DD212508A1 - METHOD OF CLEANING BETA- (P-CHLOROPHENYL) -GAMMA-AMINOBUTTERIC ACID - Google Patents

Abstract

The invention relates to a process for the purification of Betta (p-chlorophenyl) -gamma-aminobutyric acid, which as an active ingredient of medicaments must meet particularly high purity requirements. According to the invention, the high amino acid is treated with acetic acid, the acetic acid solution is filtered and, by adding an aprotic, water-immiscible solvent, the hydroacetate is deposited in crystalline form. After separation, the hydroacetate is converted back into the free amino acid by hydrolysis with water or water-containing solvents.

Description

Method of purification; of P - (- p -chlorophenyl). - l · aminobutyric acid

Field of application of the invention;

The invention relates to a method of purifying £. - (p-chlorophenyl) -ja-aminobutyric acid (? ormel i) for

K ₂ Ii-CH ₂ -CE-CH ₂ -COOH

Purpose of obtaining a quality sufficient for the pharmaceutical application "This compound has as a ffirksxcff of spasmolyticin Baclofen a great importance for the treatment of various diseases such. 3. Multiple sclerosis, so acquired from spasmodic states of different genesis. Therapy brer e of this compound is still expanding. It has been proposed to use baclofen in combination with Neuroleptica for the treatment of schizophrenia. Another recent application is to repair or ameliorate neuronal disorders. The use of this medicine for the symptomatic treatment of predominantly chronic illnesses at the rate of short-term, but predominantly long-term or lifelong treatment with this

1SDEL 1982 * 0 * 5036

-. 1 g. is. Desnalb is; a particularly pure quality of the action is required. The presentation of sufficient quality for pharmaceutical use of Baclofen - 'Virkstof f it ^-.. .Var ΰ ede anyway after the previously known cleaning methods are difficult to implement.

Characteristic of the known technical solutions

Although some purification methods are known in the Baclofen-'tYirkstcff manufacturing patents, these docn have significant disadvantages. In patents which deal with the preparation of the r- (p-chlorophenyl) -benzoic acid (eg 3. CH-PS ^ Дб 376, CH-PS ώ62 84Ί), in the examples a crystallization from water is described . Reinigungsmethоde indicated the only purity skri te Ministry the melting point of this value (206 ⁰ C) is in this case referred to is currently in all of the β -.? (p-chlorophenyl) - ρ-aminobutyric quite unsuitable purity criterion since it can be shown that the ignition and melting process is accompanied by decomposition of the amino acid, inter alia, splitting off of the dehydration and transition into ^ (p-chlorophenyl) -2-pyrrolidone. "Significant disadvantages are attributed to the crystallization of water, for the sake of solubility this amino acid in 'Wet on the one hand relatively low ⁽⁴ 5 g / l at 100 ⁰ C) and, moreover, after cooling to 2C' "C for about 20 - / £>, after cooling to 2" Z Zech 2C% of to remain dissolved, so ia2 evaporated 7 / erden muJ. The failed reading ratio of 1: 56.5 (weight ¹ D, 7 mol.) At * jQ ⁰ C also requires that large volumes be processed in the technical haw stick. "Further, practice has shown, ia." colored terroir

v, -; -... ^^. _ar> . "-; ^ -, a ^ "oq ⁴ тр-рол ^ р ^ опзі" D "7T ~ - ~ ci er ρ --s -" - ^ ο Ό -ro ¹ ^ S1j "P" h - ^ c- ¹ - sun

can be difficult to remove on this' voyage. If one dissolves a slightly yellowish raw Bacicfen substance in hot water, and leaves it in it. Cooling the solution off again

n man oeooacnten, тѵіэ oi

5T "" ¹ 1: ¹ ^. ~ 1 І C.Yl

.tion iss Jeststoffes be -again adsorbed on this, so again in 2 nient pure white Kristaiiisar "i ^ ^J - ^ o

