HU196753B - Process for cleaning of triptamin and its derivatives - Google Patents

Abstract

The present invention relates to a tryptamine derivative represented by the general formula (I) wherein R1 is hydrogen or C1-4alkyl and R2 is hydrogen and acid addition salts thereof. The essence of the process is that the acid addition salt of the tryptamine derivative of formula (I) is formed in a solvent mixture in which any tryptamine derivative of the general formula (I) can be neutral, weakly basic or has a basicity very close to the tryptamine derivatives, or their acid addition salts are soluble, while the acid addition salts of the tryptamine derivatives of formula (I) precipitate out of the solvent mixture in a pure state, practically free of contamination. (I) -1-

Description

The present invention relates to a process for the purification of tryptamine derivatives of the formula I in which R ¹ is hydrogen or C 1 -C 4 alkoxy and R ² is hydrogen.

(a) a crude tryptamine derivative of formula (I) wherein R * and R ² are as defined above in an amount of 0.8 to 1.2 parts by weight of water-miscible polar organic solvent and optionally 0.2 to 0.4 parts by weight of water-miscible dipolar aprotic in an organic solvent, to a solution of 1.0 to 1.1 molar equivalents of an aqueous solution of 20 to 80% by weight, the mixture is cooled to give the tryptamine derivative of formula (I) wherein R ¹ and R ² are as defined above. - the acid addition salt is filtered off and washed with a water-miscible polar organic solvent, or

b) tryptamine of formula (1) derivative - wherein R ^J and R ² are as defined above - forming reaction mixture was known phenylhydrazine derivative and gamma-halo-butiraldelúd derivative way, after the various layers are separated, the formula (I) In the phase comprising the acid addition salt of a tryptamine derivative of the formula wherein R ¹ and R ² are as defined above, depending on the composition of the solution, the ratio of each solvent component to the acid addition salt is 1.0-2.5 parts water and 0.7-1.7 parts is mixed with a water-miscible polar organic solvent and the mixture is heated, the acid addition salt of the precipitated tryptamine derivative of formula (I) wherein R ¹ and R ² is as described above is filtered and the wet salt obtained by any one of optionally washed with water or, if desired, a polar mass miscible with water After suspension in organic solvent, cooling and filtration, the solubilized solution is made alkaline with a base of greater strength than the tryptamine derivative until the tryptamine derivative is completely formed, and the pure tryptamine derivative of formula (I) wherein R ¹ and R ² has the same meaning as above -

The present invention also relates to a process for the purification of tryptamine derivatives of formula I wherein R 'is hydrogen or C 1-4 alkoxy and R ² is hydrogen by

(a) a crude tryptamine derivative of formula (I) wherein R ¹ and R ² are as defined above, in an amount of 0.8 to 1.2 parts by weight of water-miscible polar organic solvent and optionally 0.2 to 0.4 parts by weight of water-miscible dipolar aprotic in an organic solvent and then added with 1.0 to 1.1 molar equivalents of an acid aqueous solution of 20 to 80% by weight is added, the mixture hfltjíik, the precipitated tryptamine of formula (I) derivative - wherein R ¹ and R ² are as defined above Filtering its acid addition salt, or

(b) in a known reaction mixture of a tryptamine derivative of formula (I) wherein R ¹ and R ² are as defined above, from a phenylhydrazine derivative and a gamma-halobutyraldehyde derivative, after separation of the various phases,. The tryptamine derivative of formula (I) wherein R ¹ and lv are as defined above, in the phase containing the acid addition salt, depending on the composition of the solution, the ratio of each solvent component to the acid addition salt is from 1.0 to 3.0 parts water.

0.7 to 1.7 parts of water is miscible polar organic solvent, followed by cooling, the precipitated tryptamine of formula (I) derivative - wherein R ¹ and R ² are as defined above - the acid addition salt is filtered, and a) and b) the wet salt obtained by any of the processes is optionally washed in any order with water and / or water, or, if desired, a part by weight, covered with the above water miscible polar organic solvent. After suspension in water-miscible polar organic solvent, cooling and filtration, the solubilized solution is solubilized in water with a base of greater potency than the tryptamine derivative until the complete tryptamine derivative is obtained. R ¹ and R ² are as defined above by filtration.

