoménl-acid in fractions to a mixture of 5 <S2 g (0.03 mol) of sodium hydroeyifite and 35 ml of water while maintaining the pH between 5.0- and 6.0 by adding a 12N solution of sodium hydroxide according to needs. The addition took 15 minutes, and the temperature rose to 42 ° C. No product could be detected by paper chromatography after 15 minutes of stirring the mixture at
 EMI64.3
 dab, iante temperature, Dn then heats 1 mixture to reflux temperature and, after 15 minutes at this temperature, chromatography
 EMI64.4
 on paper indicates the presence, in the reaction mixture, of acid 6-> m <Sthylcomenic with moderate yield.



    We repeat the same procedure, but replacing the acid
 EMI64.5
 6-raorpholnomethylcom (Snique by the following products 1 6-piperidinomóthylcomónic acid, 6-dimethylaminom6thYlcomónie, and 6-di-n-butylaminonéthylcoménic acid. Substantially the same results are obtained.
 EMI64.6
 



  The same procedure is repeated, but replacing the fine sodium HYdrOSU1 with atoichiometric equivalent amounts of the following other hydrogen, potassium, calolum, magnesium, zinc, and ammonium. The same results are substantially obtained.

  <Desc / Clms Page number 65>

 
 EMI65.1
 Exent 3.e XKXVZ: C In a flask of 2 free h round bottom * 1, three-nozzle equipped with a stirrer, 142 g (1.0 mole) of kojic acid and 500 μl of d 'are placed. 'water. To this was added 50 ml of 50% aqueous sodium hydroxide solution, and the pH of the resulting mixture reached 01. After five minutes, a small amount of crystal substance.
 EMI65.2
 India is starting to separate.

   16 ml are then added to the mixture of 16 ml of aqueous maldehyde at 37 $ # The reaction ne *} angel becomes homogeneous, where it is left to stand for 2 hours at 25 ° C. The M41ange, there is then treated with 65 ml of 50% by weight aqueous sulfuric acid, the mixture is ff'dIdU 'up to 5 ° C., which purely results in crictallizing 40 the. <Kti4 '6.-hydroxymethylkojique from solution * As, 1 crystals are collected on a filter, partially air-dried. then in
 EMI65.3
 dissolved in 500 ml of hot methanol, the solution is filtered hot, then allowed to cool so that the product crystallizes at 200C.

   The crystals are collected on a filter, dried at
 EMI65.4
 air, and thus collects 81.1 g of a product of g.! ", 1 + 8-, GC. A further 21.0 g of 6-hydroxymthylkojic acid are obtained by concentrating the methanolic filtrate to 'to a quarter of its volume * The concentration of the aqueous filtrate still gives 38.7 <? of product. This gives a total of 14098 g of 6-hydroxymethylkojic acid, ie 81 ", of the theoretical roundness.



   Example XXXIX - In a 300 ml flask fitted with a stirrer, a thermometer, a condenser-condenser and an ampoule * robi-
 EMI65.5
 net, are placed 180 m3 of water, 3.g (0.2 mole) of 6hydraxyarethyl, i kojic acid prepared as described in Example XXXVIII, and 26, ig (0.4 mole) of powder of metallic zinc To this mixture is added drop by drop 95 mil (1 µ 3 equivalent of hydrochloric acid conoturated at such a rate that the temperature does not rise above
 EMI65.6
 The time required is about 15 minutes * The reaction mixture was then added and heated to 60-70 ° C for a further 1 hour.
 EMI65.7
 hour and a half.

   The mixture is then heated to 9000 and filtered to remove unreacted metallic zinc. The pH of the filtrate is adjusted to about 2.0 by the addition of sodium hydroxide solution, and the resulting mixture is left for 12 hours

  <Desc / Clms Page number 66>

 
 EMI66.1
 at rest at 5 "Ct" The yellow product which crystallizes is collected on ut
 EMI66.2
 ! 'liter, squeezed to get rid of solvent, and air dried.
 EMI66.3
 



  6-Raethylkojic acid pbae 13.9 g, or 45% of the theoretical yield, F.Th. 1333-Li 0 C, 6-MethylkoJic acid is purified by polishing 1592 g of crude product in 30 ml of water 1, \ ud'e: cooling the resulting mixture to 5 * G, the product ( : 1'-I. "', \ 11ise .. It is collected by filtration and dried in a de-ai' eTrr on P2050 After a new rOOrit'ltalli: \ tion in its own '..khl of methanol , a 6..thylkojic acid of Pli 2 is obtained. 145-145.3 ° C.



