CN110872293A - Chemical synthesis and purification method of biopterin - Google Patents
Chemical synthesis and purification method of biopterin Download PDFInfo
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Abstract
The invention provides a method for synthesizing and purifying sapropterin hydrochloride, which takes diacetylbiopterin as a raw material, hydrolyzes under alkaline conditions, obtains a crude sapropterin product after extraction, hydrogenation and acid adjustment, and obtains a refined sapropterin product after recrystallization of a mixed solution. The preparation method of sapropterin hydrochloride provided by the invention has the advantages of short hydrolysis reaction time, simple and efficient post-treatment and high purity of the obtained biopterin aqueous solution. The solvent used by the method is environment-friendly, short in production period and low in cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a chemical synthesis and purification method, and particularly relates to a chemical synthesis and purification method of biopterin.
Background
Sapropterin hydrochloride is an artificially synthesized Tetrahydrobiopterin (BH 4) with the chemical name of (6R) -2-amino-6 [ (1R,2S) -1, 2-dihydroxypropyl ] -5,6,7, 8-tetrahydro-4 (H) -pteridine dihydrochloride, and the chemical structural formula is shown in formula I:
I
sapropterin is a cofactor of Phenylalanine hydroxylase (PAH) in human body, and can be used as replacement therapy for BH 4-responsive Phenylketonuria (PKU) in children over 4 years old and adults.
Various synthetic methods of sapropterin are reported in documents, including CN101792445, CN102627644, CN101959891, CN102633799, EP0191335, WO2006120176, WO2007072911 and the like. Wherein, CN101959891 provides an improved synthetic method of sapropterin. According to the method, in a biphase mixed solution containing an aqueous phase and an organic phase, under an alkaline condition, the diester group of diacetylbiopterin (shown as a formula II) is hydrolyzed to generate biopterin (shown as a formula III), and the biopterin is subjected to catalytic hydrogenation by a platinum catalyst under a high hydrogen pressure of 1.4-10MPa to form salt, so that the sapropterin hydrochloride is obtained.
In the method, hydrolysis reaction is carried out in a two-phase mixed solution, the reaction solution needs to be stirred overnight, so that the two phases are fully separated, and the hydrolysis step takes too long time; secondly, in the hydrogenation step, the applied hydrogen pressure is higher, and the requirements on the material and pressure resistance of the hydrogenation reactor are higher. The biphase hydrolysis reaction system enables the post-treatment of the reaction liquid to become one of the rate-limiting steps in the production of the sapropterin hydrochloride, and the production period is prolonged, so that the production cost of the raw material medicine is increased. In addition, the higher hydrogenation pressure causes a greater safety hazard in the hydrogenation step. Therefore, it is necessary to develop a more economical and safer method for synthesizing sapropterin hydrochloride.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to solve the technical problem of how to optimize the process and the parameters for preparing the sapropterin hydrochloride by the diacetylbiopterin one-pot method, simplify the post-treatment method, shorten the production period and further save the production cost. In order to solve the technical problems, the invention creatively adopts a single alkaline aqueous solution to hydrolyze diacetylbiopterin, then directly extracts and separates to obtain the biopterin-containing aqueous solution, and the biopterin-containing aqueous solution directly participates in the next hydrogenation reaction. In addition, in the refining and purifying process, the crude sapropterin hydrochloride product is recrystallized by adopting an acid mixed solution system, so that a final product with the purity of more than 99.9 percent can be obtained.
The invention relates to a preparation method of sapropterin hydrochloride, which has the advantages of short production period, simple operation and safety. According to the method, diacetylbiopterin is subjected to hydrolysis reaction in a single alkaline aqueous phase for no more than 2 hours, extracted for 1-3 times to obtain a biopterin-containing aqueous solution, then subjected to catalytic hydrogenation under the hydrogen pressure of no more than 1.2Mpa to generate sapropterin, added with concentrated hydrochloric acid to form salt, filtered and dried to obtain a sapropterin hydrochloride crude product, and subjected to recrystallization and refining by using an acidic mixed solvent to obtain a sapropterin hydrochloride refined product with the purity of over 99.9 percent. The invention has the other beneficial effects that the provided technical scheme has low requirement on the purity of the reaction starting material (namely diacetylbiopterin), and even if the diacetylbiopterin has the purity of only 50 percent, the biopterin aqueous solution with the purity of more than 95 percent can be obtained after hydrolysis and extraction, and the biopterin aqueous solution is used for preparing qualified sapropterin hydrochloride.
