Method for synthesizing sapropterin dihydrochloride

A method for synthesizing sapropterin dihydrochloride, wherein it comprises the following specific steps:

• Step 1:
• adding (R)-(+)-1,1′-bi-2-naphthol, triphenylphosphine oxide and a 4A molecular sieve in the presence of a tetrahydrofuran solution of a samarium catalyst having a concentration of 5% to 10%, after stirring uniformly, controlling the system temperature at 0° C. to 25° C., adding an oxidant, and adding a main raw material compound 1
• to the system after adding the oxidant, where X═NH or O, R═C1 to C6 alkane or benzyl, reacting for 20 to 36 hours while preserving the temperature, then adding citric acid to the system to stop the reaction, and performing centrifugation, concentration and rectification to obtain compound 2 having a structural formula of
• when X is NH, compound 1 is alkyl crotonate or benzamide, and compound 2 is (2S,3R)-2,3 epoxy-alkylamide butyrate;
• when X is oxygen, compound 1 is alkyl crotonate or benzyl crotonate and compound 2 is (2S,3R)-2,3 epoxy-alkylbutyrate or (2S,3R)-2,3 epoxy-benzyl butyrate,
• wherein the molar ratio of
• to the samarium catalyst is 1:0.05 to 0.5, the molar ratio of
• to (R)-(+)-1,1′-bi-2-naphthol is 1:0.05 to 0.5, the molar ratio of
• to triphenylphosphine oxide is 1:0.05 to 0.5, the mass ratio of
• to the 4A molecular sieve is 1:5 to 15, the molar ratio of
• to the oxidant is 1:0.5 to 3, and the molar ratio of
• to citric acid is 1:0.05 to 0.5;
• Step 2:
• adding a Lewis acid in the presence of acetone, controlling the temperature at 10° C. to 30° C., adding compound 2, reacting for 5 to 10 hours while preserving the temperature, adding an inorganic base aqueous solution having a concentration of 5% to 10% to the system, and performing liquid separation, extraction and concentration to the system to obtain compound 3 having a structural formula of
• when X is NH, compound 3 is (4S,5S)-2,3-acetonide-alkylbutyramide or (4S,5S)-2,3-acetonide-benzylbutyramide;
• when X is oxygen, compound 3 is (4S,5S)-2,3-acetonide-alkylbutyrate or (4S,5S)-2,3-acetonide-benzyl butyrate;
• wherein the molar ratio of compound 2 to acetone is 1:1 to 4;
• the molar ratio of compound 2 to the Lewis acid is 1:0.1 to 1;
• and the molar ratio of compound 2 to the inorganic base is 1:0.5 to 3;
• Step 3:
• adding compound 3 in the presence of a polar solvent, increasing the temperature to 25° C. to 40° C., adding pure water and an alkaline solution, reacting for 3 to 8 hours while preserving the temperature, performing centrifugation, dissolving a filter cake in a polar solvent which is the same as the reaction polar solvent, adding a resolving reagent, preserving the temperature at 15° C. to 30° C. for 3 to 5 hours, performing centrifugation and drying to obtain compound 4, i.e. 1-phenylalkylamine (4S,5S)-2,2,5-trimethyl-1,3-dioxolane-4-carboxylate having a structural formula of
• where n=0,1;
• wherein the ratio of the use amount of compound 3 to that of the reaction polar solvent is 1 g/3 to 10 ml;
• the molar ratio of compound 3 to pure water is 1:0.5 to 3;
• the molar ratio of compound 3 to an alkaline substance in the alkaline solution is 1:0.5 to 2;
• the ratio of the use amount of compound 3 to that of the polar solvent for dissolving the filter cake is 1 g/2 to 10 ml;
• the molar ratio of compound 3 to the resolving reagent is 1:1 to 5;
• Step 4:
• adding compound 4 in the presence of an ether solvent, then adding an inorganic acid aqueous solution having a concentration of 5% to 10% to the system to regulate the pH to 1 to 3, controlling the temperature at −10° C. to 10° C., preserving the temperature for 1 hour, performing liquid separation to obtain an organic phase, adding N,N-diisopropylethylamine to the organic phase, and concentrating the system to obtain compound 5, i.e. (4S,5S)-2,2,5-trimethyl 1,3-dioxolan-4-methanoic acid having a structural formula of
• wherein the ratio of the use amount of compound 4 to that of the ether solvent is 1 g/3 to 10 ml and the molar ratio of compound 4 to N,N-diisopropylethylamine is 1:0.8 to 3;
• Step 5:
• adding compound 5 and N,N-diisopropylethylamine in the presence of an ether solvent, reducing the temperature to −30° C. to 0° C., adding a chloroformate, reacting for 1 to 2 hours while preserving the temperature, introducing a diazomethane gas for 1 to 2 hours, adding a hydrochloride ethanol solution, reacting for 1 to 2 hours, adding an alkaline reagent to regulate the pH value to 7 to 9, performing extraction, liquid separation and concentration to obtain compound 6, i.e. (4S,5S)-2,2,5-trimethyl-5-chloroacetyl-1,3-dioxolane having a structural formula of
