Method for preparing 5-aminolevulinic acid alkyl ester hydrochlorides

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention proposes a method for preparing 5-aminolevulinic acid (ALA) alkyl esters and their hydrochlorides. Method for preparing ALA alkyl ester hydrochlorides involves the esterification reaction of ALA hydrochloride with primary or secondary (C1-C6)-alcohols in the presence of a heterogenous acid catalyst wherein cation-exchange resins in H+-form can be used as a catalyst with their preliminary dehydration by thermal treatment or azeotropic distillation off. Invention provides preparing indicated compounds by development of ecologically safe, technologically effective and economy method. ALA alkyl esters are used in fluorescent diagnosis and photodynamic therapy of malignant tumors of different localization and in treatment of cutaneous diseases of nontumor nature.

EFFECT: improved preparing method.

7 ex

 

The invention relates to a method for alilovic esters of 5-aminolevulinic (5-amino-4-oxopentanoate) acid in the form of their hydrochloride General formula HCl×H2NCH2COCH2CH2CO2R, where R is a primary or secondary alkyl radical C1-C6.

Esters of 5-aminolevulinic acid (ALA), which, as the hydrochloride ALA, the source of the biosynthesis of porphyrins, including fluorescent protoporphyrin IX (PP IX), in recent years more and more used in fluorescence diagnosis and photodynamic therapy of malignant tumors and some non-neoplastic skin diseases (K. Berg. Comprehensive Series in Photosciences, 2002, 2 (Photodynamic Therapy and Fluorescence Diagnosis in Dermatology), 115-162). In addition, the ALA esters can be used as plant growth regulators, herbicides, etc. [H.Takeya, JP 0409360 (1992); Chem.Abstr., 1992, v. 116, 189633 m].

Methyl ester of ALA was obtained with a yield of 81% esterification ALA methyl alcohol in the presence of excess chloride tiomila in [Zavialov SR, Zavozin A.G. Izv. An SSSR, Ser. Chemical, 1987, No. 8, str-1798], selected as a prototype. This same method has also been obtained with yields of 60-70% linear alkalemia esters (ethyl to oktilovom) ALA [Kloek j, Beijersbergen van Henegouwen G.M., Photochem. Photobiol., 1996, 64, 994-1000]. Despite the effectiveness of this method, the use of significant amounts of toxic chloride thionyl which is a significant disadvantage.

The present invention is to develop a technologically advanced, safe and economical method of producing esters of ALA. The problem is solved in that the esterification is carried out in the presence of a heterogeneous acid catalysts, which were selected cation-exchange resin Amberlyst-15 or KU-2/8 emergencies, representing the sulfonated copolymers of styrene and divinylbenzene, N+-form. The problem is solved also by the fact that the used cation exchange resin were additionally subjected to dehydration by drying at 100-120°With vacuum or by azeotropic distillation of water in toluene. The application of the classical esterification with alcohols in the presence of a strong inorganic or organic acids as catalysts in the case of ALA is unacceptable due to possible replacement of the chloride anion to balance the other acid.

For the esterification were chosen as a linear primary alcohols (methanol, ethanol, hexanol)and branched secondary alcohol (isopropanol). The esterification was performed by heating in excess of the corresponding alcohol by the end of the reaction the catalyst was filtered, the solvent is kept off, the residue was treated with acetone, the precipitated ester was filtered and dried.

We have shown that the heating of ALA hydrochloride and the above alcohols with Amberlyst-15 or KU-2/8 emergencies, leads to the formation of the corresponding ester of ALA with outputs from very high to moderate.

Etherification with methanol in the presence of dehydrated cation-exchange resin Amberlyst-15 or KU-2/8 emergency yields a hydrochloride of the methyl ester of ALA with the release of 91% and 89%, respectively. The impurity source neeterificirovannah ALA in the product, which was determined by high performance liquid chromatography (HPLC), is 0.1-0.2%. Methyl ester obtained for comparison with the use of chloride tiomila method-prototype contained the same amount of impurities ALA.

When using a cation exchange resin, air-dried in the usual manner without dehydration, the impurity content of ALA in the methyl ether was increased to 1-2%, due to the reversibility of the esterification reaction in the presence of water.