The technical scheme provided by the invention is as follows:
a preparation method of sapropterin hydrochloride comprises the following steps:
(1) weighing a proper amount of diacetylbiopterin at room temperature (25 +/-5 ℃), adding water, stirring, adjusting the pH value of the reaction solution by using an alkaline reagent to keep the pH value between 10.5 and 11.5, and reacting for 30 to 90 min;
the purity of the diacetylbiopterin is more than 50%;
the mass-volume ratio (w/v) of the diacetylbiopterin to water is (1: 100) - (1: 5);
preferably, the mass-to-volume ratio (w/v) of diacetylbiopterin to water is (1: 50) - (1: 10);
more preferably, the mass-to-volume ratio (w/v) of diacetylbiopterin to water is (1: 30) - (1: 10);
the alkali reagent is selected from one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia water, methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, piperidine, ammonium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide and tetrabutylammonium hydroxide;
preferably, the alkali reagent is selected from one or more of potassium hydroxide, dipotassium hydrogen phosphate, tetramethyl ammonium hydroxide, tetraethyl ammonium hydroxide and tetrabutyl ammonium hydroxide;
more preferably, the alkali reagent is selected from one or more of tetramethyl ammonium hydroxide, tetraethyl ammonium hydroxide and tetrabutyl ammonium hydroxide;
(2) adding an extracting agent according to 20-60% of the volume of the reaction liquid in the step (1), stirring for 10-60 min, standing for layering for 30-60min, separating liquid, collecting an aqueous phase solution, and adjusting the pH value of the aqueous phase solution to 10.5-11.5;
preferably, the volume of the added extracting agent is 30-50% of the volume of the reaction liquid in the step (1);
more preferably, the volume of the added extracting agent is 35-45% of the volume of the reaction liquid in the step (1);
the extractant is selected from one or more of diethyl ether, ethyl acetate, butyl acetate, n-pentane, n-hexane, n-heptane, dichloromethane, chloroform, benzene, toluene, n-butanol, n-pentanol and n-hexanol;
preferably, the extractant is selected from one or more of ethyl acetate, dichloromethane, chloroform, n-butanol, n-pentanol and n-hexanol;
more preferably, the extractant is selected from one or more of ethyl acetate, dichloromethane, chloroform and n-butanol;
(3) adding the aqueous phase solution obtained in the step (2) into a hydrogenation kettle, adding a catalyst, replacing with nitrogen for three times, then, hydrogenating to 1-1.2 MPa, and reacting for 7-9 hours at room temperature (25 +/-5 ℃);
the catalyst is selected from one or more of palladium carbon, palladium hydroxide carbon, palladium alumina, platinum black, platinum carbon, platinum dioxide, platinum alumina, rhodium carbon and ruthenium carbon;
preferably, the catalyst is selected from one or more of palladium hydroxide carbon, palladium alumina, platinum dioxide and platinum alumina;
the addition amount of the catalyst is 6-9% (w/w) of the feeding amount of diacetylbiopterin;
preferably, the addition amount of the catalyst is 8% (w/w) of the charge amount of diacetylbiopterin;
(4) discharging, adding concentrated hydrochloric acid, adjusting the pH value to 1.0-1.5, adding activated carbon for decolorization, filtering, collecting filtrate, performing vacuum rotary evaporation on the dry solvent at 35 +/-5 ℃, adding an absolute ethyl alcohol-acetone mixed solution, stirring for crystallization for 30-60min, and filtering to obtain a wet sapropterin hydrochloride crude product;
the volume ratio of the absolute ethyl alcohol to the acetone in the absolute ethyl alcohol-acetone mixed solution is (1: 30) - (1: 5);
preferably, the volume ratio of the absolute ethyl alcohol to the acetone in the absolute ethyl alcohol-acetone mixed solution is 1: 10;
(5) recrystallizing the wet sapropterin hydrochloride crude product by using an acidic mixed solution system, filtering and drying to obtain a sapropterin hydrochloride refined product;
the acid mixed solution system is formed by mixing a hydrochloric acid aqueous solution and an organic solvent, wherein the organic solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran and isopropanol;
the concentration of the hydrochloric acid aqueous solution is 1-3 mol/L;
the volume ratio of the hydrochloric acid aqueous solution to the organic solvent in the acidic mixed solution is (1: 30) - (1: 5);
preferably, the volume ratio of the hydrochloric acid aqueous solution to the organic solvent in the acidic mixed solution is (1: 20) - (1: 10).
