BE622666A - - Google Patents

Description

       

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  The present invention relates to a new process
 EMI1.1
 dice to obtain the optical isomers of. rathylr4dihy .. droph4nylalanine in substantially pure form. More particularly, the invention relates to a process for obtaining the
 EMI1.2
 optical enantiomorph of. ' (raethyl3,4-dihydrnxyphdnylalaninei (sometimes called "mÓthY1DOPA" in substantially pure form, these processes consisting in bringing a supersaturated aqueous solution of the racemic form into contact with seed crystals of the desired ioMare,

   said solution containing from 0 to 90 of said alanine compound in an amine al form of a salt-forming acid, said salt-forming acid being a water soluble non-amphowtare acid. More particularly, the invention con-
 EMI1.3
 also identifies a method of resolution of the (avthy7.OPA in its enantiomorphs aait3letae "t ^ n by dissolving the racemate in an aqueous solution containing from 0 to 90% of the necessary acid to form the amine salt. , by transformation of this solution into a supersaturated solution of the ausdescribed type, by contact of this supersaturated solution with an enantiomorph in crystalline form, by separation of the mother liquor and by contacting this mother liquor, with or without increase of
 EMI1.4
 the èuraa'urt1on. with the other enantomorph.

   The invention concerns ..; not also in a particular way, continuous methods to operate such a resolution. In such a process, the aforementioned liquor
 EMI1.5
 "mother from the second crystallization / is recycled into the solution of the raceitiate and the enantiomorphs crystallized! are extracted from each crystallization, continuously or;

   intermittent, In another embodiment, the method of

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 EMI2.1
 Continuous resolution of 1-methylDOPA consists of dissolving the racemate in an aqueous solution usually containing a little acid, dividing this solution into two equal parts, forming a supersaturated solution of the type described above with each part, putting each part supersaturated solution in contact with one of the
 EMI2.2
 emtiomorphs, one with the D form and the other with the L form, and to recycle the mother liquors at the dissolution stage, the crystallized enantiomorphs being isolated from the suspensions of ma-;

     
 EMI2.3
 Continuous or intermittent, H ^ xmthyl-3 ,, - dihxdrocyptny, a, an, is not an important new antihypertensive drug. Form D, fine; that completely inactive as a hypotensive agent, possesses;
 EMI2.4
 the same toxicity as the J4 form, as it has been found ,, It is important, therefore, that the separate fomo D eo4.t, since it does not contribute to the antihypertanscur Llef ± ctt. antihyportenwivw activity of this composition is entirely found! in the form L.



  It has been found that it is possible to: ra, sa, l, link a41ectiv "ment each enant-tomqrphe in turn, in a sensiblemernt pure form from an aquetigse solution of I $ pi-méthyly3,4.dïgydroxlf % racemic phenylalanine forming a supersaturated solution and
 EMI2.5
 contacting this solution with seed crystals of the desired enantiomorph. The formation of the saturated aur- * solution can take place in the presence of the seed crystals.
 EMI2.6
 or the supersaturated solution can be seeded later. The stages of formation and contact with seed crystals can therefore be simultaneous or successive, as conditions require.

   The key to such crystallization is to maintain the acid used as a solvent in such a proportion to the compound.
 EMI2.7
 alanine phenyl used that 0 to 90,, v of the latter compound and not more is present as the amine salt of the acid forming the salt, the remainder being present as an alsni- base.

 <Desc / Clms Page number 3>

 
 EMI3.1
 free picnic. Lk'-methyDOPA is present in the supersaturated solution, essentially as a racemate. Excesses of an enantiomorph may be present, due to the elimination of part of the other, out of solution, during a previous crystallization, before recycling of
 EMI3.2
 the J.qfeur-mother.

   Although a single crystallization does not allow to separate the whole of a particular isomer, an insulator: the L form and the D form separately, in this way, adding as much of the extra racemate between each isolation or between each pair. of isolations, in order to maintain the sa solution. turée or almost saturated, in order to facilitate the forma.
 EMI3.3
 tion of supersaturated solutions, it is poaaiole cited ae expensive closer to complete isolation of all the L form.



   Soil-forming acids, which can be used,
 EMI3.4
 including any non-amphoteric acid soluble in water. Acids which contain at least one acidic hydrogen atom, which exhibit an ionization concentration greater than 10.) and which are non-oxidizing, are preferred. Because of the hydroxyl groups of this compound, the oxyf
 EMI3.5
 In order to form two quïnotdeo structures, the acid will be pre-made non-oxidizing.

   Ainai, the expression "oxidant aon" via. to denote a via acid through which these hydroxyl groups are inert at the temperature and concentration used, at low temperatures and with good dilution, acids such as nitric acid which are considered , on the other hand, as oxidants, are inert.The minimum ionization constant is preferable, in order to provide an acid sufficiently strong as to easily form the acid.
 EMI3.6
 Phenyl alanine salts, when amounts greater than very small amounts of acid are employed, thus adding the acid to the amount of phenyl alanine in solution.

   
 EMI3.7
 When only small amounts or traces of acid are used, for the sole purpose of keeping the solution non-alkalized, any soluble acid can be used.

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 in the solvent, usually water. In the case of polybasic acids, only the hydrogen atoms
Ka
 EMI4.1
 ": Lonisable5 having a higher value,.;, I0 '": are important, when large proportions of acids are used. Among the acids which are preferred to use, there may be mentioned hydrochloride acid, bromhydrin acid, sulfurine acid, sul-
 EMI4.2
 furous, mono-chloroacetic acid, dichloroacetic acid, trichloroacetic acid, phosphorous acid, phoaphcetic acid and the like.