It has been found that by slightly increasing the amount of water in the solvent mixture in process b), precipitation of the inorganic salts present in the process and further contaminated during the industrial production of tryptamine can be avoided.

In the compound of formula (I), R 11 is a linear or branched alkoxy group having from ^{1 to} 4 carbon atoms such as methoxy, ethoxy, η-propoxy, i-propoxy, η-butoxy, sec-butoxy, may represent tert-butoxy groups.

Tryptamine and aromatic-substituted derivatives thereof are important intermediates in the synthesis of several pharmaceutically active agents, such as vincamine, apovinic acid ethyl ester (Cavinton ^K ) and many other biologically active indolase compounds. The purity of the tryptamine used and its derivatives has a decisive influence on the degree of synthesis of the indole alkaloids.

Several methods are known for the preparation and subsequent purification of tryptamine and its derivatives. In one group of processes, retrofits are made to the existing indole backbone, leading to the formation of triptanyn.

Thus, 7.411.873. s. U.S. Patent No. 1,230,494 to Tryptophan in the presence of diphenylmethane at high temperature. s. According to French Patent No. 4,600,127, tryptamine is also produced from tryptophan by heating Schiff base. No. 807,806. s. In the British patent, tryptamine is prepared by reduction of 3 - [(tert-vinyl) indole with lithium aluminum hydride.

In each of the above processes, the resulting tryptamine is converted to an hydrochloric acid salt in aqueous solution, from which the organic phase is separated to give the product as the hydrochloride salt by evaporation to dryness of the strongly acidic (pH <1) aqueous phase. The resulting tryptamine chlorohydrate is of poor quality and does not exceed 95% of the active ingredient content, which can be explained by the fact that in some of the above processes the weakly basic impurities are dissolved in the strongly acidic solution and concentrated by evaporation to contaminate the final product. and the product is damaged in the process by both acidic and basic effects.

Another set of methods for the production of tryptamine is the formation of the indpl skeleton by the so-called Fischer synthesis, and sometimes directly tryptamine. For example, Doc. Nauk. Sz.Sz.Sz.R. 1967 1 76 No. 3583; The tryptamine can be prepared directly by heating the phenyl lydrazone of γ-chlorobutyraldehyde as described in the article. However, the resulting product contains so much tar dye that it can be isolated only by fractional distillation of tryptamine at a pressure of 0.67 mbar at a pressure of 0.67 mbar, which is heavy, energy-consuming and wasteful.

Purification of tryptamine and its derivatives is disclosed in U.S. Pat. s. U.S. Patent No. 4,600,198, which evaporates the acidic reaction mixture obtained by various preparation processes to dryness and triturates crude tryptamine hydrochloride containing impurities in the reaction mixture with an aqueous solution of the solution or aqueous phase separated from the reaction mixture with alkali 7.6 and 8, 2, then extracted with chloroform. During the process, the neutral and slightly basic impurities enter the chloroform phase and the tryptamine hydrochloride remains in the aqueous phase, from which the almost over-colored tryptamine base can be separated by strong alkalization.

The material obtained in the purification process, based on titration with glacial acetic acid, contained 98.5% tryptamine. The disadvantage of this purification process, however, is that the by-products of the reaction, which have a base proximity very close to tryptamine, behave in the same manner as tryptamine and thus impure the final product by thin-layer chromatography or densitometry. However, the determination of the tryptic acid content of glacial acetic acid, in addition to tryptamine, also measures these analogs with a near base tryptamine concentration, so that although the tryptamine content is 98.5%, this purification method does not at any stage produce the 'zis.

To sum up, a common feature of various processes for the preparation of tryptamine and its derivatives is that they produce large amounts of tar, neutral, poorly or basic alkaline impurities very close to tryptamine, some of which only result in high material losses and / or complex solvent utilization however, contaminants with bases very close to tryptamine can be eliminated.