The preparation method of sapropterin hydrochloride provided by the invention has the advantages of short hydrolysis reaction time, simple and efficient post-treatment, high purity of the obtained biopterin aqueous solution, and mild hydrogenation, salification and purification under reaction conditions to obtain a high-purity final product. The solvent used by the method is environment-friendly, short in production period and low in cost, and is suitable for industrial production.
Drawings
FIG. 1 is an HPLC chromatogram for purity measurement of an aqueous biopterin solution in example 1;
FIG. 2 is an HPLC chromatogram for purity measurement of an aqueous biopterin solution in example 2;
FIG. 3 is an HPLC chromatogram for purity measurement of a purified product of sapropterin in example 5;
FIG. 4 is an HPLC chromatogram for purity measurement of a purified product of sapropterin in example 6.
Detailed Description
In order to facilitate a better understanding of the present disclosure by those skilled in the art, the applicant further describes the technical solutions of the present disclosure by the following specific examples, but the following should not limit the scope of the present disclosure claimed in the claims in any way.
Example 1
Hydrolysis of diacetylbiopterin using tetraethylammonium hydroxide
At room temperature (25. + -. 5 ℃ C.), 50g of diacetylbiopterin (50% pure) was weighed, 500mL of water was added, and tetraethylammonium hydroxide was added with stirring to adjust the pH to about 11.5, and the pH of the reaction mixture was measured every 15 to 20min at the beginning of the measurement, and was maintained at about 11.5 by adding tetraethylammonium hydroxide. The progress of the reaction is monitored by various analytical techniques known in the art (TLC or HPLC). The hydrolysis reaction proceeded for about 60min, 200ml of ethyl acetate was added, stirring was carried out for 10min, the mixture was poured into a separatory funnel, and allowed to stand for 30min, the aqueous phase and the ethyl acetate phase were separated, the aqueous phase was collected by liquid separation, and the aqueous phase was extracted twice with ethyl acetate (2 × 200 mL) to obtain an aqueous solution containing biopterin. mu.L of an aqueous biopterin solution was injected into an HPLC chromatograph (Shimadzu LC-20AT, Partisil 10 SCX column, column temperature 40 ℃ C., mobile phase of a mixed solution containing 30mmol/L ammonium dihydrogen phosphate and 3mmol/L ammonium sulfate (pH adjusted to 3.00. + -. 0.02 with phosphoric acid)), and the chromatogram was recorded as shown in FIG. 1, and the retention time of biopterin was 4.365 min. The purity of the biopterin aqueous solution is calculated to be 97.6 percent by adopting an area normalization method. Then, 20. mu.L each of a biopterin control solution (solvent: 0.1N HCl, concentration of biopterin: 0.1 mg/mL) and the above biopterin aqueous solution was injected into an HPLC chromatograph (Shimadzu LC-20AT, Partisil 10 SCX column, column temperature: 40 ℃ C., mobile phase using a mixed solution of 30mmol/L ammonium dihydrogen phosphate and 3mmol/L ammonium sulfate (pH adjusted to 3.00. + -. 0.02 with phosphoric acid), and the concentration of biopterin in the above aqueous solution was measured as 34.2mg/mL (equivalent to generation of 16.6g of biopterin, yield: 90%) by the external standard method.