U.N

Mother liquor result. Although it is possible in such cases to achieve an improvement in the degree of creeping by means of an acrolvic treatment of the solution, new disadvantages arise from this. It has been shown, for example, that Bacillus' active ingredient has a pronounced tendency to bind inorganic cations. Since most activated carbons have a certain content of heavy metals such as zinc and 3 iron, activated carbon-treated 3aclofen samples always have a relatively high content of these metals, so that several purification steps are required in order to remove them. 3s is further proposed in the manufacturing patents for 3aclofen active ingredient, for example in CH-PS 4AS 376, 449 046, 449 645 and 462 841, that for the purification of Ь - (p-chlorophenyl) - ^ - aminobutyric acid, the acid addition salts, for example to use the picrates. As a method for the conversion of the salts into the free amino acid, which is exclusively part of the Spasmolyticums 3ac1ofen, reference is made to the usual methods, such as addition of basic Hit te1 such as alkalis or ion exchangers. The latter method presents difficulties in practice because, due to the low solubility of the amino acid, it crystallizes out on the ion exchanger acid, so that it is necessary to use extremely dilute solutions. The addition of basic agents to the salts for the purpose of the conversion into the free amino acid in turn has the Jachteil that thereby salts are formed, which are due to the adsorption tendency of the active ingredient in this z. T. be bound so long '.Vaschprozesse be required, if necessary, a further Umkristaiiisation must follow.

So far there is no technical teaching as to how it is possible simply to produce an active ingredient of pharmaceutical grade 3 from contaminated 3a.clof en-active substance.

Object of the invention

The object of the invention is therefore to develop a cleaning method for crude petroleum-based products which avoids the disadvantages mentioned above and makes it possible to obtain a pure petroleum ether in as simple a manner as possible.

which allows it to work in concentrated solution, as well as activated charcoal treatment and remnant addition, as it takes place when decomposing salts with basic agents

O ^J J

avoid, wherein the obtained pounds> - (p-chlorophenyl) - / p -aninobutyric acid in heavy metal and sulfate ash content should meet the applicable purity criteria for drugs. ^; '

In accordance with the invention, the object is achieved by dissolving it in a crude solution obtained by the various synthesis variants of said patent, dissolving it in anhydrous acetic acid, filtering the solution and removing it from the clear, possibly colored filtrate by addition s "ines suitable organic solvent, which must be miscible with the solution, but must be inert, 3 brings the Hydrcacetat of formula II for crystallization, the separated Заіз separated from the mother liquor and by simply suspending z

Cl

-CH-GH ₂ -COOH

к-w _L j

ion exchange e:

m cie ireie алі

• r η Cp--; -> - чз

o ^ _ ^ зигисл .. e_ лancie j. и.

Solvent for the separation of this salt Ij. iabei aprotiscr.e, water-immiscible solvents such. 3. Aromatic compounds such as benzene, toluene or xylenes, haloaromatic, chlorobenzene, aliphatic halohydrocarbons, dichloromethane, chloroform and tetrachloroethane, furthermore tertiary ether, diethyl ether, ester of ethyl acetate, and xeton like acetone in 3e. Preference is given to Goyiep. The solution of this crude substance takes place at room temperature at most ^ C ^ Z. At the room temperature the tels erfz -xz ζ "eckma." Ig at the room temperature. .. viir * 'Vencet for the sake of! Iu.ii і-эз Hyacetacetates Favor a ratio' .Tirk-

us atz the organic -suitant

but also at other mixing ratios, eg. 3. 1: 3: S or 1: 5: 20, work. The hydrated acetate precipitates in a well-crystalline form and, even in the presence of amber-colored solutions, is obtained pure white after separation from the mother liquor and washing out.

The hydrolysis of the hydroxydate can be carried out either with pure water or with mixtures of water with aliphatic C 1 -C 4 -alcohols or acetone in the ratio 1: 1 to 1:10, Advantageously, pure water is used , In the hydrolysis is advantageously carried out at temperatures between 0 and 100 ⁰ C, advantageously at 10-20 ⁰ G. Man .Vendet thereby advantageously a ratio of hydroacetate to water, or water - Geniisch with C. -C -, - alcohols, or Acetone, of about 1: 5 (m / V) an ', but can also choose other proportions. The free amino acid is separated from the mother liquor by filtration. Depending on the solvent used and the quality of the crude product used, it is possible to obtain 70-85 % of the product used in pharmaceutically pure quality. From the weakly acidic mother liquors can be neutralized to pH 7, a further impure fraction win, which can be added again in a next batch. By the process according to the invention, with very little effort, a very pure 3aclofen-7 / irkstoff, which contains much smaller amounts of impurities than comparatively different cleaned samples 3aclofen - <'irkstcffes after also a single cleaning' Table i). The higher purity of the sample 4 purified by the process according to the invention is clearly shown by a higher ^: JV absorbance at 219 nm in 0.0Cl solution in 0.1 2 1 LiCl, lower sulfate ash content (determination according to 2. A3 of the GDR), and by lower C-content of metal, zinc, and zinc, as determined by atomic absorption spectrometry. The process of the invention further has the distribution that it can work without the use of activated carbons in relatively strong dissolved crude products and that can be -.verden worked in relatively concentrated solutions.