   Other acids, such as dilute acetic acid, nitric acid, perchloric acid, etc., can also be employed, but they are preferably avoided.
 EMI4.3
 because of their low acidity, which reduces the amount dissolved, or because of their oxidizing character. Acids should be non-amphoteric, (i.e., amino acids are not
 EMI4.4
 pas con, eillables) because of the amphoteric character of their neutral form. Their free carboxylated form requires other ions'
 EMI4.5
 hydrogen acidaa, to neutralize the amino compounds which can equally well be used to dissolve the compound phenyl alaniniqut.



   The first ionization constancy of most polybasic acids is the only important one in the form of
 EMI4.6
 preferred execution, because in most cases cl * 3t la: only * with a Ka value greater than 10 ** 3 In c * 4 cases, the function of the salt-forming acid is to nautralize the amino group, so as to form the acid salts, such;

   than bisulfite. In special cases, especially in the case of the use of sulfuric acid, the second atom of hydrogen acid also has an ionization constancy in the range of the desired values and neutral salts are obtained *, The ratio of moles of amino acid in solution to equivalents
 EMI4.7
 of acidic hydrogen with a Ka 3 concentration greater than 10 "-3 should, in the preferred embodiment, be such that 0 to 90% of the amino acid is in the form of the amine salt in the

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 final supersaturated solution, the desired enantiomorph of which must
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 be separated. So there must be a little (more than 10 /.) Of the free base present.

   The desired enantiomorph crystallizes as the free base, leaving a still mother liquor.
 EMI5.2
 supersaturated on the other 6nantioiiiorphe. The maximum recovery * of the desired enantiomorph upon any crystallization corresponds to the amount present as the free base.



  When more than 90% of the amino acid is in the form of the amine salt, the recovery is poor. Although the solubility of
 EMI5.3
 the free amino acid in water is less than that of the amino salt; in at least one embodiment of the present invention, the amino acid may be present substantially entirely as free diamine elm, with little or no amount. neutralizing acid in the presence. The solution should never be alkaline, in the presence of air, because it then undergoes decomposition. Thus, usually at least a trace of a neutralizing acid is preferably present to increase! stability.

   However, the method according to the invention can @
 EMI5.4
 9be carried out in the absence of an acid and ', 11 air is excluded, even in an alkaline medium, by using salts of. = Ruupr oarbow functional m xylic It is however easier to operate / a neutral pH or , preferably, with at least a trace of acid.



   The process according to the present invention is carried out in solution in a polar solvent, preferably an aqueous solvent,!
 EMI5.5
 that is to say a solvent containing at least 10 / e of water by volume, j The solvent can be any polar solvent rnhc: 1blè Water, such as a lower alcohol, (methanol, ethanol, sec-butanol, etc.) dioxane, acetone, etc. With de3 ij solvents
 EMI5.6
 other than alcohols, water is used to form the dissolving acid, when SO2 is used to dissolve the amino acid.

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   The formation of supersaturated solutions can take place in various ways in the process according to the invention. One of the most common ways is to make use of the change in solubility which occurs as a function of temperature.



  Thus, a saturated solution is formed at a temperature (by @
 EMI6.1
 example 30-450C) and cooled in the presence of seed crystals
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 surround at a lower temperature (for example at moix3 of 25 C). This procedure, which uses the temperature ranges in question, gives very good results, provided the amino acid is in the desired allotropic form. We have cons
 EMI6.3
 It has been observed that racemic C.methyl, ,, .. di.MydroyphnC, a7.an3ne * forms several different allotropic crystal structures.



  These structures differ in degree 801 \ ', o11: \ t' depending on the temperature. A particular structure or form, which pOGet>, 4 '' n a good temperature gradient, air, if it was observed, was characterized by tints on X-rays (Ka 2 fui copper) \ 90e 11 * and 23 *. Cotbe form (Un) is however 3t '".'! T & ble and tran3ronn in stable form (:.) On contact with water, mtmo at room temperature, 5i% that the change is ± ni. Ble at low temperature, it becomes faster & As the temperature increases.The stable tone (I) is characterized by
 EMI6.4
 X-ray points (Kx 2 $ copper) At 100 and 13, The temperature guarantor of the solubility of form I is low
 EMI6.5
 below 50 C, but surprisingly becomes much larger at higher temperatures.

   Thus, it is possible to dissolve the basic material at temperatures between 60 and 100 "C and form the supersaturated solution, by cooling to temperatures between and 40" C. Since Form I is the stable form, into which the others are transformed, this operating mode is. preferred, when the thermal supersaturation method is applied. This procedure is especially preferred
 EMI6.6
 As one proceeded for the continuous resolution of the V \ - :: r.th) '1:') 0PA.

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   In general, the greater the difference between the temperature of formation of the saturated solution and the temperature of crystallization, the greater the tendency of the racemate to precipitate. It is, therefore, necessary to keep the temperature difference between these two operations as low as possible in practice, while maintaining a satisfactory rate of crystallization. A difference of at least 10 C is required.

   The difference between the dissolution and crystallization temperatures should not exceed 60 ° C. because only when this difference is greater, the racemic material tends to precipitate. The stable form (I). although possessing a relatively flat solubility versus temperature curve at low temperatures, can thus be used in the process in which temperature differences are applied, by applying higher temperatures of up to 100 ° C. .



