CN116675612A - Method for dynamic kinetic resolution of racemic norepinephrine - Google Patents
Method for dynamic kinetic resolution of racemic norepinephrine Download PDFInfo
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- CN116675612A CN116675612A CN202310968635.XA CN202310968635A CN116675612A CN 116675612 A CN116675612 A CN 116675612A CN 202310968635 A CN202310968635 A CN 202310968635A CN 116675612 A CN116675612 A CN 116675612A
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- Prior art keywords
- stirring
- norepinephrine
- water
- filter cake
- filtering
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- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 title claims abstract description 215
- 229960002748 norepinephrine Drugs 0.000 title claims abstract description 111
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 title claims abstract description 106
- 238000000034 method Methods 0.000 title claims abstract description 83
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 254
- 238000003756 stirring Methods 0.000 claims abstract description 207
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 110
- 239000012065 filter cake Substances 0.000 claims abstract description 84
- 238000001914 filtration Methods 0.000 claims abstract description 70
- 239000011259 mixed solution Substances 0.000 claims abstract description 51
- 229960001695 norepinephrine bitartrate Drugs 0.000 claims abstract description 50
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 46
- 238000005406 washing Methods 0.000 claims abstract description 44
- 238000010438 heat treatment Methods 0.000 claims abstract description 41
- 229960001270 d- tartaric acid Drugs 0.000 claims abstract description 39
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims abstract description 37
- 235000019345 sodium thiosulphate Nutrition 0.000 claims abstract description 37
- 238000001816 cooling Methods 0.000 claims abstract description 36
- 239000000047 product Substances 0.000 claims abstract description 33
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 23
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 13
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims abstract description 12
- 230000006340 racemization Effects 0.000 claims abstract description 11
- 239000000376 reactant Substances 0.000 claims abstract description 4
- LNBCGLZYLJMGKP-LUDZCAPTSA-N 4-[(1r)-2-amino-1-hydroxyethyl]benzene-1,2-diol;(2r,3r)-2,3-dihydroxybutanedioic acid;hydrate Chemical compound O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.NC[C@H](O)C1=CC=C(O)C(O)=C1 LNBCGLZYLJMGKP-LUDZCAPTSA-N 0.000 claims abstract 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 108
- 235000019441 ethanol Nutrition 0.000 claims description 99
- 239000000243 solution Substances 0.000 claims description 85
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 72
- 238000006243 chemical reaction Methods 0.000 claims description 72
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 44
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 claims description 42
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical group [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 39
- 239000012043 crude product Substances 0.000 claims description 24
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 21
- 239000008213 purified water Substances 0.000 claims description 19
- 238000004321 preservation Methods 0.000 claims description 15
- 238000001291 vacuum drying Methods 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 235000009518 sodium iodide Nutrition 0.000 claims description 7
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 claims description 6
- 229940107816 ammonium iodide Drugs 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 239000013078 crystal Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 238000002386 leaching Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims 2
- 238000010792 warming Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 9
- 150000003839 salts Chemical class 0.000 abstract description 5
- 230000001105 regulatory effect Effects 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 abstract description 2
- WNPNNLQNNJQYFA-YIDNRZKSSA-N 4-[(1r)-2-amino-1-hydroxyethyl]benzene-1,2-diol;(2r,3r)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.NC[C@H](O)C1=CC=C(O)C(O)=C1 WNPNNLQNNJQYFA-YIDNRZKSSA-N 0.000 description 47
- 230000008569 process Effects 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 14
- 239000003814 drug Substances 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000002994 raw material Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 239000000523 sample Substances 0.000 description 10
- -1 chloroacetyl catechol Chemical compound 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000012488 sample solution Substances 0.000 description 6