  Caictia analysis for C7HS04 te at t 34H, 5.16 Find t C 34.05t Ii, 5.08.
 EMI66.4
 



  The absorption spotre of this compound in the ultraviolet present, in
 EMI66.5
 solution. & thafio1icue, maxima respectively reached at 245 mp, t. k. 840 and at 276 m} t, t .. 7,950.



  The same procedure is repeated, but replacing the zinc powder by equivalent quantities of oechiol! <He '"depending on whether aluminum, tin or magnesium. Significantly negative results are obtained.



  We repeat the <"6th procedure, but replacing the thloridic acid with atoochiomltrially equivalent amounts of the following acids! Sulfuric, formic, acetic, and 80 ° nol" acids. With the C 10 acid, it is desirable to add an appropriate amount of Co-promoter to achieve solubility in a: tt, di1 pv system. <rrt <at \ n.9. We get eena1.bl "'' '' '' l, 'li 1! 1" "" "' (! L'6l.t.ât $ w x.:rcrrx rire? 6't. art 500 mal balloon, place 40 G ("'', .26 mole) of 5-r.tc" .tt.ylko, j.que acid, 270 ml of water and:! O, 5 (0.512 mole) sodium hydroxide * When the solids are completely di. "or 8, 27% of a 5% palladium on charcoal catalyst containing 50% water by weight is added * This is equivalent to 1.72 palladium, calculated on the weight of methyl kojic acid.

   The reaction mixture is cooled by external application of a water bath, and the temperature is maintained at 0 ° C. while air is bubbled through the steam of the reaction mixture at a corresponding rate. about gas

  <Desc / Clms Page number 67>

 
 EMI67.1
 200-250 ai a la., Minute for 16 hours * After this time, we collect
 EMI67.2
 the catalyst, on a filter, then the filtrate is acidified with
 EMI67.3
 hydrochloric acid concentrated to a plt lower than ai. Go pro
 EMI67.4
 light orange color crystallizes from the mixture and, harsh *
 EMI67.5
 have it cooled well on an ice bath, one. filter the mixture, the product is collected on the filter and known in the air. don thus obtains 34) 0 e of 6-methylcotantque acid, P.y. 233-250 * (deeompoaition) or with a yield of 78 '.

   This product is converted into a poor product with a good yield by carrying out the procedure described in example two, example 5E9G - In a 12-liter flask, one places liters of alcoholg 3 *; 0 t (4.0 mole *) of morpholine and 320 g (4.0 celée) of aqueous formaldehyde at 37. The reaction mixture was stirred for about 5 minutes during which it was observed * 140 high *, * lightly, then stirred vigorously for 14 minutes. To this reaction mixture, is added in a single ci * 430 $ * (300 Melee) of al- de kojiqus at the same time as an additional fraction of 250 ml of et-
 EMI67.6
 
 EMI67.7
 thanol.

   After about 5 minutes of stirring most of the kojic acid went into solution at; after about 10 minutes, it is observed that the product crint-alisea Aite the Mixture realizes. ' ox = r, a. pett4ant another 45 minutes, then it is left at rest for one night. The crystals are collected on a filter, then slurried at 3.'ir. We thus obtain $ 632 of 6-orphx! Ndtit, icalcua, r
 EMI67.8
 164.'165 * ot cala repeats 8a e of the theoretical yield * to We repeat batch = $ me operating mode maya by replacing li li. by quantities * etotobiomlitrically equi ...... l..t.8 of other .u1Yane. 1 pipeidine, dim tnylwuine, and d1 - butylam1n .. Oh will get the :) a.1d98 6-pîperidïnom4thylkojïquo, 6-dimethyl- ..1noaéthy1koJiqu8 and 6-di-n-butylaminom4thylkojiqu respectively ..