Example 2
Hydrolysis of diacetylbiopterin using tetramethyl ammonium hydroxide
At room temperature (25. + -. 5 ℃ C.), 50g of diacetylbiopterin (95% pure) was weighed, 1000mL of water was added, tetraethylammonium hydroxide was added with stirring to adjust the pH to about 11.5, and the pH of the reaction mixture was measured every 15 to 20min with a timer, and then added with tetramethylammonium hydroxide to maintain the pH at about 11.5. The progress of the reaction is monitored by various analytical techniques known in the art (TLC or HPLC). The hydrolysis reaction proceeded for about 90min, 200ml of dichloromethane was added, stirring was carried out for 10min, the mixture was poured into a separatory funnel, allowed to stand for 30min, the aqueous phase and the dichloromethane phase were separated, the aqueous phase was collected by separatory, and the aqueous phase was extracted twice with dichloromethane (2 × 200 mL) to obtain an aqueous solution containing biopterin. mu.L of an aqueous biopterin solution was injected into an HPLC chromatograph (Shimadzu LC-20AT, Partisil 10 SCX column, column temperature 40 ℃ C., mobile phase of a mixed solution containing 30mmol/L ammonium dihydrogen phosphate and 3mmol/L ammonium sulfate (pH adjusted to 3.00. + -. 0.02 with phosphoric acid)), and the chromatogram was recorded as shown in FIG. 2, and the retention time of biopterin was 4.35 min. The purity of the biopterin aqueous solution is 97.7% by calculation with an area normalization method. Then, 20. mu.L each of a biopterin control solution (solvent: 0.1N HCl, concentration of biopterin: 0.1 mg/mL) and the above biopterin aqueous solution was injected into an HPLC chromatograph (Shimadzu LC-20AT, Partisil 10 SCX column, column temperature: 40 ℃ C., mobile phase using a mixed solution of 30mmol/L ammonium dihydrogen phosphate and 3mmol/L ammonium sulfate (pH adjusted to 3.00. + -. 0.02 with phosphoric acid), and the concentration of biopterin in the above aqueous solution was found to be 33.0mg/mL (corresponding to 32.3g of biopterin, yield: 92%) by the external standard method.
Example 3
Preparation of sapropterin hydrochloride crude product
Adding the biopterin aqueous solution obtained in example 1 into a hydrogenation kettle, adjusting the pH value to about 11.5 by using tetraethylammonium hydroxide or hydrochloric acid aqueous solution (the concentration is 3N), adding 4g of palladium carbon hydroxide, replacing air with nitrogen for three times, then adding hydrogen to 1MPa, reacting at room temperature (25 +/-5 ℃) for about 9 hours, monitoring the reaction by HPLC until the reaction is finished (the rest of the biopterin is less than 2%), discharging, adding concentrated hydrochloric acid (the concentration is 3 mol/L) to adjust the pH value to about 1, adding activated carbon (5 g) to decolor for 30 minutes, filtering, collecting filtrate, rotationally evaporating dry solvent at 35 +/-5 ℃, adding 640ml (1: 15) of absolute ethyl alcohol-acetone mixed solution, stirring and crystallizing for 30 minutes, filtering, and collecting filter cakes to obtain 29.4g of crude sapropterin hydrochloride.
Example 4
Preparation of sapropterin hydrochloride crude product
The biopterin aqueous solution obtained in example 2 was charged into a hydrogenation reactor, the pH was adjusted to about 11.5 with an aqueous solution of tetramethylammonium hydroxide or hydrochloric acid (concentration: 1 mol/L), 4g of platinum dioxide was added, air was replaced with nitrogen three times, and then the mixture was hydrogenated to 1.2MPa and reacted at room temperature (25. + -. 5 ℃ C.) for about 8 hours, and the reaction was monitored by HPLC until the reaction was completed (the amount of remaining biopterin was less than 2%). Discharging, adding concentrated hydrochloric acid (concentration of 10 mol/L) to adjust pH to about 1, adding active carbon (10 g) to decolorize for 30min, filtering, collecting filtrate, and rotary evaporating at 35 + -5 deg.C to obtain dry solvent. 660ml of an absolute ethanol-acetone mixture (1: 10) was added thereto, and the mixture was stirred for crystallization for 30min, followed by filtration to collect a filter cake, thereby obtaining 53.2g of a crude product of wet sapropterin hydrochloride.