- 239000012085 test solution Substances 0.000 description 6
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 5
- 238000007689 inspection Methods 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- 229930182836 (R)-noradrenaline Natural products 0.000 description 4
- LNBCGLZYLJMGKP-JZGIKJSDSA-N 4-[(1r)-2-amino-1-hydroxyethyl]benzene-1,2-diol;2,3-dihydroxybutanedioic acid;hydrate Chemical compound O.OC(=O)C(O)C(O)C(O)=O.NC[C@H](O)C1=CC=C(O)C(O)=C1 LNBCGLZYLJMGKP-JZGIKJSDSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229960001367 tartaric acid Drugs 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- FGTWMNOTTJTKCF-UHFFFAOYSA-N benzhydryl-[2-(3,4-dihydroxyphenyl)-2-oxoethyl]azanium chloride Chemical compound [Cl-].Oc1ccc(cc1O)C(=O)C[NH2+]C(c1ccccc1)c1ccccc1 FGTWMNOTTJTKCF-UHFFFAOYSA-N 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 229940001584 sodium metabisulfite Drugs 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- REFMEZARFCPESH-UHFFFAOYSA-M sodium;heptane-1-sulfonate Chemical compound [Na+].CCCCCCCS([O-])(=O)=O REFMEZARFCPESH-UHFFFAOYSA-M 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- SBTVLCPCSXMWIQ-UHFFFAOYSA-N (3,5-dimethylphenyl) carbamate Chemical compound CC1=CC(C)=CC(OC(N)=O)=C1 SBTVLCPCSXMWIQ-UHFFFAOYSA-N 0.000 description 1
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 1
- UUDLQDCYDSATCH-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid;hydrate Chemical compound O.OC(=O)C(O)C(O)C(O)=O UUDLQDCYDSATCH-UHFFFAOYSA-N 0.000 description 1
- KGSVNOLLROCJQM-UHFFFAOYSA-N 2-(benzylamino)acetic acid Chemical compound OC(=O)CNCC1=CC=CC=C1 KGSVNOLLROCJQM-UHFFFAOYSA-N 0.000 description 1
- QDWVRVNMKUFQJL-UHFFFAOYSA-N 2-(dibenzylamino)acetic acid Chemical compound C=1C=CC=CC=1CN(CC(=O)O)CC1=CC=CC=C1 QDWVRVNMKUFQJL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229940124225 Adrenoreceptor agonist Drugs 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for dynamically and dynamically resolving racemic norepinephrine, which comprises the following steps: dissolving D-tartaric acid, sodium thiosulfate and racemic norepinephrine in water, and adding a lower alcohol mixed solution to react; adding a racemization catalyst to dissolve, heating, adding lower alcohol, stirring reactants, cooling to 10-30 ℃, stirring, and filtering; adding water into the filter cake, stirring to dissolve, dripping a lower alcohol mixed solution to react, cooling to below 10 ℃, stirring, and filtering; washing the filter cake with lower alcohol, adding water for dissolution, adding ammonia water for regulating the pH value to 8-11, stirring, filtering and drying to obtain the R-norepinephrine. The invention also relates to a method for preparing norepinephrine bitartrate, which is prepared by reacting the R-norepinephrine with L-tartaric acid to form salt. The method for preparing R-norepinephrine has high yield, high product chromatographic purity and low isomer impurity content.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, relates to a method for preparing norepinephrine, and in particular relates to a method for preparing R-norepinephrine by using dynamic dynamics to split racemized norepinephrine, which has excellent isomer purity, and the R-norepinephrine can be further used for preparing medicinal raw material medicines of bitartrate. The prepared norepinephrine bitartrate raw material medicine meets the requirements of the quality standard of Chinese pharmacopoeia, and has high yield and high purity.
Background
Norepinephrine bitartrate, or norepinephrine bitartrate (Norepinephrine Bitartrate), which is composed of R-form norepinephrine, L-form tartaric acid, and water in equimolar ratios, and has a molecular formula of c8h11no3.c4h6o6.h2o, a molecular weight of 337.28, wherein the chemical name is (R) -4- (2-amino-1-hydroxyethyl) -1, 2-benzenediol bitartrate monohydrate, and the chemical name provided in the united states pharmacopeia is: 1,2-Benzenediol, 4- (2-amino-1-hydroxyyethyl) -, (R) -, [ R- (R. Times. ) ] -2, 3-dihydroxybutanedate (1:1) (salt), monohydrate, or (-) -alpha- (amino methyl) -3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt). The chemical structural formula of norepinephrine bitartrate is as follows:
the bulk drug of the norepinephrine bitartrate carried by the 2020 edition of Chinese pharmacopoeia contains no less than 99.0 percent of C8H11NO3.C4H6O6 calculated by anhydrous substances, and the bulk drug carried by the 43 edition of USP pharmacopoeia contains 97.0 to 102.0 percent of C8H11NO3.C4H6O6 calculated by anhydrous substances. The norepinephrine bitartrate raw material medicine is white or white-like crystalline powder; no odor; easy deterioration when encountering light and air; the raw materials are easily soluble in water, slightly soluble in ethanol, and insoluble in chloroform or diethyl ether.