  Example 3ÇLI - Into a% liter * round-bottom gag fitted with a stirrer, condenser-condenser, thermometer and a pressure cooker, 96y. 4 g (0.4 drown) of morpholinolaethyl- kojiquat 52 (096 gram atom) powder of metallic zinc and

  <Desc / Clms Page number 68>

 
 EMI68.1
 720 al of water. To this plan was added 223 ml (2.67 equivalents) concentrated hydrochloric acid at a rate such that the temperature remained compressed between 50 and 55 ° C. This addition required about 30 minutes.



  When all the acid has been added, the reaction mixture is stirred
 EMI68.2
 and we heat it at 1.0..aC for another 1 1/2 hour. We heat it -
 EMI68.3
 then the reaction mixture up to 900C, and separated by filtration! tion the metallic zinc which has not reacted * The filtrate is treated yellow; not clear by 65 at7. of a 50% allueune solution of: fiydroxycïr of qudiuz, after which the PIL reaches about 2. The resulting aa: t; es is cooled to 5 C on an ice bath, then the pH is raised to 10
 EMI68.4
 by addition of 85 ml of 50 1.4 aqueous solution of sodium hydroxide The zinc hydroxide which precipitates is separated by filtration; it is washed on a filter with 25 μl of water, and the washing waters are combined with the first filtrate.

   The filtrate fold is adjusted to 2.0 by addition of en- j
 EMI68.5
 about 65 ml of conenntro hydrochloric acid. The acidic solution is concentrated to a quarter of its volume at a pressure corresponding to about 20 mm Hg. The concentrate is cooled to 5 ° C. and allowed to stand for 48 hours. The product which has thus crystallized is collected on a filter, and it is dried in the air. We get theoretical
 EMI68.6
 thus 22.7 g of 6-methylkojic acid, or 36 of the yield / P, F, 11g6 C. This product can be purified by recrystallization from an equal volume of methanol; P.F. lk4-lt C.



  The same procedure is repeated but using, instead of 6-motpholinomethylkojic acid, ettseoh.omtriqua ment equivalent amounts of the following Mannich bases: 6-piperidino-methylkojic acid, 6-dimethylaminoinethylkojic acid, 6- acid. di-n-butyAj laminomethylkojiquo. We obtain substantially the same results.



  The same procedure is repeated, but replacing the zinc powder with stoochiometric equivalent amounts of the following metals to make aluminum, tin, and magnesium. We get his-! sibly the same results,
 EMI68.7
 The same procedure is repeated, but replacing the hydrochloric acid with atoichiometric amounts * aivalolite of the following acids, sulfuric acids # formic, acetic and isodecnh

  <Desc / Clms Page number 69>

 than.

     With the C10 'acid it is desirable to add an appropriate amount of a cosolvent to achieve solubility in a medium.
 EMI69.1
 where water predominates. We get substantially the same. results * By solidifying, the procedure of the oxample is carried out, con. turns 6-f acid! <4thylkojique acid 6-methylQomniqu "t which itself is converted into waltol by carrying out the procedure of Example XXXV.
 EMI69.2
 



  Example XLITI - The procedure is repeated 40 1 * example t & Spt 'but replacing the 6-morpholinomethylkojîquo acid by> 4 *; (, qîtlt4 * i etoechionritrically equivalent oq1i'vantig4aiïâég acids, <$ * 'by <nt0 methyloomonic 6-chloromethylcomene and ë-'iodoothytaon'A, "1 prepared 1: 1 as described in Example XXXIX.
 EMI69.3
 6-methylconjéniquo acid. 1; Example LIV - To a suspension of 20 g (0.1 mole) of 6-hydroxymethylooTll, Cnic acid (prepared as in Example XXIX) and 13 (0.2 moles). ) of metallic zinc powder in 130 ml of water, 35 ml of concentrated hydrochloric acid are added over 10 minutes.

