http://rdf.ncbi.nlm.nih.gov/pubchem/patent/ES-2613453-T3
Outgoing Links
| Predicate | Object |
|---|---|
| assignee | http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_b62cb32afc7b1f80c182729687b5d573 http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_1074d9060e4dc8cb78490dd30c77f84d http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_4fad377afd21f5549be0ad01a37666c6 http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_ff43a892ac0d223af33ddea13ddaf8ce http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_c7a77d4f935a52c4b7d51c0011a5310d |
| classificationCPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D475-04 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07C221-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D301-14 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D317-28 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D317-32 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D239-50 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D301-12 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D301-03 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D317-26 |
| classificationIPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D301-12 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D239-50 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D301-14 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D301-03 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D475-04 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D317-26 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07C221-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D317-32 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D317-28 |
| filingDate | 2012-12-27-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| grantDate | 2017-05-24-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| inventor | http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_2f9e6938595f08003cc883d5b89b946e http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_dc5e9c8c329d87ab389b562701bdca2e http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_e087b15417e0b6666be26a2dd505aa00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_8e5a5fe3fc40425cbb626ecc8a459364 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_481eadef70dfccb9209fa23a46ab1cca http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_d40fac330086dcd79032eae7955be128 |
| publicationDate | 2017-05-24-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationNumber | ES-2613453-T3 |
| titleOfInvention | Method to synthesize sapropterin dihydrochloride |
| abstract | Method for synthesizing sapropterin dihydrochloride, characterized in that it comprises the following specific steps: step 1: add (R) - (+) - 1,1'-bi-2-naphthol, triphenylphosphine oxide and a 4A molecular sieve in the presence of a solution in tetrahydrofuran 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, the compound 1 ** Formula ** to the system after adding the oxidant, in which X> = NH or O, R> = C1 to C6 alkane or benzyl, react for 20 to 36 hours while maintaining the temperature, then add citric acid to the system to stop the reaction, and perform centrifugation, concentration and rectification to obtain compound 2 having a structural formula of ** Formula ** when X is NH, compound 1 is alkyl or benzamide crotonate, and the 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 2,3-epoxy-alkyl (2S, 3R) -butyrate or (2S, 3R)-2,3-epoxy-butyrate benzyl, in which the molar ratio of ** Formula ** with respect to samarium catalyst is 1: 0.05 to 0.5, the molar ratio of ** Formula ** with respect to (R) - (+ ) -1,1'-bi-2-naphthol is 1: 0.05 to 0.5, the molar ratio of ** Formula ** with respect to triphenylphosphine oxide is 1: 0.05 to 0.5 , the mass ratio of ** Formula ** with respect to the molecular sieve of 4A is 1: 5 to 15, the molar ratio of ** Formula ** with respect to the oxidant is 1: 0.5 to 3, and the molar ratio of ** Formula ** with respect to citric acid is 1: 0.05 to 0.5; the oxidant in step 1 is N-bromobutanimide, meta-chloroperoxybenzoic acid, hydrogen peroxide having a concentration of 35% or a solution in toluene of tert-butyl hydroperoxide having a concentration of 50%; step 2: add a Lewis acid in the presence