Norepinephrine bitartrate is already carried in the pharmacopoeia of the current version of multiple countries, and multiple versions of the Chinese pharmacopoeia also carry the crude drug of the variety and small-volume injection, and is used as a classical adrenoreceptor agonist, and the norepinephrine bitartrate is a very commonly used product in clinic.
It has been described that norepinephrine bitartrate is prepared by resolution using racemic norepinephrine (i.e., a 1:1 molar mixture of S-and R-configuration norepinephrine) as a starting material, using tartaric acid as a resolving agent.
Although resolution of racemic compounds is of increasing importance in pharmaceutical synthesis, one significant disadvantage of this resolution process is that the highest yield expected based on the racemic starting material is 50%, that is to say 50% each of the two isomers, with a theoretical highest yield of 50% of one of the isomers obtained after complete resolution. However, in contrast to conventional kinetic resolution methods, dynamic Kinetic Resolution (DKR) is capable of simultaneously carrying out the racemization reaction, i.e. one of the two isomers, which would otherwise be 50% each, is capable of carrying out the racemization reaction to the other desired isomer during resolution and separating out, thus obtaining yields which can theoretically exceed 50%.
The resolution of the existing literature on the racemic norepinephrine adopts a common resolution method.
Liang Dawei (Liang Dawei, et al, (-) -norepinephrine bitartrate synthesis research, chemical technology and development, 2014,43 (08): 11) reports that a crude drug of norepinephrine bitartrate was successfully synthesized by using chloroacetcatechol as a raw material, sequentially carrying out ammonification and catalytic hydrogenation reactions to obtain racemic norepinephrine, and then carrying out resolution by using L-tartaric acid. The literature carries out detailed study on the feeding sequence, the reaction time, the reaction temperature and the chiral resolution condition, and results show that the method is a better reaction condition for preparing norepinephrine under the catalysis of 10% ammonia water ethanol solution and palladium/carbon and the hydrogen pressure of 3.0MPa, and can obtain high-yield and purity norepinephrine bitartrate through crystallization resolution and refining of L-tartaric acid for 2 times under the temperature condition of 5-10 ℃. The detailed splitting operation in this document is: 10mL of water and 5.0g of L-tartaric acid are sequentially added into a reaction bottle, stirring and heating are carried out to 60 ℃, after all solids are dissolved, 5.0g of racemic norepinephrine is added, stirring is carried out at 60 ℃ for reaction for 30min, then cooling is carried out to 30 ℃, 10mg of (-) -norepinephrine bitartrate seed crystal is added into the mixture, stirring is stopped until a small amount of solids appear, stirring is stopped, and the temperature is slowly reduced to 5 ℃ to enable the reaction solution to carry out natural crystallization for 10 hours. Filtering, washing the filter cake with alcohol, vacuum drying to obtain crude product, and refining the crude product once again by the above method to obtain final product 0.4g of norepinephrine bitartrate. The results of this document show that in the final resolution stage, the yield is only 4% (mol), and this low yield process for the preparation of norepinephrine bitartrate is not acceptable in production practice.
CN112225665a relates to a process for preparing norepinephrine bitartrate comprising the steps of: using chloroacetyl catechol as a starting material, and carrying out coupling reaction with dibenzylamine in a reaction solvent to prepare 2- (benzhydryl amino) -3',4' -dihydroxyacetophenone hydrochloride; then, 2- (benzhydrylamino) -3',4' -dihydroxyacetophenone hydrochloride is subjected to hydrogenation catalysis and reduction in a solvent to prepare racemic norepinephrine; then, resolving racemic norepinephrine in an alcohol-water mixed solution by using D-tartaric acid to obtain D-tartaric acid L-norepinephrine; finally, neutralizing the D-tartaric acid L-norepinephrine with alkali in water to obtain L-norepinephrine; however, the preparation method of the invention adopts D tartaric acid for resolution, needs to further carry out dissociation and displacement to L tartrate, and has very complicated reaction process.