In our experiments, we have surprisingly discovered that crude tryptamine derivatives containing very close bases of tryptamine derivatives can be effectively purified by mixing the crude tryptamine derivatives or their acid addition salts in a suitable amount of water and a water-miscible polar organic solvent. If appropriate, a suitable amount of water miscible dipolar aprotic solvent is added, dissolved, and optionally an appropriate amount of acid added. At this point, the acid addition salt of the tryptamine derivative will be liberated from the solution upon cooling, while the impurities or their salts will remain substantially in solution. Depending on the purity of the product obtained, further purification steps, such as suspension, cooling, filtration and clarification of the above water miscible polar solvent, may be performed if desired. From the pure acid addition salt thus obtained, the corresponding tryptamine derivative can be liberated by treatment with a strong base. This highly pure tryptamine derivative can be used without difficulty in further syntheses of vincamine and apovincinic acid esters, which require high purity starting materials.

The crude tryptamine derivative is dissolved in a water-miscible polar solvent, optionally containing a water-miscible dipolar aprotic solvent, preferably at 50-60 ° C, and the resulting suspensions are preferably cooled to 0 to -10 ° C.

The water-miscible polar organic solvent used in the purification process of the invention is a straight or branched chain alkanol having from 1 to 3 carbon atoms, such as methanol, ethanol, isopropanol and the like.

If desired, acetonitrile is preferably used as a water miscible dipolar organic solvent.

The acid addition salt of the tryptamine derivative (1) obtained in the purification process of the present invention can be purified, for example, with cellulite, ahunium oxide, preferably activated carbon. In the latter case, the salt is preferably dissolved in 15-20 times of water, preferably 50 to 60 ° C, using 0.01 to 0.05 parts by weight of activated carbon, preferably 0.03 to 0.04 parts by weight.

Suspension in a water-miscible polar organic solvent, if desired, is preferably carried out at 45-55 ° C.

The strong acid base can be liberated from the pure acid addition salt by using a strong base such as an alkali metal or alkaline earth metal hydroxide or an aqueous solution thereof, or an organic base having the same basic strength as guanidine and its substituted derivatives.

The purification process of the present invention is suitable for the purification of any tryptamine derivative of the formula (I) which is neutral, weakly alkaline and contaminated with chemicals that are close to the tryptamine base, and for the purification of all trtamine derivatives of the general formula As a last step in the isolation process, which is otherwise neutral in nature, weakly alkaline or tryptamine base, the process can be eliminated in the production process.

The significance of the purification process of the present invention is that its use achieves a significant purification which was not achieved by the known production methods or by the purification methods known to date. This significant purification is due to the discovery that the acid addition salt of the tryptamine derivative (I) is formed in a solvent mixture which is neutral in nature to any weakly basic or very close base to the tryptamine derivative in any of the processes for and the acid addition salts thereof are soluble, while the acid addition salts of the tryptamine derivatives of general formula (I) are practically free from the solvent mixture used in pure form. This precipitation may also be facilitated by the fact that the reaction mixture has a very concentrated and salting effect during the purification process of the invention. Further purification can be achieved in the purification process of the invention, if necessary, by suspending the acid addition salt obtained by the purification process with a water-miscible polar organic solvent, then filtering or, if necessary, dissolving it in water and preferably purifying it with activated carbon. wherein the acid addition salt of the resulting tryptamine derivative (I) is liberated in an aqueous-alkaline medium.

The advantage of the purification process according to the invention over the purification methods known to date is that it is extremely easy and simple to implement in the industry. The known processes, on the one hand, use a large amount of solvent for extraction, the regeneration of which is a separate energy-intensive process, and the temperature used during the reaction to evaporate the aqueous phases to dryness and contaminant degradation of the final product. and a difficult process to implement, it requires great care. In contrast, the solvent utilization of the purification process according to the invention is very low, the individual operations are very simple, they do not use any significant energy, eliminate thermal damage and result in a highly pure product having purity impurities with very close basicity can be removed, exceeding the tryptamine derivative of the formula I prepared or purified so far, as a white crystalline material having a content of 99,591 by titration with glacial acetic acid and by thin layer chromatography densitometry.