   The preferred method of applying temperature differences is generally to form a saturated solution of the racemist at 60-100 ° C, preferably about 75 ° C, in water containing a small amount (for example, less than 0.2 equivalents per mole of alanine) of an acid, such as hydrochloric acid or sulfurous acid, so as to form a solution of [alpha] -methyl DOPA, in which 0 to 20% of the amino act is present in the form of salt. The ratio of amino acid salt to amino acid salt is advantageously controlled by adding an excess of the phenylalanin compound to a given amount of acid.

   Preferably only a trace of acid, usually sulfurous acid, is present for reasons of stability. Undissolved racemate is filtered and the filtrate automatically contains acid, as well as hydrochloride or bisulfite. amino acid dissolved in solution. The filtrate is inoculated using crietaux of the desired enanthiomorph. The seeded solution is then cooled to 5 to 40 C, preferably to about 35 C.

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   Although the above-described method is the preferred method of using temperature differences to form a supersaturated solution, the method can also be applied at low crystallization and dissolution temperatures. Thus, the racemate can be dissolved at 35 ° C and cooled.
 EMI8.1
 di at a temperature below 20 ° C. Because of the flat solubility gradient over this temperature range, these procedures are not as efficient as when the preferred temperature ranges are used, especially when low amounts of acid are used. present.



   The seeded and cooled solution, which is either plain,
 EMI8.2
 or still somewhat supersaturated with the enantiomorphic air, depending on the aging time and which is still supersaturated: with the enantiomorph Other, is filtered, so as to recover;
 EMI8.3
 30 â, 50, w; of one of the enantiomorphs with purities ranging from | 95 to 100.6. The use of enantic seed crystals; desired morph will vary depending on the operating mode. Preferably, at least 5 g of seed crystals per liter of supersaturated solution is added, usually using 150 g of seed crystals per liter or even more. The
 EMI8.4
 amount of enaementeement crystals used is a question; convenient.

   The upper limit is a function of the / iscosity of the suspension. The amount of seed crystals to be used also depends, in part, on the callus, ibrr the particles, being; since the small size particles have a surface; of anaer, encesv: nt plus gr \ .n.5 j 1) {! 1 "unit of weight. Seeding efficiency (key to the combination of quantity and cal-Vre of particles ) controls speed 4 Jequ0> 3li 1 * supersaturation decreases. If the quantity is small or if the par-
 EMI8.5
 ticles are r05e5t the speed is low. Large amounts and small sizes of particles increase the rate of crystallization. The slower this speed, the more contamination is possible.

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   Another variation of the process for forming a supersaturated solution is to operate at a constant temperature, but change the amount of al-forming acid present, by neutralization. This procedure is especially advantageous, when the amino acid is transformed into one of the allotropic forms having a very low solubility temperature difference. The process consists in preparing a solution in the acid forming a salt. The latter should not be in excess, but it can be, in which case the solution is not saturated and contains all the amino acid, in the form of the amine salt.

   If the acid is present in excess, more base is needed, to form a supersaturated solution, then a supersaturated solution and thereby to free some of the amino acid from the amine salt. It is best to darken a saturated solution, not using excess acid. The undissolved material is again separated, then a base is added. When the dissolving acid is neutralized, a supersaturated solution forms.

   The ratio of amino acid to salt forming acid should again be such that 0 to 90% of the [alpha] -methl1DOPA is present as the free amine. Neutralization proceeds slowly. - in the presence of seed crystals of one of the enantiomorphs, or else the supersaturated solution thus formed is subsequently seeded, with vigorous stirring.

   The neutralization technique can be used either at constant temperature or in conjunction with a change in temperature, although it is generally preferable to maintain the mixture at a constant temperature, in order to prevent the racemate from contaminating the product. Neutralization can be carried out with any desired base, for example, with atomic hydroxide, sodium hydroxide, lime, magnesia, hydroxide. of potassium and analogous bases, of Mars that

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 carbonates or bicarbonates of these metal ions. When the cation forms soluble salts with both the diso-
 EMI10.1
 lution that with the phenyl alanic compound, the neutralization technique can be used in the presence of seed crystals.

   When insoluble salts are formed with the salt forming acid, the supersaturated solution must be filtered before seeding. Bases forming inso-
 EMI10.2
 uOPA methyl ubles should be edited, as they neutralize the bad acid and remove the racemate from the solution,
Another method of forming a supersaturated solution is to volatilize the solvent, either by raising the temperature.
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 This procedure is especially applicable when the aqueous solution contains a small amount of a polar solvent, such as methanol, which is highly volatile, either by lowering the preaolone into the saturated solution.



   Another method of forming the supersaturate solution is
 EMI10.4
 aiate to dissolve the alaino acid dtne an excess of a bej'de, which has a volatile anhydride in aqueous solution, and to convert the solution into a supersaturated solution, one vola-
 EMI10.5
 lian dissolving acid anhydride. the 801u ... saturated tion.

   An example of such an acid is sulfurous acid.
 EMI10.6
 whose first ionization constancy is greater than 4 10 "": Thus, in the practice of this variant, a saturated cation of the racemic amino acid, in the form of bisulphite, is formed by bubbling sulfu anhydride
 EMI10.7
 They are placed in a suspension of the alcoholic phenyl compound or by adding an excess of-methOPA to a solution of SO2 in water. An excess of the amino acid should be used in
 EMI10.8
 each case so that at least 10v of the dissolved amino acid present in the final supersaturated solution is in the form of free base. Undissolved matter is separated and
 EMI10.9
 the filtrate is seeded, mahouts preceded.