   Temperature
 EMI69.4
 rises from 250 to 60 "; the mixture is then filtered to remove 1.7 g of unreacted metallic zinc, then the filtrate is treated with an aqueous solution of 22.5 g (0.178 mol) of acid The zinc oxalate which precipitates is separated by filtration, the filtrate is adjusted to pH 1 by the addition of a 20% aqueous solution of sodium hydroxide, and the mixture is evaporated to dryness in vacuo. . We mix the
 EMI69.5
 Residue with 4 parts by weight of glacial acetic acid, is the insoluble ala '. ""': The insoluble H1if {UeS are separated by filtration.

   A 4va, po: ra1i: 1.on. filtrate in vacuo and trituration of the reaction mixture with hot ethyl acetate followed by cooling afforded the release of M3.r 9.6 of 2,3..dihydra-6-methylamic acid, PF 156-157 C True second jet of 2.91 C is obtained by evaporating the filtrate to a fifth of its volume and by filtering off the crystals which form. The-
 EMI69.6
 overall yield is 32: '6, Neutrality equivalent s calculated bzz2; found 174.

  <Desc / Clms Page number 70>

 
 EMI70.1
 



  Friend seen% Calculated for 7il 805s <C 48e941 Il 4.68 Found îfp.ll? there 4.78.



  We carry out the same procedure, but replacing the zinc powder by quantities! '\ To "chiQlIIf.:, The iqul! 1or.t 6quiva.lorltes of the following metals for, aluminum, etaln . latfsit'sium. We obtain substantially the same * t fhultatat One reputed to be the same procedure, (% it replacing the acid by d (\! 1 qU / 'In.ti t6! i .stéH.tcl1iolnH, 1': 1f <! J (> ut equivalent of acid * following t igulfurillue acids, formic, l1 <"'ethic and it'Jod6C! to'" noic. With the acid in 610f it is dl "8i1 ' <J.bl to add an amount of one cvtlol.r. \ 1: .t for r61 \ 1ieur la. solubility in a raille * Where the elute predominates We obtain senalblem (, tit the MÔmea results b ±. # Jl! .é, XL \ "... We dissolve 1.72. (0.01 mole) of acid 2, J -dlhydro ...



  6-m thylcomdnique in 50 ml of glacial acetic acid, and the solution is treated with 4.53 e (u, ol mole) of tetraac4taste of lead. In what ... that * minutes. the Read a'elcv from 24o to 3oo. The mixture is stirred for one hour at 250, well it is heated up to 4l " <3 and we Itagitates one: Uhour during which it customs) 0 eml of CD-2. The mëlaneo is heated at 620 C for one hour, during which 20 cm) of Co 20 is released. The reflux is finally heated and stirred for one hour at this temperature, and during this time 11 d ± caf: another 110 en3 from Co ..

   The mixture is cooled to 2500 and diluted by tut equal volume of water, then extracted twice with a t * tiX YQ1.t.Á ,! dl> chloroform and ':! t l''j <"with ur volume
 EMI70.2
 d 1 étlier * On r 4 kr 1 1 'L "' 7 ist W 15 Vï ', x, Fiil, iîi = f 1 i- a 3vi :: le! t at -" 1LO?!
 EMI70.3
 The weight of anhydrous sodium sulphate, then the solvent is evaporated off. Thus 0tub5 is obtained; of maltol, which corresponds to 67 of the render * - *
 EMI70.4
 theoretically,
 EMI70.5
 ! Xèmp1è, XtI - We repeated the operating mode of the example. XXXIII, but we replace 6brom'tJjylcomnic acid by * quantities tOeOhidattï'iqu.Omeht equivalent dom acids auïvinte s 6-morhoiinoethylcomenic, 6-pipé7C'l.ûi.riDnôthyirtlltriiqtte 6 * -dimthyl-, and 6! -di-rx-butyl'aminom4thylcomenic.

   We obtain,

  <Desc / Clms Page number 71>

 in each case, 6-methylcomenic acid.