of acetone, control the temperature at 10 ° C to 30 ° C, add compound 2, react for 5 to 10 hours while maintaining the temperature, add an inorganic base aqueous solution having a concentration of 5% to 10% to the system, and perform liquid separation, extraction and concentration to the system to obtain compound 3 having a structural formula of ** Formula ** when X is NH, compound 3 is (4S, 5S) -2,3-acetonidoalkylbutyramide or (4S, 5S) -2,3-acetonide-benzylbutyramide; when X is oxygen, compound 3 is 2,3-acetonide-alkyl butyrate or (4S, 5S)-2,3-acetonide-benzyl butyrate; wherein the molar ratio of compound 2 with respect to acetone is 1: 1 to 4; the molar ratio of compound 2 with respect to Lewis acid is 1: 0.1 to 1; and the molar ratio of compound 2 with respect to the inorganic base is 1: 0.5 to 3; step 3: add compound 3 in the presence of a polar solvent, increase the temperature up to 25 ° C to 40 ° C, add pure water and an alkaline solution, react for 3 to 8 hours while maintaining the temperature, perform centrifugation, dissolve a Filter cake in a polar solvent that is the same as the polar reaction solvent, add a resolution reagent, maintain the temperature at 15 ° C to 30 ° C for 3 to 5 hours, perform centrifugation and drying to obtain compound 4, it is ie, (4S, 5S) -2,2,5-trimethyl-1,3-dioxolane-4-carboxylate of 1-phenylalkylamine having a structural formula of ** Formula ** in which n> = 0.1; wherein the ratio of the amount of use of compound 3 with respect to that of the polar reaction solvent is 1 g / 3 to 10 ml; the molar ratio of compound 3 with respect to pure water is 1: 0.5 to 3; the molar ratio of compound 3 with respect to an alkaline substance in the alkaline solution is 1: 0.5 to 2; the ratio of the amount of use of compound 3 with respect to that of the polar solvent to dissolve the filter cake is 1 g / 2 to 10 ml; the molar ratio of compound 3 with respect to the resolution reagent is 1: 1 to 5; the polar solvent is tetrahydrofuran, methanol or ethanol, the resolution agent is L-alphaphenylethylamine or L-alpha-amphetamine; step 4: add compound 4 in the presence of an ether solvent, then add an aqueous solution of inorganic acid having a concentration of 5% to 10% to the system to regulate the pH at 1 to 3, control the temperature at - 10 ° C to 10 ° C, maintain the temperature for 1 hour, perform liquid separation to obtain an organic phase, add N, N-diisopropylethylamine to the organic phase, and concentrate the system to obtain compound 5, that is, acid (4S, 5S) -2,2,5-trimethyl-1,3-dioxolan-4-methanoic acid that ** Formula ** has a structural formula in which the ratio of the amount of use of compound 4 with respect to that of the solvent ether is 1 g / 3 to 10 ml and the molar ratio of compound 4 with respect to N, N-diisopropylethylamine is 1: 0.8 to 3; step 5: add compound 5 and N, N-diisopropylethylamine in the presence of an ether solvent, reduce the temperature to -30 ° C to 0 ° C, add to chloroformate, react for 1 to 2 hours while maintaining the temperature, introduce a diazomethane gas for 1 to 2 hours, add a solution of hydrochloride-ethanol, react for 1 to 2 hours, add an alkaline reagent to regulate the pH value from 7 to 9, perform extraction, separation of liquid and concentration to obtain compound 6, that is, (4S, 5S) -2,2,5-trimethyl-5-chloroacetyl-1,3-dioxolane having a structural formula of ** Formula ** in which the ratio of the amount of use of compound 5 with respect to that of the ether solvent is 1 g / 5 to 15 ml; the molar ratio of compound 5 with respect to N, N-diisopropylethylamine is 1: 1 to 5; the molar ratio of compound 5 with respect to chloroformate is 1: 1 to 3; and the molar ratio of compound 5 with respect to hydrogen chloride in the hydrochloride-ethanol solution is 1: 1 to 5; step 6: add compound 6, a trinitride and a catalyst in the presence of a polar solvent, react the system at 15 ° C to 40 ° C for 20 to 30 hours while maintaining the temperature, then perform filtration 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 ** Formula ** having a structural formula in which the ratio of the amount of use of compound 6 with respect to that of the polar solvent is 1 g / 5 to 15 ml; the molar ratio of compound 6 with respect to