   The seeded iltrate is then heated either at atmospheric pressure, by heating, either ao, 1; 3 preosion rs, .iCe,

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 or rinsed with an inert gas such as nitrogen, to remove part of the SO2 and thereby form a supersaturated solution in the free amino acid. Also in this case, an optically active amino acid having excellent purity can be isolated by filtration.



   The process is especially advantageous when it is adapted to constitute a continuous process. One advantage is the ease with which the process is controlled. that it is run continuously. Another advantage lies in the fact that, unlike what happens in the technique of! neutralization, there is no accumulation of Inorganic salts in the recycle mother liquor. However, for economic reasons8, the thermal method is ready.



   A very important advantage of the present invention, both in the case where the process is intermittent as well as continuous, but especially in a continuous process, is the purity of the enantioorph recovered. Both in the case where the process according to the invention is carried out intermittently and in the case where it is carried out continuously, this process is remarkable in that it makes it possible to obtain a substantially pure isomer (i.e. (i.e., an isomer containing more than 97% of one enantiomorph over the other and usually containing close to 100% (this enantiomorph).

   No other straightforward and simple method applied, as described, with other compounds gives such complete resolution in the bags indicated while no other continuous resolution method is described.



   A continuous process is carried out by supplying a saturated or nearly saturated solution of non-alkaline aqueous [alpha] -methyl1DOPA in aqueous solution into separate crystallization vessels containing seed crystals of the enantiomorphs and forming saturated solutions, in a continuous fashion, by presence of seed crystals of each enantioplorph

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 which then crystallizes in part. The separate crystallizations of each enatiomorph can be carried out in series or in parallel.

   When the crystallizations are carried out in series, the mother liquor from the first crystallization is fed continuously into the second crystallization vessel and its mother liquor is recycled continuously to a dissolving vessel feeding. saturated solution crystallization vessels, When crystallizations are carried out in parallel, the saturated solution stream is divided into two parts, each of which is sent to one of the crystallizers, and the mother liquors are combined and recycled to the dissolution vessel.

   More racemate is regularly added to the dissolving vessel, to keep the outlet solution saturated, keeping an amount of solid racemate present at all times. It is possible to achieve complete resolution of the racemic amino acid to its enantiomorphs by this technique.



   The continuous character of this process depends on the control of the transfer rates of the respective solutions in each successive vessel of the circuit, so as to constantly maintain in each crystallizer, the conditions suitable for crystallization of the seeded enantiomorph. The dissolution vessel is maintained at the desired temperature, if a temperature technique is applied to form the supersaturated solution, or is treated with SO2, if the volatile anhydride technique is used, at a controlled rate. . An additional amount of racemate is charged, intermittently, to maintain a solid phase still present in the dissolving vessel.

   The saturated solution is removed at a rate controlled by the filter inlet nozzle (to prevent entrainment of the solid racemate) and is passed into the first seeded crystallization vessel.



  In the crystallizer, the supersaturated solution forms continuously in the presence of the seed crystals.

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   (maintaining the temperature at the desired value by adding; continuously a neutralization base, rinsing with
 EMI13.1
 of an inert gas, keeping the pressure low, etc, according to the technique used).



   In the serial technique, the mother liquor (which is now supersaturated, in one enantiomorphic, but not in the other} is; continuously fed through a filter nozzle into the second inoculated crystallization vessel. the other enan-
 EMI13.2
 tianarphe, The second criatallizer returns its mother liquor, da; similarly to the dissolving vessel and the rate of each of these transfers is carefully controlled to form a balanced system.

   To make in aorta that the almost
 EMI13.3
 all of the second enantiomorph in excess with respect to the racemic mixture is recovered in the second criataller, it is preferred that an additional but smaller quantity of Z30 2 be sent to this criataliizer or, in the case where the method of differences temperature is applied, which the second crystallizer is at a slightly lower temperature, but this is not absolutely necessary to recover part of the second enantiopmorph.
 EMI13.4
 The connection is provided with a discharge pipe of the auspen..wr aion and the crystallized enantiomorphs are discharged rei, further ./ "'\ Meqtp to prevent the suspension from becoming too thick,

        The suspensions thus discharged are filtered and the filtrates are either returned to the container from which the suspension has been discharged, or sent to the dissolution vessel.



   In the parallel technique, the saturated solution is
 EMI13.5
 divided and continuously fed into separate crystallization vessels. The suspension of crystallized enantiomorph is kept stirred and the overflow is sent
 EMI13.6
 on a filter. The Ilqulur3-mèr 8 have been collected and returned to the dissolution vessel.



   The invention can be illustrated by the following examples

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 EMI14.1
 EXAMPLE 1
 EMI14.2
 3? grams of racemic mehylJ, 4dihydroxyphenylalanine are su3pea3ion at 350C in 100 cc of acid
 EMI14.3
 hydrochloric acid 1, C N. Excess solid matter is filtered off *,
 EMI14.4
 in aorta that a saturated solution is obtained containing:) 4i & s of racemic amino acid, of which about 61 are present in the form of hydrochloride, The solution is then inoculated. at 350C using 7 g of L-methyl 3 4-dihydroxyphenyl, al, inan hydrate (6.2 g of anhydrous material). The mixture is then re. cooled to 200C in 30 minutes and maintained for. 1 hour at 20 ° C. The material which separated is isolated by filtration, washed twice with 10 cc of cold water and dried in vacuo.