The by-product tryptamine produced by the purification process of the present invention, having a basicity very close to tryptane, has a very significant advantage over the tryptamine produced by the previous processes. So far, with the further synthetic use of tryptamine, due to their similar chemical properties, impurities with a basicity very close to tryptamine have reacted and resulted in mostly tar-like substances which contaminate the end product. Even at low concentrations, they made certain operations (such as phase separation) or reactions (such as Michael type addition) impossible. Since tryptamine can be used as a synthesis agent in the synthesis of ebuman skeletal compounds, it is essential that this higher degree of purity achieved by the process of the present invention affects the production of the next key intermediate in the synthesis. In our studies, we obtained the methoxycarbonyl-ethylhexahydro-indolequinolizln derivative of tryptamine from 4-step synthesis of tryptamine from alpha-ethyl-delta-valerolactone followed by phosphorus oxychloride, basic treatment and acrylic acid methyl ester. prepared from the tryptamine produced by the purification process of the present invention, the overall yield of the 4-step synthesis is 5-11% higher than that of the tryptamine obtained by the purification process known hitherto (Hungarian Patent No. 178,708). This is of great economic importance, in particular for the production of useful therapeutic end product (s).

The purification process of the present invention is illustrated in more detail by the following non-limiting examples.

Example 1 Tryptamine

Dissolve 10.0 g of crude contaminated tryptamine (95% by weight in tryptamine), 8.0 g of ethanol and 2.0 g of acetonitrile at 50-55 ° C and keep this solution under water-cooling at this temperature. while adding a molar equivalent of concentrated aqueous hydrochloric acid (about 5.4 mL of a 36% aqueous hydrochloric acid solution). The crystalline precipitation is already started during the addition. After the addition of hydrochloric acid, the suspension containing solid tryptamine hydrochloride was cooled to -5 ° C and filtered cold. The resulting crystals were washed twice with 1 mL of cold ethanol.

The crystals obtained in the above manner were dissolved in 150 ml of water in a wet moist, clarified with activated carbon (0.4 g), and the clarified solution was made basic to pH 14 with 40% aqueous sodium hydroxide. The off-white, white crystalline tryptamine base is dried and dried at max.

Thus 7.6 g of tryptamine are obtained.

Yield: 80% (based on tryptamine starting material). Melting point: 116-119 ° C. Tryptamine content: min. 99.5% (by thin layer chromatography, densitometry and titration with glacial acetic acid).

Example 2 Tryptamine

All of the procedures of Example 1 were followed except that acetonitrile was not used to dissolve the nyrps material.

7.6 g of tryptamine are obtained.

Yield: 80% (based on tryptamine tartrate starting material). Melting point: 116-119 ° C.

The resulting material has a tryptamine content of min. 99.0% (by TLC by densitometry and titration with glacial acetic acid).

Example 3 Tryptamine

The reaction mixture containing tryptamine is described in Doc. Oh Nauk. No. No. R. 1976 176 No. 3, 583, is prepared as follows.

10.8 g (0.1 mol) of phenylhydrazine were dissolved in 30 ml of t-butanol was added at room temperature 10.7 g (0.1 mole) and 30 ml of freshly fractionated squares ^- diluted with butanol-chloro-gamma butiraldelúdet was added. After standing for 20 minutes, the reaction mixture was quenched with 90% methanol (250 mL) and heated at reflux for 20 hours. The solvent mixture was removed by distillation in vacuo, the residue was dissolved in methanol (25 ml) and water (25 ml), cooled to -5 ° C and filtered.

The crystals thus obtained are dissolved in 180 ml of water in a wet moist, clarified with activated carbon (0.5 g) and basified to pH 14 with 40% aqueous sodium hydroxide solution. The precipitated white crystalline tryptamine base is filtered off and dried at a maximum of 60 ° C.

12.0 g of tryptarnine are thus obtained.

Yield: 75%. Melting point: 116-119 ° C.

Content of tryptine: min. 99.0% (by thin layer chromatography, densitometry and titration with glacial acetic acid).

Example 4 Tryptamine

All the procedures described in Example 3 were followed except that the nucleus wet crystals obtained after dissolving and cooling the methanolic alcohol in water were suspended in 12 g of ethyl alcohol before heating to 50 ° C for 15 minutes at this temperature. then cooled to -5 ° C, giving birth.

The resulting wet wet crystals were subjected to the clarification described in Example 3.

11.2 g of tryptarnine are thus obtained.

Yield: 70%. Melting point: 117-119 ° C.

Content of tryptamine: min. 99.5% (thin layer chromatography by densitometry and titration with glacial acetic acid).