• wherein the ratio of the use amount of compound 5 to that of the ether solvent is 1 g/5 to 15 ml;
• the molar ratio of compound 5 to N,N-diisopropylethylamine is 1:1 to 5;
• the molar ratio of compound 5 to the chloroformate is 1:1 to 3;
• and the molar ratio of compound 5 to hydrogen chloride in the hydrochloride ethanol solution is 1:1 to 5;
• Step 6:
• adding compound 6, a trinitride and a catalyst in the presence of a polar solvent, reacting the system at 15° C. to 40° C. for 20 to 30 hours while preserving the temperature, then performing filtering and concentration to obtain a solution of compound 7 which is used directly in the next step;
• compound 7 is (4S,5S)-2,2,5-trimethyl-5-(2-azidoacetyl)-1,3-dioxolane having a structural formula of
• wherein the ratio of the use amount of compound 6 to that of the polar solvent is 1 g/5 to 15 ml;
• the molar ratio of compound 6 to the trinitride is 1:1 to 4;
• and the molar ratio of compound 6 to the catalyst is 1:0.05 to 0.8;
• Step 7:
• adding triphenylphosphine and water, or palladium on carbon and hydrogen, or Raney nickel and hydrogen in the presence of an ether solvent, regulating the pH of the system to 1 to 4 with an acid reagent, adding a solution of compound 7, preserving the temperature at 10° C. to 30° C., reacting for 5 to 10 hours, performing suction filtration and concentration to obtain a filtrate containing compound 8, the filtrate being used directly in the next step or a solid of compound 8 being separated from the filtrate for use in the next step;
• the compound 8 is (3S,4S)-1-amino-3,4-dihydroxy-2-pentanone having a structural formula of
• wherein the ratio of the use amount of compound 7 to that of the ether solvent is 1 g/5 to 15 ml;
• the molar ratio of compound 7 to triphenylphosphine is 1:0.1 to 3;
• the ratio of the use amount of compound 7 to that of water is 1:0.1 to 3;
• the mass ratio of compound 7 to 5% palladium on carbon or 10% palladium on carbon or Raney nickel is 1:0.05 to 0.6;
• the hydrogen is introduced until the pressure of the system is 0.4 to 0.9 MPa;
• Step 8:
• adding a catalyst, compound A, i.e. 2-amino-6-chloro-5-nitro-3H-pyrimidin-4-one having a structural formula of
• compound 8, and an alkaline reagent in the presence of an alcoholic solvent and pure water, reacting the system at 30° C. to 80° C. for 4 to 8 hours while preserving the temperature, adding a buffer solution to regulate the pH of the system to 6 to 8, and filtering the system to obtain compound 9, i.e.
• 2-acetylamino-5-nitro-6((3S,4S)-3,3-dihydroxy-2-oxo-pentylamino)-pyrimidin-4-one having a structural formula of
• wherein the ratio of the use amount of compound 8 to that of the alcoholic solvent is 1 g/5 to 15 ml;
• the ratio of the use amount of compound 8 to that of pure water is 1 g/1 to 5 ml;
• the molar ratio of compound 8 to compound A is 1:1 to 1.5;
• the molar ratio of compound 8 to the catalyst is 1:0.05 to 0.5;
• and the molar ratio of compound 8 to the alkaline reagent is 1:3 to 8;
• Step 9:
• adding a catalyst in the presence of compound 9 and a polar solvent, introducing hydrogen until the pressure of the system is 0.4 to 0.9 MPa, controlling the temperature of the system at 15° C. to 30° C. and the pressure at 0.4 to 0.9 MPa, reacting for 18 to 24 hours, filtering the system, and regulating the pH of the system to 11 to 12 with an alkaline reagent to obtain a solution of compound 10 to be used directly in the next step, compound 10 is acetylamino-7,8-dihydropteridine having a structural formula of
• wherein the ratio of the use amount of compound 9 to that of the polar solvent is 1 g/20 to 50 ml and the mass ratio of compound 9 to the catalyst is 1:0.05 to 0.6;
• Step 10:
• adding a catalyst in the presence of the solution of the compound 10 obtained in Step 9, introducing hydrogen until the pressure of the system is 0.4 to 0.9 MPa, controlling the temperature of the system at 10° C. to 30° C., controlling the pressure at 0.4 to 0.9 MPa, reacting for 72 to 84 hours, performing quenching in dilute hydrochloric acid having a concentration of 10% to 20% after reacting thoroughly, and performing suction filtration and drying to the system to obtain compound 11, i.e. a target product, a sapropterin dihydrochloride crude product, and further crystallizing and purifying the sapropterin dihydrochloride crude product with an alcoholic solvent or a ketone solvent at 0° C. to 40° C. to obtain a sapropterin dihydrochloride pure product,
• wherein the mass ratio of compound 10 to the catalyst is 1:0.05 to 0.6;
• the molar ratio of compound 10 to hydrochloric acid is 1:3 to 10;
• and the ratio of the use amount of compound 10 to that of the alcoholic solvent or the ketone solvent is 1 g/5 to 25 ml.