  The product yield was 14.1 g of L 't-m (ithyl-394-diliy4 1 droxyph4n "' 1'inine in the form of a e.aqu.hydl" at .. purity.
 EMI14.5
 
 EMI14.6
 do 100, o, determined by the rotational power of the complex at
 EMI14.7
 copper.
 EMI14.8
 



  A fraction of the 11queul "e-l1'Ièr.ars from the preC stage (J dant (45ml) contains J.Ó5g of hydrochloric acid and lOs4g of lI (.. mothy3.w), 4..dihydroxyphdnylatan: tne, airao one of 61>, d'f;
 EMI14.9
 form D. The mother liquor is heated to 35 C and. aité1 <v <tc J4 'S of racimate, Excess solid matter is, trimmed. by filtration, in the aorta which one obtains a filtrate containing approximately 12.2 g of (methylDUPA consisting of 6'i (q of hydrochloride. L6 filtrate is seeded at 3500 using 2 # 7 g of 1.ra3thyl, -3,4w:
 EMI14.10
 hydrated dihydroxyphenylalanine (2.4 g of anhydrous material). The
 EMI14.11
 The mixture was then cooled to 20 ° C over 30 minutes and held for 1 hour at a precipitated temperature of 1 hour, isolated by filtration, washed twice with 5 cc of cold water and dried in vacuo.

   A total of 5.5 g of D # <anef, hyl-3,4dihydraxyphnyla7, anine, is obtained in the form of a 4c3qUi-hydrate with a purity of 100:. The mrea liquors contain the racemic aroino acid with only a mi-li ..; 1;. '1. Excess, of either enontiomorph, uea 3icu.urs. rt: <. res August then

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 will recycle to the above-described process, being used as an acidic solution, to make up the original reaction mixture.
 EMI15.1
 



  : - .. 'fL.'PM l'. {:..'AND. 1. ' ,., 10 g of 1L - mLtiiy-3, k-dihydroxyphlnyxa, ani, na crystalline fona 2A characterized by X-ray absorption maxima (Ka) at z> ', 11 "and: 3",% are added to 50 cc of 0.5N hydrochloric acid at 35 C, The ziuepeniion obtained is stirred for about 30 minutes at 35 C. The undissolved solids are separated by filtration and weigh, after se-
 EMI15.2
 cha-le, 0, X g. The temperature of the filtrate and the suspension is maintained at 35 ° C during filtration.

   We add
 EMI15.3
 Li5 gram of L- -methYl-Jt4.dîhyuy, oxyphenylolanine in the filtrate '
 EMI15.4
 the temperature of which is still at .10500, the seeded filtrate is then cooled to 20 * 0.4 at a rate of 0, $ ttC per minute, then maintained for 1 oil at this temperature and filtered. The wet cake weighs 4 H r <tnintaa (2,3; r'anM! Ea aprl> 8 drying at
 EMI15.5
 ooo), The product had the 8eaquihygrt 'and the rotatory power
 EMI15.6
 specific, at a wavelength of light do bzz mut of the copper salt is t-u of + 170% The roundness of isomer is 26%.
 EMI15.7
 



  8X.r: .Pp ;, 46 rammQ8 de v.dnéhy-y4d.hydraxyphdny, r.n.n [form I, characterized by ray absorption maxima.



  X (Ka 2 4 copper) at, 0 and 13 'Jusant put in eusponaion in 100 cc of hydrochloric acid <!, 0 N z 2500, for 1 hour, The undissolved solids are separated by filtration.
 EMI15.8
 tion and dried. The dry weight in aolidw ways is 0.90 g., 8.0 grams of L-mGY.y-3 rlidihydroxyhé.ny, ala.
 EMI15.9
 nine seeds are added to the filtrate, 40 cd of 2N sodium hydraxyé are added to the filtrate at a rate of 0.5 cc per @ t
 EMI15.10
 minute. The tesperaturc ii - t maintained at 25 C. 'W ;; e8t. maintained for 1 hour at 25 C, then filtered. The weight

 <Desc / Clms Page number 16>

 
 EMI16.1
 of the dry product (including seed crystals) is
 EMI16.2
 t3, g.

   The product consists of i, -.'- mrthyl-.3, .- di .. rot'1t1 "e im hydroxyphenylalanine sesquihydrate and the power! Sp7-clt'ÁQüe at a wavelength in the light of 539 mu, of its copper salt is + 170 * The isomer yield is 39%.



  '? Y' "OT C 'J; t'.ri <!: <35 g do ilLmthy.-3, t-di.hyr3raxyphrylalanize August mis
 EMI16.3
 suspended in 200cc of 0.46 molar aqueous solution
 EMI16.4
 sulfur dioxide 24 * 0. After 70 minutes, the suspension
 EMI16.5
 is filtered under pressure (using nitrogen to facilitate.
 EMI16.6
 liter training). The weight of the undissolved fishing solid is 10%. 210 cc (total -214 cc) of the filtrate and! 12.6 grams of D (-ra <$ thyl¯3> iV¯dihydroxyphenylalanine are loaded into a 500 cc Morton flask fitted with a stirrer and nitrogen inlet tubpea. waved "
 EMI16.7
 turn at 420 revolutions per minute, we pass 0.42 feet. cubiqvs
 EMI16.8
 nitrogen in a wet metering device, then in the cria-
 EMI16.9
 talliaation, within 35 minutes.