Example 5

5-Methoxy-triptanrín

Dissolve 13.8 g (0.1 mol) of 4-methoxyphenylhydra7, int in 30 ml of tert-butanol and add 10.7 g (0.1 mol) of freshly fractionated and diluted with 30 ml of tertiary butanol, We are added. After stirring for a few minutes, 250 ml of 90% w / w methanol was added to the reaction mixture and the mixture was refluxed for 20 hours. The solvent mixture was then removed by distillation in vacuo, the residue was dissolved in 25 ml of ethyl alcohol and 25 ml of water, then cooled to -5 ° C and filtered.

The crystals thus obtained were dissolved in 150 ml of water in a wet moist, clarified with activated carbon (0.4 g) and basified to pH 14 with 40% w / w aqueous sodium hydroxide. The precipitated white crystalline base of 5-methoxy-tryptamine is filtered off and dried at a maximum of 60 ° C.

9.1 g of 5-methoxy-tryptarnine are prepared in ecl ·

Yield: 48%, m.p. 119-120 ° C.

Volume content: min. 99.0% (by TLC by densitometry and titration with glacial acetic acid).

Example 6 Tryptamine

All were carried out as in Example 3, except that the aqueous phase was basified with calcium oxide to pH = 13. The precipitated white crystalline tryptamine base is filtered off, washed with 50 ml of cold water and dried at a maximum of 60 ° C.

12.0 g of tryptarnine are thus obtained.

Yield: 75%. Melting point; 116-119 ° C.

The substance contains tryptamine: min. 99.0% (by thin layer chromatography from densitometry and titrated with glacial acetic acid)

Example 7 Tryptamine

All were carried out as in Example 3, except that the aqueous phase was basified by the introduction of ammonia gas until complete removal of the tryptamine. The precipitated white crystalline tryptamine base is filtered off and dried at a maximum of 60 ° C.

12.0 g of tryptarnine are thus obtained.

Yield: 75%. Melting point: 116-119 ° C.

The substance contains tryptamine: min. 99.07 '(TLC by densitometry and titration with glacial acetic acid).

Example 8 Tryptamine

All were carried out as in Example 3, except that the aqueous phase was basified with guanidine until complete removal of the tryptamine. The precipitated white crystalline tryptamine base is filtered off, washed with ethyl alcohol and then washed with water, dried to a maximum of 60 ° C.

12.0 g of tryptarnine are thus obtained.

Yield: 757 «. Melting point: 116-119 ° C.

The substance contains tryptamine: min. 99,077 (TLC determination by TLC, titration with ¹ Al and glacial acetic acid).

Example 9 Tryptamine

Phenylhydrazine (10.8 g, 0.1 N) was dissolved in toluene (30 mL) and a toluene solution (ca. 40) obtained by hydrogenation of gamma-dichlorobutyraldehyde chloride (10.7 g, 0.1 mol) at room temperature. ml) was added dropwise. After standing for 1 hour, 90 ml of 50% aqueous methanol are added to the reaction mixture and the mixture is refluxed for 10 hours. The reaction mixture is cooled to 25 ° C and the organic phase and aqueous phase are separated. The aqueous fist was removed by vacuum distillation of 30 mL, ca. 70% MeOH, and the resulting solution (1.5 parts methanol, 2.6 parts water) was cooled to -5 ° C and filtered. The resulting crystals were washed with 5 mL of water at 0 ° C, washed with slurry in ethyl alcohol and swallowed with tryptamine base as in Example 3.

11.0 g of tryptarnine are thus obtained.

Yield: 68.8%. Melting point: 116-119 ° C.

Claims (10)