Cation-exchange resins may be used repeatedly without appreciable reduction of the yield of products of the esterification.

The proposed method is illustrated by the following examples.

Example 1. A mixture of 7 g of resin Amberlyst-15 (or resin KU-2/8 es) and 50 ml of 15% hydrochloric acid was stirred for 5 hours. The precipitate was filtered, washed with water, then acetone, and dried in air at room temperature until constant weight, after which it was heated for 8 hours at 110-120°and a residual pressure of 100-150 mm Hg, cooled is kept above pjatiokisi phosphorus.

In the solution 16.76 g (0.1 mol) of the hydrochloride of 5-aminolevulinic acid in 160 ml of methanol was introduced 3 g of resin Amberlyst 15, heat-treated as above, and heated under stirring for 2 hours at 60°C. Then the catalyst was filtered, washed with methanol and the filtrates were combined, the solvent was evaporated on a rotary evaporator, the residue was treated with acetone, filtered, dried and got 16.56 g (91%) of the hydrochloride of the methyl ester of ALA, so pl. 119-121°C. the Sample is mixed with the sample obtained by the method-prototype (example 4), gives no depression of the melting temperature; their performance and IR spectra are identical. Found, %: C 39.60, H 6.57, N 7.78, C1 19.46. With6H12ClNO3. Calculated, %: 39.68, H 6.66, N 7.71, C1 19.52. According to HPLC, the sample contains 0.1% of the original hydrochloride ALA.

Example 2. Methyl ester of ALA was obtained analogously to example 1, but was used as the catalyst resin KU-2/8 emergencies, thermally processed as described in example 1. Got 16.11 g (89%) of the hydrochloride of the methyl ester of ALA, so pl. 120-121°C. Found, %: C at 39.64, H 6.71, N 7.79, C1 19.56. With6H12ClNO3. Calculated, %: 39.68, H 6.66, N 7.71, C1 19.52. According to HPLC, the sample contained 0.2% of the original ALA.

Example 3. Sample resin Amberlyst-15 (or resin KU-2/8 es), air-dried, boiled in toluene with a nozzle Dean-stark ending the division of the Oia moisture, was filtered, dried at 70°and a residual pressure of 100 to 150 mm Hg, then cooled and kept on pjatiokisi phosphorus.

Methyl ester of ALA was obtained analogously to example 1, but was used as the catalyst resin Amberlyst 15, processed azeotropic distillation as described above. Received 16.25 g (90%) of the hydrochloride of the methyl ester of ALA, so pl. 120-121°C. Found, %: C at 39.64, H 6.63, N 7.65, Cl 19.58. With6H12ClNO3. Calculated, %: 39.68, H 6.66, N 7.71, Cl 19.52. According to HPLC, the sample contains 0.1% of the original ALA.

Example 4. Obtain hydrochloride of the methyl ester of ALA by the method prototype To 120 ml of methanol was slowly pinned under stirring to 40 ml of chloride tonila, made 16.76 g (0.1 mol) of the hydrochloride of 5-aminolevulinic acid and heated for 5 hours at 50°C. Then the solvent and excess chloride thionyl was evaporated on a rotary evaporator, the residue was treated with acetone, filtered, dried and got 14.89 g (82%) of the hydrochloride of the methyl ester of ALA, so pl. 120-121°C. Found, %: C 39.75, H 6.62, N 7.65, Cl 19.39. With6H12ClNO3. Calculated, %: 39.68, H 6.66, N 7.71, Cl 19.52. According to HPLC, the sample contains 0.1% of the original neeterificirovannah ALA.

Example 5. Methyl ester of ALA was obtained analogously to example 1 using as the catalyst sample resin Amberlyst-15 (or resin KU-2/8 es), processing the aqueous and air-dried, but without further dehydration. Got 16.03 g (88%) of the hydrochloride of the methyl ester of ALA, so pl. 119-121°C. Found, %: C 39.60, H 6.57, N 7.78, Cl 19.46. With6H12ClNO3. Calculated, %: 39.68, H 6.66, N 7.71, Cl 19.52. According to HPLC, the sample is contained 1.7% of the original ALA.