   The suspension is maintained for. 1 clash 24'C, then filtered doua precaion
 EMI16.10
 (using nitrogen to aid training). The weight of the product (including seed crystals) is
 EMI16.11
 dice 14.6 s' Lee 7..cusuro..mîxxsa are drawn with the aid of sodium hydroxide, ju: that in blue coloring of the green trowocreal. The sulfur dioxide content is assumed to be 3% of the cauitic solution used. The concentration of sulfurous anhydride by this technique is 0.2e Ht The product obtained is' la>). C-mwthy7.3, t, -hydraxyptaény.alana ^ seaquihydrate, the pou-
 EMI16.12
 see specific rotary of copper salt 4t & nt from 170-172 *
 EMI16.13
 a 589 ni y. L <: r '..- nt.-n. #. Nt in isomer D is 17 / û "â: - :? on 5 ..



  The apphrhil used for continuous crystallization is made up of three nvr glass vessels; it is 3 liters svec
 EMI16.14
 four glass baffles and a turbine-type stirrer

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 with four pallets. Each container is equipped with an inner filter (5/8 inch outside diameter and 4 inch long) of medium porosity Pyrex.



  The use of this filter makes it possible to work at any desired concentration of suspended solids.



  A slurry discharge line is also provided in each crystallizer (i.e. in two
 EMI17.1
 containers). The temperature is controlled by soaking the containers in a thermos statically controlled bath. Each container is equipped with a thermometer to measure the temperature, The solutions are pumped from one container to the other, in a closed circuit in
 EMI17.2
 using peristaltic pumps and rubber tubes. Nitrogen is supplied to the filters by rotameter3. The dissolving tank is equipped with a rota * meter to measure the flow of sulfur dioxide added.



  A typical test I described below. Each participant is charged with the liquor contained by this container during a previous test. The temperature of the water bath is
 EMI17.3
 set at 42 * 0, to provide an internal temperature of 40 * 0 in the vessels, z +, 3 grams of seed crystals encircled of type L are added in crystallizer L, while 98.4 grams of Seed crystals L7 are added to cistallizer D and that 458 grams of t4-mthyi- 3,4-dihydroxyphenylalanine, which has been repaired by filtering the contents of the dissolving apparatus, during the test previous, are added to the apparatus or dissolution vessel.

   The periataltic pumps are started and adjusted so as to deliver 50 cc per minute. Sulfur dioxide is supplied to the dissolving vessel at a rate of 1 liter per minute. Nitrogen is supplied to the
 EMI17.4
 crystallizer U at a flow rate of z ,, 8 liters per minute., and in the criat & 111Beur L at a flow rate of 0.96 liters per minute,:

 <Desc / Clms Page number 18>

 
 EMI18.1
 I gratnmea of DLthyl.t.dihYdrQyphénYEllan1ne are added to the dissolution vessel after each time interval of 30 minutes.

   De3 samples are taken from each container at 30 minute intervals and tested to determine their sulfur dioxide content, by titration with the aid of a causative alkali until the final blue color of the green bromocresol.
 EMI18.2
 and in order to determine their .methylDOPt interferer by absorption of ultra violet light 401 m in a Beckman apectrophotometer, these values are reasonably constant and can be summarized as follows:
 EMI18.3
 
<tb> Concentration <SEP> in <SEP> Concentration <SEP> in
<tb>
 
 EMI18.4
 S09 ethylDORA. ol / 1-Hye JlSī¯¯ Dissolving vessel 4, fez3 0.5 D-criatalli3eur 0.30 0519 L-crystallizer 05 0.47
 EMI18.5
 ..k 'r (:

  d 6 hours of Operation under conditions, l% 38 i is stopped The content of each container is filtered Z59 grams of D isomers (including seed crystals) are recovered05 caris crstaJ.l.8euf 'D .267% of L-tecmere are recovered in the core and 359 grams of DL crystals are recovered in the duolution vessel. The values are lep The rotatory power of the copper salt of the L igomer and + 170/17! ", At SS9 mv while that of the i, eomtp * D tut 44 170 * / 172wf at 599 mp The productivity" in hours 8 L per 1.5 liter of crisper capacity., 1 ', of 26 grams per hour. The yield is 97.4 (' 0.



  During the running of the continuous ey * test for the initial test, the dissolving vessel is charged with 3 liters of water and sulfurous anhydride is passed at a flow rate. of 1.8 liters per minute. We add approximately
 EMI18.6
 1 kilo of racemate. When the content of SC2 is 0.62 M, the saturated solution transfer, through the filter
 EMI18.7
 internally, to cri3tallist3ur D is primed at a rate of 50 cc per minute. Water is then charged into the

 <Desc / Clms Page number 19>

 dissolution vessel, at the same flow rate, so as to maintain a constant volume.

   After every half hour, an additional 28 grams of racemate is
 EMI19.1
 also charged in the dissolution vessel.



   When the crystallization vessel U contains 1200 cc, a stream of nitrogen at a flow rate of 4.8 liters? through
 EMI19.2
 minute is primed. A 100d load of pmethY1POPA. is added. When the "0" crystallizes at 500 cc, the elimination of mother liquor 4 in the proportion of 5 μm per minute by the internal filtrate is initiated, the first mother liquor being sent to the critalior.v + .1.