   The invention relates more particularly to certain modes of application, as well as certain embodiments, of the aforementioned improvements; and it aims more particularly still, and this as new industrial products, the compounds of the kind in question obtained with the aid of said procedures, the devices suitable for the
 EMI71.1
  <.3 <we work 'Ars proceeds 5p (' if161'1 ci # <! ###?> # iv.s, as well as 3-es <? p¯ S eml, '1; 6% tI i.Yt¯n:%,. t 1. (', j18 CI <> t.1f1r f'nan: ': CI.;! '1: i - ¯1 - ,; i 1; ifs.


    

Claims (1)

CLAIMS 1.- Process for the preparation of maltol consisting essentially of; a) to reduce, a compound of the following formula EMI72.1 in which A is a hydroxyl, chloro, bromo, iodo, di-alkyl (lower) amino, piperidino or morpholino radical, or else b) to dcarboxylate a compound having the following formula: EMI72.2 2. A process according to claim 1, wherein the hydroxymaltol is reduced under acidic to substantially neutral conditions. 3. A process according to claim 2, wherein a hydroxymaltol solution is treated with a reducing agent, the 3-hydroxyl group of said hydroxymaltol being mostly in the non-ionized form. 4.- Method according to one or the other of the claims! Articles 2 and 3, in which the reduction is carried out using a metal-acid combination, said metal being zinc, iron, aluminum, tin or magnesium and the acid being an acid mineral or an organic aliphatic monocarboxylic acid saturated Open chain with 1 to 10 <Desc / Clms Page number 73> carbon atoms and which was soluble in the reaction system EMI73.1 t1o% 1.nel .... 5. - Process according to one or the other of claims 2 to 4-, in which the. reduction. using hydrosulfurous acid or an alkali metal salt or EMI73.2 alkaline earth metal of this acid. 6. "A method according to one or more of roven41c tiona 2 to 4, in which the reduction is carried out using hydrogen activated by a catalyst of the noble metal type. 7. A method according to either of claims 3 and 4, wherein maltol is obtained by treating a hydroxymaltol solution with a reducing agent consisting of zinc and hydrochloric acid. 8. A method according to claim 1 wherein EMI73.3 Maltol is obtained by treating a 2-disubsti "amino-methylpyromeconic acid under reducing conditions using a metal-acid combination as a reducing agent. 9. A method according to claim 8, wherein EMI73.4 said 2-disubatituted-aminomethylpyromeconic acid is 2-morpholinomethylpyromeconic acid or 2-piperidinomethylpyromeconic acid. 10. A process according to either of claims 8 and 8, wherein the metallic agent is zinc and the acidic agent is hydrochloric acid or acetic acid. 11. A process according to either of claims 8 to 10, in which the reaction is carried out at a temperature of between about 51 and about 125 C, EMI73.5 . 12.- The method of claim 1 1 danu feqU4è is obtained 3u maltol by treating a halogenoma.i.tol posJ4àt the following formula: <Desc / Clms Page number 74> EMI74.1 wherein X is chlorine, romo or ioda with a reducing agent selected from the group consisting of (a) alkali or alkaline-earth metal salts of hydrosulfuric acid, zinc hydrosulfite or hydrosalfite of ammonium, or (b) hydrogen activated by a noble metal catalyst * 13.0 A process according to claim 13, wherein the reducing agent is sodium hydrosulfite * 14.- The method of claim 12, wherein the noble metal catalyst is palladium * 15.- The method of claim 12, wherein halogenomaltol is obtained by treating hydroxymaltol with hydrogen chloride, hydrogen bromide or hydrogen iodide. 16. A process according to claim 1, wherein the maltol is obtained by placing 6-methylocom, enic acid in suspension in a decarboxylation solvent, after which it is heated to a temperature of up to about! 250 C. 17.- The method of claim 16, wherein the 6-m: thylcomenic acid is suspended in about 2 'to 5 parts by weight of the decarboxylation solvent. 18.- A method according to either of the claims! 16 and 17, wherein the decarboxylation solvent is dimethyl phthalate, dibutyl carbitol or 1Ó-methyl-naphthalene, 19.