Example 5
Refining of sapropterin hydrochloride crude product
The wet crude sapropterin hydrochloride obtained in example 3 was charged into a reaction flask, 100mL of aqueous hydrochloric acid (3 mol/L) was added, the mixture was stirred and heated to 60. + -. 5 ℃ to dissolve it completely, 1000mL of acetone was added, crystallization was performed for 60min under stirring, filtration was performed, the filter cake was rinsed with acetone, and forced air drying was performed at 30. + -. 5 ℃ to a constant weight, whereby 20.5g of purified sapropterin hydrochloride was obtained. The HPLC chromatogram shown in FIG. 3 was obtained by detecting a purified product of sapropterin hydrochloride (Shimadzu LC-20AT, Partisil 10 SCX column, column temperature 40 ℃ C.) with a mixed solution of 30mmol/L ammonium dihydrogen phosphate and 3mmol/L ammonium sulfate (pH adjusted to 3.00. + -. 0.02 with phosphoric acid) as a mobile phase, the concentration of the sample solution being 0.5mg/mL, and the sample amount being 10. mu.L) using HPLC analysis techniques known in the art, wherein the retention time of the main peak of sapropterin hydrochloride was 6.64min, and the purity of the purified product of sapropterin hydrochloride was 99.90%.
Example 6
Refining of sapropterin hydrochloride crude product
The wet crude sapropterin hydrochloride obtained in example 4 was charged into a reaction flask, 100mL of aqueous hydrochloric acid (3 mol/L) was added, the mixture was stirred and heated to 60 ± 5 ℃ to be completely dissolved, 1500 mL of ethanol was added, the mixture was stirred and crystallized for 60min, filtered, the filter cake was rinsed with ethanol, and air-dried at 30 ± 5 ℃ to a constant weight, to obtain 40.1g of a purified sapropterin hydrochloride. The HPLC chromatogram shown in FIG. 4 was obtained by detecting a purified product of sapropterin hydrochloride (Shimadzu LC-20AT, Partisil 10 SCX column, column temperature 40 ℃ C.) with a mixed solution of 30mmol/L ammonium dihydrogen phosphate and 3mmol/L ammonium sulfate (pH adjusted to 3.00. + -. 0.02 with phosphoric acid) as a mobile phase, the concentration of the sample solution being 0.5mg/mL, and the sample amount being 10. mu.L) using HPLC analysis techniques known in the art, wherein the retention time of the main peak of sapropterin hydrochloride was 6.64min, and the purity of the purified product of sapropterin hydrochloride was 99.95%.
Claims (10)
1. A method of preparing sapropterin hydrochloride comprising the steps of:
(1) adding diacetylbiopterin into water at 25 +/-5 ℃, stirring, adjusting the pH value of the reaction solution by using an alkaline reagent to maintain the pH value between 10.5 and 11.5, and reacting for 30 to 90 min;
(2) adding an extracting agent according to 20-60% of the volume of the reaction liquid in the step (1), stirring for 10-60 min, standing for layering for 30-60min, separating liquid, collecting an aqueous phase solution, and adjusting the pH value of the aqueous phase solution to 10.5-11.5;
(3) adding the aqueous phase solution obtained in the step (2) into a hydrogenation kettle, adding a catalyst, replacing with nitrogen for three times, then, hydrogenating to 1-1.2 MPa, and reacting for 7-9 h at 25 +/-5 ℃;
(4) discharging, adding concentrated hydrochloric acid, adjusting the pH value to 1.0-1.5, adding activated carbon for decolorization, filtering, collecting filtrate, performing vacuum rotary evaporation on the dry solvent at 35 +/-5 ℃, adding an absolute ethyl alcohol-acetone mixed solution, stirring for crystallization for 30-60min, and filtering to obtain a wet sapropterin hydrochloride crude product;
(5) and recrystallizing the wet sapropterin hydrochloride crude product by using an acidic mixed solution system, filtering and drying to obtain a purified sapropterin hydrochloride product.