trinitride is 1: 1 to 4; and the molar ratio of compound 6 with respect to the catalyst is 1: 0.05 to 0.8; the polar solvent is acetonitrile, methanol, ethanol, acetone or tetrahydrofuran; step 7: add triphenylphosphine and water, or palladium on carbon and hydrogen, or Raney nickel and hydrogen in the presence of an ether solvent, regulate the pH of the system from 1 to 4 with an acid reagent, add a solution of compound 7, maintain the temperature at 10 ° C to 30 ° C, react for 5 to 10 hours, perform filtration by suction and concentration to obtain a filtrate containing compound 8, the filtrate being used directly in the next step or by separating a solid from compound 8 of the filtered for use in the next stage; compound 8 is (3S, 4S) -1-amino-3,4-dihydroxy-2-pentanone which has ** Formula ** a structural formula in which the ratio of the amount of use of compound 7 with respect to the ether solvent is 1 g / 5 to 15 ml; the molar ratio of compound 7 with respect to triphenylphosphine is 1: 0.1 to 3; the ratio of the amount of use of compound 7 with respect to that of water is 1: 0.1 to 3; the mass ratio of compound 7 with respect to 5% palladium on carbon or 10% palladium on carbon or Raney nickel is 1: 0.05 to 0.6; hydrogen is introduced until the system pressure is 0.4 to 0.9 MPa; step 8: adding a catalyst, compound A, that is, 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 alcohol solvent and pure water, react the system at 30 ° C to 80 ° C for 4 to 8 hours while maintaining the temperature, add a buffer solution to regulate the pH of the system to 6 to 8, and filter the system to obtaining compound 9, that is, 2-acetylamino-5-nitro-6 - ((3S, 4S) -3,3-dihydroxy-2 oxo-pentylamino) -pyrimidin-4-one having a structural formula of ** Formula ** in which the ratio of the amount of use of compound 8 with respect to that of the alcoholic solvent is 1 g / 5 to 15 ml; the ratio of the amount of use of compound 8 with respect to that of pure water is 1 g / 1 to 5 ml; the molar ratio of compound 8 with respect to compound A is 1: 1 to 1.5; the molar ratio of compound 8 with respect to the catalyst is 1: 0.05 to 0.5; and the molar ratio of compound 8 with respect to the alkaline reagent is 1: 3 to 8; step 9: add a catalyst in the presence of compound 9 and a polar solvent, introduce hydrogen until the system pressure is 0.4 to 0.9 MPa, control the system temperature from 15 ° C to 30 ° C and the pressure a 0.4 to 0.9 MPa, react for 18 to 24 hours, filter the system, and regulate the pH of the system at 11 to 12 with an alkaline reagent to obtain a solution of compound 10 to be used directly in In the next step, compound 10 is acetylamino-7,8-dihydropteridine which ** Formula ** has a structural formula in which the ratio of the amount of use of compound 9 with respect to that of the polar solvent is 1 g / from 20 to 50 ml and the mass ratio of compound 9 with respect to the catalyst is 1: 0.05 to 0.6; the polar solvent is pure water, methanol or ethanol; step 10: add a catalyst in the presence of the solution of compound 10 obtained in step 9, introduce hydrogen until the system pressure is 0.4 to 0.9 MPa, control the system temperature from 10 ° C to 30 ° C, control the pressure at 0.4 to 0.9 MPa, react for 72 to 84 hours, perform extinction in dilute hydrochloric acid having a concentration of 10% to 20% after reacting meticulously, and perform suction filtration and drying the system to obtain compound 11, that is, an objective product, a crude product of sapropterin dihydrochloride and, in addition to crystallizing and purifying the crude product of sapropterin dihydrochloride with an alcoholic solvent or a ketone solvent of 0 ° C to 40 ° C to obtain a pure sapropterin dihydrochloride product, in which the mass ratio of compound 10 with respect to the catalyst is 1: 0.05 to 0.6; the molar ratio of compound 10 with respect to hydrochloric acid is 1: 3 to 10; and the ratio of the amount of use of the compound 10 with respect to that of the alcoholic solvent or the ketone solvent is 1 g / 5 to 25 ml. |
| priorityDate | 2012-04-10-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| type | http://data.epo.org/linked-data/def/patent/Publication |
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