- The method of claim 1, wherein maltol is obtained by simultaneously carrying out a decarboxylation and dehydration of 2,3-dihydor-6-methyl- acid. <Desc / Clms Page number 75> EMI75.1 comenic by treatment with pic'mb tetraacetate ;. 20.- Process for the preparation. maltol, in substance, as described above, in particular in the ex ple. EMI75.2 21.- Yaltol prepared by carrying out a process according to any one of the preceding claims 22.-. A method according to claim 19. wherein EMI75.3 2,) - dihydro-6-ethyluoméiue acid and obtained by treating 6-hydroxYI: 1éthY: 'co1: lep.: Iq, ue acid with a reducing agent consisting of a metal association -aei4 * 23.- A method according to claim 2 $ ds wherein the metallic agent is zinc, iron, aluminum, tin or magnesium and the acidic agent is a mineral acid EMI75.4 or an open chain saturated allphatic organic acid having 1 to 10% carbDt and which is soluble in the reaction system. 24. - A method according to claim 23, wherein the metallic agent is zinc and the aced agent is hydrochloric acid or acetic acid. 25. A method according to any one of claims 1. to 8, in which is obtained in frai- ' EMI75.5 both pyromeconic acid by: frma1.d {hyüe at a pH of at least about 5 26.- The method of claim 25. wherein EMI75.6 hydroxymaltol is obtained by adding appyoxijcaiiiyemeat a molecular equivalent of formaldehyde to an aqueous solution EMI75.7 l, yromeconic acid, the pH of which has been adjusted to at least en-. about 8. 7,7.- A process according to either of claims 25 and 26, wherein the reaction between foraaldehyde and pyromeconic acid is carried out <m elu.1o.:1, iuus un alcohol with 1 to 3 carbon atoms and cefinariv <Desc / Clms Page number 76> substantially stoichiometric proportion, calculated on pyromeconic acid, of a - hydroxide, of an alkali metal or of an alkaline earth metal hydroxide, 28. A process according to any one of claims 1 to 8 and 22 to 24, wherein maltol is obtained by treating pyromeconic acid with formaldehyde at a pH of at least about 5 to form 1. hydroxymaltol, after which this hydroxymaltol is reduced in situ. 29. - Process for the. preparation of hydroxymaltol, in substance, as described above, in particular in the examples. 30.- Hydroxymaltol prepared by carrying out a process according to any one of claims 22 to 26. 31. A process according to either of claims 8 to 11, wherein 2-disubstituted-aminomethyl-pyrpomeconic acid is obtained by reacting pyromeconic acid with a mixture of formaldehyde and of an organic amine. 32. A method according to claim 31, wherein the organic amine is dimethylamine, di-n-butylamine, piperidine or morpholine. 33. Process for the preparation of a 2-di-substituted-aminomethylpyromeconic acid, in substance as described above, in particular in the examples. 34.- 2-disubstituted-aminomethylpyromeconic acid prepared by the process according to any of claims 31 to 33. 35. The process according to any of claims 12 to 15, wherein the hydrogen halide reactant is dissolved in an inert solvent, and the reaction is carried out at a temperature of up to 4 about 120 C. <Desc / Clms Page number 77> 36. The method of claim 35, in lequal the solvent is acetic acid, formic acid or chloroform. EMI77.1 37.- Method according to one or the other of r8vaxdica. Articles 35 and 36 in which the reaction resulting in the formation of chloromaltol is carried out in the presence of a small proportion of a strong acid. EMI77.2 38.- Process for the preparation of a halomaltol, in substance, as described above, in particular in the examples. EMI77.3 39.- Halogenomaltol prepared by carrying out a process according to any of claims 35 to. 38. ' 40. - A method according to any of claims 25 to 28, wherein pyromeconic acid is obtained by EMI77.4 decarboxylation of comenic acid or meconic acid. 41. The method of claim 40, wherein pyromeconic acid is obtained by heating comenic acid in a solvent selected from the group consisting of EMI77.5 by naphthalene or a mono- or di-s.leay. (. nfHr.eur) naphtha? .b- ne, tetrahydronaphthalene or a mono-or di-alkyl (lower)! tetrahydronaphthalene, unsubstituted or mono- or di.