Example 6. Methyl ester of ALA was obtained analogously to example 1, but using as the catalyst sample resin KU-2/8 es), processed and dried in the air, but without additional dehydration. Got 15.62 g (86%) of the methyl ester of ALA, so pl. 119-121°C. Found, %: 39.65, H 6.52, N 7.81, Cl 19.55. C6H12ClNO3. Calculated, %: 39.68, H 6.66, N 7.71, Cl 19.52. According to HPLC, the sample is contained 2.0% of the original ALA.

Example 7. Ethyl ester of ALA was obtained analogously to example 1, but the solvent used is anhydrous ethanol and heated for 5 hours. Got 14.34 g (73%) of ethyl ester of ALA, so pl. 110-112°C. Found, %: C at 42.68, H 7.15, N 7.29, Cl 18.35. With7H14ClNO3. Calculated, %: 42.97, H 7.21, N 7.16, Cl 18.12.

Example 8. Hexyl ALA ester was obtained analogously to example 1, but the solvent used is anhydrous hexanol, downloaded 6 g of catalyst and heated for 12 hours. Got 15.48 g (62%) hexyl ester of ALA, so pl. 98-100°C. Found, %: C 52.08. N 8,35, N 5.69, C1 14.43. C11C22ClNO3. Calculated, %: C 52.48, N 8.81, N 5.56, Cl 14.08.

Example 9. Isopr pillowy ether ALA was obtained analogously to example 1, but as solvent used anhydrous isopropanol and heated for 7 hours. Got 10.06 g (48%) of isopropyl ester of ALA, so pl. 115-119°C. an NMR Spectrum -1N (ppm): 1.98 (6N, 2CH3), 4.42 (2H, CH2), 6.0 (3H, NH3+), 6.21 (2H, CH2), 6.32 (2H, CH2), 7.35 (1H, CH). Found, %: C 52.08, H 8,35, N 5.69, Cl 14.43. C8H16ClNO3. Calculated, %: 45.83, H 7.69, N 6.68, Cl 16.91.

Thus, we offer technologically advanced and cost-effective way of obtaining hydrochloride alilovic esters of 5-aminolevulinic acid, do not use toxic chemicals.

1. The method of producing hydrochloride alilovic esters of 5-aminolevulinic acid esterification of the hydrochloride of 5-aminolevulinic acid, primary or secondary alcohols, characterized in that the esterification is carried out in the presence of cation exchange resins in the H+form.

2. The method according to claim 1, characterized in that the cation exchange resin previously subjected to dehydration by heat or azeotropic processing.



 

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22
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Electrodialyzer // 2050176
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FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing the synthetic 5-aminolevulinic (5-amino-4-oxopentanoic) acid hydrochloride (5-ALA) representing an endogenous substance (metabolite). Method for preparing 5-ALA involves electrochemical reduction of 5-nitrolevulinic acid methyl ester in acid aqueous medium on graphite cathode at temperature 60-75°C and the current density value 2-10 A/dm2. 5-ALA can be used in medicine for photodiagnosis and photodynamic therapy of malignant tumors of different localization and for treatment of diseases of non-tumor nature also. Invention provides simplifying technology of synthesis of 5-ALA, improved economy indices and provides ecological safety of the process.

EFFECT: improved preparing method.

4 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention proposes a method for preparing 5-aminolevulinic acid (ALA) alkyl esters and their hydrochlorides. Method for preparing ALA alkyl ester hydrochlorides involves the esterification reaction of ALA hydrochloride with primary or secondary (C1-C6)-alcohols in the presence of a heterogenous acid catalyst wherein cation-exchange resins in H+-form can be used as a catalyst with their preliminary dehydration by thermal treatment or azeotropic distillation off. Invention provides preparing indicated compounds by development of ecologically safe, technologically effective and economy method. ALA alkyl esters are used in fluorescent diagnosis and photodynamic therapy of malignant tumors of different localization and in treatment of cutaneous diseases of nontumor nature.

EFFECT: improved preparing method.

7 ex

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