Verse. -I Г. Reclamation з me triode л -ι ι cm 19 nm Suïfá о - ash "Ό -1 are SS ^ j-Пл 0 1 . crystallization on H ₀ O -r 5? з A-Xohle " 0 0.52 2 • ю- ² Second Crystallization as HGl salt in methanol / HCl, Zerlegiang of the salt with ZTaOH ⁴ , 482 с, з 2 • 1c- ³ 7.1c- ⁴ 3 _# Crystallization as H-TO3 salt in HpO, decomposition of the salt with ITaOH C , 436 0.16 1 .1c- ³ O 1 BJ 4th Inventive process in toluene 0 , 496 0.0 / i 6 4 Ί 0 ~

It was surprising that the process according to the invention gave such good results, since it could not readily be expected that a salt which crystallizes well in a nonaqueous medium would yield the free amino acid to a high percentage by hydrolysis with water without the addition of basic and, for example, it is not possible to obtain the corresponding salts of other aliphatic carboxylic acids, such as, for example, the salts of formic acid or

^ a "^ * ~ D -v% ri -r- * -ipv» c: ο ι τ τ · α і ^ с * Ί Д ^ л '^ ^{1 1} ^ ^/ ~ ч ^ о ~' ** Ь 'Ц>-> 1 · л ¹ O л ρ "?] О ^ с * о ^г 7іт * ^ѵ * ⁴ \ 'η f л Ό г> -ι

training z

bring to. With these acids arise using

: he g_eicr.en i.ösungsn: ittel scnleimige, scnlecnt riltrieroare -Jie-

e analytical determination by titration

"erscn._age, üie, such as <C, 1 ZT ZTaCH teaches not from the expected salts, special d 5 from the τι in locally) from? o rm ^{зЬ585сЬ.і} а с. ° кэ" f " ^r% e "^; en * 4.minc acid. Cleaning can not be achieved on this occasion in these!

Outsider s; i e 1 ί

example 1

1CO g contaminated Baclof s - ' »7irkstcff are dissolved in 300 ml acetic acid at 2C-25 ⁰ C. The solution is filtered and mixed with 800 ml of Tcluen with stirring. Ss immediately crystallizes out of the hydroacetate. After cooling to + 10 C, the mixture is filtered off with suction, washed several times with ethanol and hydrolyzed by stirring with 500 ml of distilled water at a temperature between 0 and 20 ⁰ C. After suction and drying 80-35 g of pure active ingredient.

Example 2

The procedure is analogous to Example 1 with the difference that Dichlcrmethan is used in place of toluene

 The yield is $ 68 from use

From the aqueous mother liquor obtained by neutralizing 10 ° h of the amount used zuia ¹ STi ede pure set.

With SOJel 3

The procedure is analogous to Example 1 with the difference that Sssigsäureethylester is used instead of TоIuen. The yield is 32 to 36% of use.

Claims (7)

^ ₁ r_f ir.dur.gsansOruche A process for the purification of ρ- (p-chlorophenyl) - , p- aminobutyric acid, characterized in that crude P - (p-chlorophenyl) - J ^ -aminobutyric acid, as obtained by the known preparation method, mix acetic acid to Hydrcacetat This is brought to crystallization by addition of an aprotic, immiscible with water solvent, separated and by hydrolysis with barrels or water-containing mixtures in the free amino acid zurückverwandelx. 2. The method according to item 1, characterized in that are used as solvents for the deposition of the hydroacetate aromatic hydrocarbons, preferably toluene, and chlorinated hydrocarbons, aliphatic ^ chlorinated hydrocarbons, aliphatic ethers, esters or ketones. 3. The method according to Punlcx 2, characterized in that a ratio of E-ch-amino acid: acetic acid: solvent such as 1: 3: 6 to 1: 5: 20 (m / V / V) is applied. 4. The method according to item 3, characterized in that the treatment with acetic acid at a temperature within the range 2 0 ⁰ C to 40 ^ C is made. 5. The method according to item 4, characterized in that the hydrolysis mix pure '.Yasser is made. 5. The method according to item 4, characterized in that the hydrolysis with C-emischen mix of water 0 _Λ - ois C .-, - alcohols ι J the acetone is mixed in the ratio of 1: 1 to 1: 1, preferably 1: 5, (v / v). 7. Verfanren according to item 5 and 6, characterized in that dis -ydrclyse at a temperature within the range C to ^ CC ⁰ C, preferably at 1С ^Z Z to 20 ⁰ C, durcn-