-alkyl-lower) substituted or mono- or di a7 diphenyl ether, coxy (inferior) aubatitud, a diether or a monoether-mono and polyglycol having the formula RO (CE29lÎ20) nRI in the - which n is an integer from 2 to 6, r is a lower alkyl or phenyl radical, and R 'is a lower alkyl, lower acyl or phenyl radical, a triphenyl phosphate or phosphite or their substituted derivatives having no more than one lower alkyl substituent per ring, an amide EMI77.6 cyclic aliphatic having the formula CH 2OH2cE2 COK-R in which R is an alkyl radical comprising from 4 to 8 EMI77.7 carbon atoms, saturated aliphatic acids monocarboxy- <Desc / Clms Page number 78> open chain ticks containing 8 to 16 carbon atoms, or lower di-alkyl esters of phthalic acid or substitution derivatives not having more than one lower alkyl radical per ring, at a temperature at least equal to that for which the release of carbon dioxide is notable, by controlling this temperature until the evolution of carbon dioxide has practically ceased, and by collecting the pyromeconic acid thus formed 42. A process according to either of claims 40 and 41, in which pyromeconic acid is obtained, heating comenic acid in di-phenyl ether until it is obtained. a temperature of at least about 230 C, maintaining said temperature until the evolution of carbon dioxide has substantially ceased and collecting the pyromeconic acid formed. 43.- Process for the preparation of pyromeconic acid, in substance, as described above, especially in the examples. 44.- Pyromeconic acid prepared by carrying out a process according to any one of claims 40 to 43. 45. A method according to any of claims 40 to 42. wherein comeric acid is obtained by EMI78.1 treating d.7I ..!. "ac: .. d, I ± tl,. '" xß, s.'tE. ".% .; X dc l'yj'itic \.' 1 'p1." t : lenCfJ of a catalyst of the t5tal type ncole. a pH of no Ans: '' '' '1.:;:')n 10. 46. The method of claim 45, wherein a solution of kojic acid is adjusted to a pH of at least 10 with an alkali metal hydroxide, the oxygen being introduced into said solution in the presence of a catalyst of the type. noble metal from the group consisting of finely divided platinum or palladium, platinum oxide, platinum on vegetable charcoal or palladium on vegetable charcoal, a minimum pH being <Desc / Clms Page number 79> maintained during oxygenation, continuing oxygenation until the alkali metal salt of kojic acid is practically consumed, after which the pH is adjusted to EMI79.1 a value less than about 2.5 with a mineral acid and the acid thus produced is collected, 47.- The method of claim 46, wherein the Ph of the aqueous solution of kojic acid is known to EMI79.2 king * 10 avoc # .1o hydroxide after which one in- -M'.ti "- c -v / gene #IojlS inditc 3ol <.tcn in pres: ac.e nor palladium catalyst. 48. - Process for the preparation of a comenic acid, in substance, as described above, in particular in the examples * EMI79.3 49.- Coadnic acid prepared by mlae by carrying out a process according to any one of claims 43 to 4-6. 50.- Process according to uysquelcona.uedes claims 16 to 18, in which 6 "Btthyloontenic acid (a) is obtained by oxidizing 6wmethyl acid '!?: O; i ,, ue Qi (b) 'by reducing 6-halomethylcomenic acid or (and reducing di 6-hydroxymethylcomenic acid or (d) reducing 6t61N # -disubotïtuê-aminomethylcomic acid. 51. A process according to claim 50, wherein the reduction of 6-hydroxymethylomenic acid to 6-methylicomic acid is carried out by (a) treatment with hydrogen in the presence of a metal catalyst. noble, or (b) an alkali metal hydrosulfite all iur trait. 52. The method of claim 51, wherein the reduction of 6-hydroxyoethylcomenic acid is carried out in acetic acid. 53.- Process according to either of the claims EMI79.4 tions 51 and 52, wherein the noble metal type catalyst is palladium or platinum. <Desc / Clms Page number 80> 54. The method of claim 49, wherein EMI80.1 the alkali metal hydrosulfite is sodium hydrosulfite. 