  When the screening agent gives this 4th solution 1200, 100 g of Le (-! NethylDuPA 3Qilt added and the r $ nq4ge using nitrogen 1, a flow rate of 0.96 liters per minute is started. r1stalli $ eQur contains X5ÓO oce we start to evacuate the liqller ... trtfa '"filter part i nterr4a at a flow rate of 50 cc per minute. This second uqueur-black is loaded into the di no;!. uti1Qn l \ \ .I ntr is interrupted. The system is extended in phase aQnH.n ot one operates in the manner described pue hat4tq The apparatus consists of three r4oipientob-an,., InA with a capacity of 3 liter liters, three pumped , an internal porous H \ W *, two product filters, 4th agtAto4M thermometers, rubber hoses and constant temperature baths.

   These elements are arranged as follows}
 EMI19.3
 the first container, namely the dh, out container, 1ent is equipped with a stirrer, thermometer, bath and internal porous filter. The line coming from the filter is divided into two lines which each pass through a pump and each end in one of the other two re-
 EMI19.4
 containers (cri8t..lli'.9.teur). Each of these is ,,
 EMI19.5
 de n ::!: ne equipped with a thormo # ètrft, an aviator and a baiR.

 <Desc / Clms Page number 20>

 
 EMI20.1
 the tt'QPIilljlGiI \ of each container 'goes to a product filter.



  Lon filtrate ducts of the latter filter are joined together or pass through a pump, the output of which is connected ... the ep ...
 EMI20.2
 similar dissolution.
 EMI20.3
 AT first, the system is loaded as yes
 EMI20.4
 2600 ml are loaded into the dissolution vessel
 EMI20.5
 0.1 hydrochloric acid and 266 g of DL- <-mi5thyldihyeiro) cy- phéftyïalattinei The ootenua suspension is heated% 3p'C in balriwmarle and maintained at 560 throughout the operation. t) ah0 the ceiotmllieeurs, 152.4% of 01. "'- <" I! \ thyldihyt; .roX: yphê ...' nylalanine are dissolved in 3100 ml of hydrochloric acid ool N at 2000. The solution is filtered. to prevent the prurticulea prejbëndo in suspension and is loaded Jane the
 EMI20.6
 and
 EMI20.7
 cr1talli $ eUr8, at the rate of 1.550 ml in the e; r.1 ..t.31li3eur D j
 EMI20.8
 (; d 16U ml in the criatelliser L.

   The container rates are tt) air) te! I''9 to 2u C in a water bath during the operation.



  17 to 5 kmmet of D * meh * 4′l> ydroxyphenylalariino of high purity (our hydrate form) are added to the crystallizer 0 and 1717 of the L isomer (as hydrate) Pu cri-l; - tr. 3 reader The grLHt & llitià'iiofi of rabolution is done by pumping. From the dissolution post, through the internal porous filter, a solution of DL.methyldihydroxyPhenylalanine, 1
 EMI20.9
 
 EMI20.10
 a flow rate of 24? 1 per minute. This, 4c (oulen <3bt is set, from
 EMI20.11
 6h & provide 12 ml of product per minute to each of the cria
 EMI20.12
 F; to, .iseUrs (2) and L).

   From each crystallizer, a> '- uspetî.gîon of the respective isomer in the liquor of Cree. ; ita, .ïsa'tisr 3c: oule, by t "op-plein to a pro- filter
 EMI20.13
 
 EMI20.14
 From each filter, at regular intervals, an equivalent volume of mother liquor D and mother liquor L is returned to: the aliaentation funnel of the dissolving vessel, in which, 1 of 0 are launched and returned to the dissolution vessel.



  During 9 hours of operation of the installation

 <Desc / Clms Page number 21>

 
 EMI21.1
 tione IG # 2 of DL "Methyldihydfottyphnyl & lanine (solid) are changed in the container dà djeBbltidft4 (additional 8.65 g materials * in 8 their 9 and L pueb (solids) are expensive ,,, in their criotalli4m toupa reapoctitbs A la At the end of the oaaai, the 8apeh81Qrtl 66 found in each container are filtered * separately and the substances eQl1das. as well as the clear liquid, 8t m4sured and titrated. From the filtrates and the filters of the continua products one obtains 415 gram of bi8omr.



  (in the form of the hydrate) and 51.5 grams of L * <isomer (aoua formed from hydrate) which represents: lbnt.6 one met (per weight bearing of the seed crystals) of 21125 grams of 'D isomer and 4.g of L isomer read opm purity
 EMI21.2
 ticked of these products is determined pul- tàti6i power
 EMI21.3
 té dyne solution of the aluminum complex! L, .I n- .. 26, s 3 D J 26; 2-.



  Analysis of the liquor3 and dissolved boUdée tnatiêlleo * from the dissolving vessel revealed all remains dt ... mltttiyld1hYt! I QXYi'hlor \ ylsldhihe of 96.Sj E7.LE.



  15 g of I7, .wt IrihylDF't are mb térl ruïY9Eli.iin dhris 200 bè of 0.001 N hydrochloric acid for 30 useless. Ó8 to $ 3 * Gt) The auspertaion is filtered and the filtrate is seeded * using of 1 $ 7 g de tt! hjclCF4 $ equlhydtàt4. there where
 EMI21.4
 lutioft is r.ò1d 'A 0, $ OC by mihute t) u $ that at zooo and oiil [
 EMI21.5
 then stirred moderately for 1 hour * the product is filtered washed twice with) 3 eu of cold water and $ 'h6 under vacuum * The net anhydrous product weighs 1.5 g and weigh "" nte urie purity Cpt ue of 99 / o Î4EI iPLE ##### 2 g of eont di8sous in 50 cd of diluted water by heated to 75 * C- The solution is filtered and inoculated with O, POO g of LamÓthyi0PA 80aquihydeât4i It is then cooled to $ 2 * ' C and maintained for 115 huuet SQumise at a moderate state * * The pruduct is tilt

 <Desc / Clms Page number 22>

 very,

   washed with 4 cc 6 'cold water and vacuum dried. The resulting net anhydrous product weighs 191 mg and has an optical purity of 100.