A method for synthesizing norepinephrine bitartrate disclosed in patent document CN115073312a, comprising the steps of: under the protection of inert gas, under the action of auxiliary reagent, N-benzyl glycine and catechol or N, N-dibenzyl glycine are subjected to condensation reaction in a reaction solvent, so that N-benzyl norepinephrine hydrochloride or N, N-dibenzyl norepinephrine hydrochloride can be obtained; then, in the presence of purified water under inert atmosphere, carrying out catalytic hydrogenation on N-benzyl norepinephrine hydrochloride or N, N-dibenzyl norepinephrine hydrochloride, and deprotecting to obtain racemized norepinephrine; finally, splitting, adding L-tartaric acid, racemic norepinephrine and water into a reaction bottle under the protection of nitrogen, and heating and stirring to dissolve the materials; adding activated carbon for decoloring; filtering while the mixture is hot, slowly cooling the filtrate under the protection of nitrogen, and continuously stirring after a large amount of solids are separated out by stirring; filtering to obtain a filter cake, washing with absolute ethyl alcohol to obtain a resolved norepinephrine bitartrate wet product; then adding the norepinephrine bitartrate wet product and water into a reaction bottle under the protection of nitrogen, heating and stirring for dissolution; adding activated carbon for decoloring treatment; after hot filtration, the filtrate is slowly cooled under the protection of nitrogen, and the solid is stirred and separated out; filtering, washing the filter cake with absolute ethyl alcohol, and vacuum drying to obtain the pure norepinephrine bitartrate. The inventor discovers that the yield of R-norepinephrine obtained by the method of the patent document is only 22 percent, the solubility of water to tartaric acid norepinephrine is very good, the solvent consumption is very large, the yield is very low, the materials are very viscous, the stirring is difficult, and the industrial scale-up production is not easy.
In addition, CN115073312a also reports a method of racemizing S-norepinephrine into R-norepinephrine, specifically racemizing it under heating using a strong acid, but norepinephrine is unstable under a strong acid condition and is easily degraded, and thus is not suitable for industrial production.
CN113717060a discloses a synthesis method of norepinephrine, which comprises the steps of taking 3, 4-dihydroxyl-2 '-chloroacetophenone or 3, 4-dihydroxyl-2' -bromoacetophenone as raw materials, reacting with chiral compounds in polar aprotic solvents, reducing by a reducing agent, and catalyzing hydrogenation reaction. The invention also discloses a method for preparing norepinephrine bitartrate by salifying and splitting the norepinephrine and L-tartaric acid. The method is believed to induce and increase the content of R-configuration products in the carbonyl reduction step by introducing chiral reagents into the chemical structure of the intermediate, reduce the subsequent resolution times of salifying with L-tartaric acid and greatly improve the yield. The method for synthesizing the norepinephrine bitartrate is simple, raw materials are easy to obtain, the optical purity of the prepared norepinephrine bitartrate is high, the cost of the preparation method is low, and the method has excellent industrial production and application prospects. However, when the present inventors repeated the preparation of norepinephrine bitartrate of inventive example 3, it was found that the yield of norepinephrine bitartrate from wet norepinephrine to pure end product was only 18% in terms of R configuration.
Therefore, a process for preparing R-norepinephrine from dynamic resolution of racemic norepinephrine in high yield is still expected by those skilled in the art, and the process is expected to be simple and easy to be carried out, and the product purity is expected to be high, especially the aim of achieving a theoretical resolution yield exceeding 50% is expected, and thus the obtained R-norepinephrine can be used for preparing norepinephrine bitartrate which can be used as a pharmaceutical raw material.
Disclosure of Invention
The invention aims to provide a method for preparing a norepinephrine bitartrate pharmaceutical bulk drug, which is expected to have one or more of the advantages of simplicity, easiness in implementation, high yield, high purity of products and the like, and particularly is expected to realize the advantage that the theoretical resolution yield exceeds 50%. It has been found that at least one of the above-mentioned benefits is obtained by using the method of the present invention.
The invention achieves the purpose of resolving racemic norepinephrine by using D-tartaric acid for resolving and adding a catalyst, thereby greatly improving resolution yield.
In the method, a catalyst such as iodide ions of sodium iodide, potassium iodide and the like is added in the resolution process to catalyze S-configuration norepinephrine to convert the S-configuration norepinephrine into R-configuration norepinephrine, so that the aim of dynamic kinetic resolution is fulfilled. The resolution and catalysis process is shown in figure 1, in the figure, after racemized norepinephrine (R and S configuration norepinephrine account for 50 percent of each) and D tartaric acid form salt, the salt is dissolved in a water/alcohol mixed solvent, R configuration norepinephrine lithospermate is less soluble and separated out, S configuration norepinephrine lithospermate in mother liquor is catalyzed by iodide ions and then racemized norepinephrine lithospermate is generated, and the racemized norepinephrine lithospermate enters the next cycle of salifying and resolution with D tartaric acid, so that the purpose of dynamically resolving racemized norepinephrine is achieved.