PATENT CLAIMS 1. A method (I) of tryptamine derivatives of formula - wherein R ^r is lúdrogénatom or C1 -C4 alkoxy radical, and R ² represents hydrogen - for cleaning, characterized in that a) a crude tryptamine derivative of the Formula I wherein R ¹ and R ² are as defined above, in an amount of 0.8 to 1.2 parts by weight of water-miscible polar organic solvent and optionally 0.2 to 0.4 parts by weight of water-miscible dipolar in an aprotic organic solvent, an aqueous solution of 1.0 to 1.1 molar equivalents of acid, 20 to 80% by weight, is added and the mixture is cooled to give the tryptamine derivative of formula (I) wherein R ¹ and R ² are above - an acid addition salt is obtained, washed with a mixture of the above water and polar organic solvent, or b) a tryptamine derivative of the formula I in which K ¹ and R ² are prepared in a known reaction from the above-phenyl-lydrazine derivative and gamma-halobutyraldehyde derivative, after separation of the various phases, in the phase comprising the acid addition salt of a tryptamine derivative wherein R ¹ and R ² are as defined above, the ratio of each solvent component to 1.0 to 2.5 parts by weight of water and 0.7 to 1.7 parts by weight, depending on the composition of the solution is immiscible polar organic solvent, followed by cooling the tryptamine formula precipitated (S) derivatives of - which the above R ¹ and R ² is wherein - the acid addition salt is filtered, and the a) and b) methods employing either optionally wet salt wash with water or, if desired, a part by weight of water miscible polar after suspending in an organic solvent, cooling and sz.űrés water dissolved, clarified, the clarified solution was basified complete separates the tryptamine derivative of a higher derivative are tryptamine base strength of a base and the resulting clear (I) tryptamine formula derivative is - wherein R ¹ and R ² is as defined above by filtration. (Priority: June 12, 1986) 2. A process for the purification of a tryptamine derivative of the Formula I wherein R ¹ is hydrogen or C 1 -C 4 alkoxy and R ² is hydrogen. a) a crude tryptamine derivative of the Formula I wherein R * and R ² are as defined above in a 0.8 to 1.2 parts by weight water-miscible polar organic solvent and optionally 0.2 to 0.4 parts water-miscible in a dipolar aprotic organic solvent, a solution of 1.0 to 1.1 molar equivalents of acid in 20% to 80% by weight of an aqueous solution is added. cooling the mixture by filtration of the acid addition salt of the precipitated tryptamine derivative of formula (I) wherein R ¹ and R ² are as defined above, or (b) the. A tryptamine derivative of the formula (I) wherein R ¹ and R ^{2 in} the reaction mixture obtained above from the phenyl-lydrazine derivative and the gamma-halobutyraldehyde derivative, after separation of the various phases, wherein R ¹ and R ² are as defined above, depending on the composition of the solution in the phase containing the acid addition salt, the ratio of each solvent component to 1.0 to 3.0 parts by weight of water and 0.7 to 1.7 parts by weight of water-miscible polar organic prepared solvent, and the mixture was cooled, tryptamine formula precipitated (I) derivative - wherein R ¹ and R ² are as defined above - an acid addition salt thereof szíhj uk, and the resulting wet salt of any of a) and b) methods, if desired, in any order wash with water-miscible polar organic solvent above and / or washed with water or, if desired, after suspension, cooling and filtration in a pellet of water, dissolved in water, clarified, the clarified solution is made alkaline with a base of greater than tripta.uin until complete separation of the tryptamine derivative. ki'dlt derivative of the tryptamine derivative of formula (I) wherein R 'and R ² are isolated by the above filtration. (Őbb Seniority: 10/28/1988) 3. A process according to claim 1 wherein the water-miscible polar organic solvent is a straight or branched alkanol having from 1 to 3 carbon atoms. (Priority: June 12, 1986) A process according to claim 1 wherein the water miscible dipolar aprotic solvent is acetonitrile. (Priority: June 12, 1986) 5. A process according to claim 1, wherein the purification is carried out with activated carbon. (Priority: June 12, 1986) 6. A process according to claim 1, wherein the base is selected from the group consisting of alkali metal or alkyl alkaline earth hydroxide and aqueous solutions thereof, ammonia gas or guanidine. (Priority: June 12, 1986) 7. The process of claim 2 wherein the water-miscible polar organic solvent is a straight or branched alkanol having 1 to 3 carbon atoms. (dated 10/27/1988) The process of claim 2 wherein the water miscible dipolar aprotic solvent is acetonitrile. (Priority: 10/28/1988) 9. A process according to claim 2, wherein the clarification is carried out with activated carbon. (Priority: 10/28/1988) 10. The process according to claim 2, wherein the base is an alkali metal or alkaline earth metal hydroxide or an aqueous solution thereof, mnonium gas or guanidine.