   EXAMPLE 9
The apparatus consists of three receptacles with a capacity of 3 liters each surrounded by a heating or cooling bath. Each vessel is equipped with an agitator and an internal filter connected to an outlet pipe. The first vessel, the dissolving vessel, contains solid DL- -methylDOPA as well as saturated solution.

   Its bath is maintained at 75 C, The outlet pipe connected to its internal filter is divided into two branches each leading to one of the other receptacles, the crystallization receptacles, via a metering pump and d 'a heat exchanger *, These are maintained at 45 C by circulation of cooling water in the jacket, each pipe then passes through a second filter (to prevent a racemate which can have crystallized in the heat exchanger contaminates crystallization) and ends up in one of the crystallization processes.

   The baths surrounded these sost vessels held at 35 ° C. and each bath contained a supersaturated solution, as well as the crystals of an enantomorph, as described below. The outlet pipe coming from the internal filter of each crystalUser passes through a metering pump and these pipes are then joined together, to form a return pipe to the devolution vessel.



   To begin the test, the crystallizers are initially charged with almost saturated racemate solutions at bath temperature (35 ° C) but free of dissolved material. These solutions contain 0.069 equivalent of SO2 per liter. Each crystallizer is then loaded with 225 g of seed crystals per liter of solution. A

 <Desc / Clms Page number 23>

 
 EMI23.1
 Thealliator receives form D seed crystals and the other receives form 1 seed crystals.

   The dissolving vessel is then charged with racemate and
 EMI23.2
 o.aai, of as saturated solution containing 0.069 equivalent of SO2 per liter and it is heated, while stirring, until the solution is saturated at the temperature of the container through the pipes? or .le the exit in 3 the:
 EMI23.3
 ** of dissolution (/ 590 d This solution is alor3 Uin-en-ée ,, 'r-, tÎ3- 3U ÜHIIJf' 6, / flow rate such that the nominal residence time in each criatallizer is one hour. At the same time. , liqueurs-
 EMI23.4
 Mothers from the crystallizers are returned to the dissolving vessel at an equivalent rate.

   The pumping is continued, in this circuit, by adding, in a so called contained manner, the solid racemate to the dissolution vessel, in order to maintain the solid racemate in the presence in this vessel. Fractions of the suspensions are discharged, from
 EMI23.5
 intermittently, from each criatalliser, and filtered, the filtrates being returned to the dissolving vessel, using a pipe separate from the recycling pipe, the inlet of which is introduced into the crystallizer.
 EMI23.6
 ta1A $ tor, when using it. This drainage is often sufficient to maintain a seed crystal concentration of 225 g per liter in each
 EMI23.7
 cr.ats, .iser.



   Samples of the contents of each container are taken from time to time for analysis and at the end a material balance is obtained, recovering the contents of each container. The results are as follows;
 EMI23.8
 Concentration in c (.. methyZL7A (g / liter} Dissolution vessel 55 -58
 EMI23.9
 D-cril $ tal1i: $ e'.tr..a '50 - 53 1' ... criatalli: .tll1t.tr.l ;; ' S0x- 53 Product quality, (specific rotation of the Cu complex)! 3 1; '28 a 546 1ri L ¯ 152 a 546 m

 <Desc / Clms Page number 24>

 
Productivity - 1-9 g / liter / hour Material balance 832.0 g DL starting material 301.0 g criatal seedling D 301.0 g seed crystal;

     surrounding L final material 429.6 g D
422.1 g L
 EMI24.1
 257 110 g 0L solid in dissolving container 221.8 g DL in liquors 34.9 g lost * in washing liquor
 EMI24.2
 25sO i; lost during sampling net 12S, 6 g D 121.1 g L
 EMI24.3
 RBV BN DICATI 0 U S. leu Process for the preparation of the optical isomers dtméthy.3 yd, hydraypheny, axantne acaus substantially pure form, characterized in that a supersaturated aqueous solution of the racemic mixture of said alanine compound is used one cantate with the seed crystals of the desired isomer, said solution containing 0 to 90% of the alanine preanine
 EMI24.4
 , ... above.

   as the ae of a non-amphoteric, water-soluble acid.


    

Claims (1)

2.- Method according to claim 1, characterized in that the proportion of seed crystals is at least 5 g per liter of solution, the supersaturated acid solution containing 10% to 90% of the alanine compound under amine salt form of the dissolving acid and acid comprising EMI24.5 at least one acidic hydrogen viburnum with an ionization constant greater than 10-3. 3. A process according to either of claims 1 and 2, characterized in that the supersaturated solution is formed by preparing a substantially saturated solution of the racemic mixture in an aqueous solution of said non-amphoteric and water-soluble acid. , this acid being a steel of which <Desc / Clms Page number 25> the acid anhydride of which is easily evaporated from its aqueous solutions, by separating the excess of the racemic mixture and by evaporating a part of said acid anhydride. 4. A method according to claim 3, characterized in that the acid anhydride is sulfur dioxide.