55. The method of claim 51. wherein EMI80.2 the reduction of the conical 6-halCgenomethylmated acid is effected by reaction with (a) an alkali metal hydrosulphite at ;, L'7, yuroultit tL: fiw'tLlt; 312.ZI: c Du d, , a.'l.11 "cILt. k, - zinc or or alkaline earth metal or / do "as'aonium hydrosulphite, or (b) hydrogen activated by a noble t7pQ ..t.¯I catalyst such as platinum or palladium, or (c) a reducing agent of the metal-acid combination type. 56. The method of claim 55, wherein the metal-acid association comprises a metal from the group con- EMI80.3 andlocated by zinc, iron, aluminum, tin or magnesium and a strong mineral acid or an open chain saturated monocarboxylic aliphatic acid having from 1 to 10 carbon atoms, said saturated aliphatic monocerboxylic acid being soluble in the reaction system. 57.- Process according to one or the other of the claims EMI80.4 tions 50, 55 and 56, wherein the 6-halogenomethylcomenic acid is 6-broraomethylcomenic acid. 58. The method of claim 50, wherein! EMI80.5 the reduction of 6-litli-dlsubstituted-aminom6thylcomenic acid is effected by treatment with an alkali metal or alkaline earth metal hydroaulphite or magnesium hydrosultite or zinc hydroulphite or 1 Ammonium hydrosulphite * 59. The process of claim 50, wherein the oxidation of 6-methylkojic acid to 6-methylcom- EMI80.6 nic is effected by treating said 6-methyl kojic acid; with oxygen in the presence of a noble metal catalyst at a pH of at least about 10. 60. The method of claim 59, wherein <Desc / Clms Page number 81> an aqueous solution of 6-methylkojic acid is adjusted to a pH of at least 10 with an alkali metal hydroxide, the oxygen being introduced into said solution in the presence of a catalyst of the noble metal type from the group constituted by finely divided pltina or palladium, platinum oxide, platinum or palladium on vegetable carbon, a minimum pH being maintained during the oxidation which is continued until the alkali metal salt of 6-methylkojic acid is practically completely consumed, after which the pH is adjusted to less than about 2.5 with mineral acid, and the desired 6-methgylcomonic acid thus produced is collected. 61.- Process for the preparation of 6-methyl-comenic acid, in substance, as described above, in particular in the examples. 62. - 6-methylcomenic acid prepared by carrying out a process according to any one of claims 50 to 61. - 63. A process according to either of claims 50 and 55 to 57, wherein a 6-hareg methylcomenic acid is obtained by treating 6-hydroxymethylomenic acid with a hydrogen halide. 64. A process according to any of claims 50 to 54, wherein 6-hydroxy-methylcomenic acid is obtained by treating comenic acid with formaldehyde at a pH of. at least about 7. 65.- Process according to either of claims 50 and 58, in which a 6-N, N-disubstituted-aminomethylcomenic acid is obtained by reacting comenic or ojic acid with a mixture containing - a secondary amine and formaldehyde. 66. A process according to either of claims 50, 59 and 60, in which 6-methyl-acid is obtained. <Desc / Clms Page number 82> kojic by reducing 6-hydroxymethylkojic acid or a EMI82.1 6-'Î, N-dii3ubutîtu6-aminomethylkojique with a reducing agent consisting of a metal-acid association. 67. The method of claim 66, wherein the metallic agent is zinc, iron, aluminum, tin or magnesium and the acidic agent is a mineral acid or an acid. saturated aliphatic monocarbox / lique in cat. open only containing 1 to 10 carbon oats and soluble in the reaction system 68. The method of claim 67. wherein the metallic agent is zinc and the acidic agent is hydrochloric acid. 69.- A compound with the following formula EMI82.2 in which P is a hydrogen atom or a hy- radical EMI82.3 droxy1.e, chlorot bromo, lodo, .di..alcoyl (interior) a.mino, piperidino or morpholino. '70.-' 6-Taethylomenic acid. 71.- 6-Hydroxymethylcomèniquet acid 72, - 'Compound -.sda.'. '- -> ovivirte raule EMI82.4 in which P is a hydrogen atom or a di-n- radical EMI82.5 butyl = ino, 73.- 6-methylkojic acid. 1 74 * - 2,3-dihydro-6-methylcomenic acid