2. The method of claim 1, wherein the base reagent is selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, aqueous ammonia, methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, piperidine, ammonium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide.
3. The method of claim 2, wherein the extractant is selected from the group consisting of diethyl ether, ethyl acetate, butyl acetate, n-pentane, n-hexane, n-heptane, dichloromethane, chloroform, benzene, toluene, n-butanol, n-pentanol, n-hexanol.
4. The method of claim 3, wherein the catalyst is selected from the group consisting of palladium on carbon, palladium on carbon hydroxide, palladium on alumina, platinum black, platinum on carbon, platinum dioxide, platinum on alumina, rhodium on carbon, ruthenium on carbon.
5. The method of claim 4, wherein the acidic mixed solution system is formed by mixing an aqueous hydrochloric acid solution with an organic solvent.
6. The method of claim 5, wherein the organic solvent is selected from the group consisting of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, and isopropanol.
7. The method according to any one of claims 1 to 6, wherein the mass-to-volume ratio of diacetylbiopterin to water in step (1) is (1: 30) - (1: 10).
8. The method according to claim 7, wherein the catalyst is added in the amount of 6-9% (w/w) based on the amount of diacetylbiopterin in step (3).
9. The method according to claim 8, wherein the volume ratio of the absolute ethanol to the acetone in the absolute ethanol-acetone mixed solution in the step (4) is (1: 30) - (1: 5).
10. A method of preparing sapropterin hydrochloride comprising the steps of:
(1) adding diacetylbiopterin into water at 25 +/-5 ℃, stirring, adjusting the pH value of the reaction solution by using tetramethylammonium hydroxide or tetraethylammonium hydroxide to maintain the pH value between 10.5 and 11.5, and reacting for 30 to 60 min;
(2) extracting with ethyl acetate or dichloromethane according to 40% of the volume of the reaction solution in the step (1), stirring for 10-60 min, standing for layering for 30-60min, separating, collecting aqueous phase solution, and adjusting the pH value of the aqueous phase solution to 10.5-11.5;
(3) adding the aqueous phase solution obtained in the step (2) into a hydrogenation kettle, adding a catalyst, replacing with nitrogen for three times, then, hydrogenating to 1-1.2 MPa, and reacting for 7-9 h at 25 +/-5 ℃;
(4) discharging, adding concentrated hydrochloric acid with the concentration of 10mol/L, adjusting the pH value to 1.0-1.5, adding activated carbon for decolorization, filtering, collecting filtrate, performing vacuum rotary evaporation on the dry solvent at the temperature of 35 +/-5 ℃, adding an absolute ethanol-acetone (1: 10) mixed solution, stirring for crystallization for 30-60min, and filtering to obtain a wet sapropterin hydrochloride crude product;
(5) adding the wet sapropterin hydrochloride crude product into a hydrochloric acid aqueous solution with the concentration of 1-3 mol/L, stirring, heating to 60 +/-5 ℃, fully dissolving, adding acetone, stirring, crystallizing for 30-60min, filtering, and drying to obtain a sapropterin hydrochloride refined product.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101959891A (en) * | 2008-01-07 | 2011-01-26 | 生物马林药物股份有限公司 | The method of tetrahydrobiopterin synthesis pterin HB2 |
| WO2016189542A1 (en) * | 2015-05-28 | 2016-12-01 | Natco Pharma Ltd | Novel process for the preparation of sapropterin dihydrochloride and its key intermediate, l-biopterin |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101959891A (en) * | 2008-01-07 | 2011-01-26 | 生物马林药物股份有限公司 | The method of tetrahydrobiopterin synthesis pterin HB2 |
| WO2016189542A1 (en) * | 2015-05-28 | 2016-12-01 | Natco Pharma Ltd | Novel process for the preparation of sapropterin dihydrochloride and its key intermediate, l-biopterin |
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