In particular, the present invention provides a process for the preparation of norepinephrine bitartrate using racemic norepinephrine, comprising the steps of:
(1) Adding D-tartaric acid and racemic norepinephrine into water, stirring under warm condition to dissolve, then dropwise adding lower alcohol mixed solution into the reaction solution at a certain temperature, stirring at a certain temperature to react;
(2) Adding a racemization catalyst into the reaction solution to dissolve, heating the reaction solution to 50-80 ℃, for example, 60-70 ℃, adding lower alcohol, continuing stirring, adding lower alcohol again, continuing stirring, cooling to 10-30 ℃, for example, 20-30 ℃, continuing stirring, and filtering to obtain a filter cake which is the crude product of R-norepinephrine D-tartrate;
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into water, stirring under warm condition to dissolve, then dropwise adding lower alcohol mixed solution into the reaction solution at a constant temperature, stirring under a constant temperature to react, cooling to below 10deg.C, continuing stirring, and filtering;
(4) Washing the filter cake with lower alcohol, adding into water, stirring to dissolve, adding ammonia water to adjust the pH to 8-11, continuously stirring, filtering, washing the filter cake with water, and drying to obtain R-norepinephrine.
According to the method disclosed by the invention, in the step (1), the molar ratio of D-tartaric acid to racemic norepinephrine is 1-1.2: 1, for example, 1 to 1.1:1.
The process according to the invention, wherein in step (1), sodium thiosulfate is added together with D-tartaric acid.
According to the method disclosed by the invention, in the step (1), sodium thiosulfate is also added together with D-tartaric acid, and the molar ratio of the racemic norepinephrine to the sodium thiosulfate is 25-40: 1, for example 29 to 36:1.
the process according to the invention, wherein in step (1) the amount of water added per 1mol of racemic norepinephrine feed is 0.2l to 1l, e.g. 0.3l to 0.5l.
According to the method of the present invention, in step (1), dimethyl sulfoxide is further added in an amount of 10 to 25% (v/v), for example 11 to 18% (v/v), of water.
According to the method of the invention, in the step (1), the temperature of the warm condition is 30-40 ℃.
According to the method of the present invention, in the step (1), the lower alcohol mixed solution is a mixed solution of two or three of methanol, ethanol and isopropanol, preferably two solutions in a volume ratio of 0.5 to 5:1 preferably 1 to 3: 1.
The method according to the present invention, wherein the total amount of the lower alcohol mixed solution added per 6.51mol of the racemic norepinephrine feed in step (1) is 14 to 18l, for example 15 to 16l.
The method according to the invention, wherein step (1) is performed according to the following operations: adding 6.6-7.2 mol of D-tartaric acid, 0.18-0.22 mol of sodium thiosulfate and 6.51mol of racemic norepinephrine into 2.5-3L of water and 0.35-0.45L of dimethyl sulfoxide, stirring at 30-40 ℃ for 0.5h to dissolve, dropwise adding 15-16L of lower alcohol mixed solution at a constant temperature, and stirring at a constant temperature for 3h.
The process according to the invention wherein in step (2) the racemisation catalyst is selected from potassium iodide, sodium iodide, ammonium iodide.
The process according to the invention, wherein in step (2) the amount of racemisation catalyst added per 6.51mol of racemisation norepinephrine charge is 0.2 to 0.5mol, e.g. 0.30 to 0.38mol.
The process according to the invention, wherein in step (2) the lower alcohol is selected from methanol, ethanol, isopropanol.
The process according to the invention, wherein in step (2) the lower alcohol is selected from methanol, ethanol, isopropanol, the amount of lower alcohol added in each case in two times being independently 3 to 8l, for example 4 to 6l, per 6.51mol of racemic norepinephrine feed.
The method according to the invention, wherein step (2) is performed according to the following operations: adding 0.30-0.38 mol of racemization catalyst into the reaction liquid to dissolve, heating the reaction liquid to 50-80 ℃, for example, 60-70 ℃, adding 4-6L of lower alcohol selected from methanol, ethanol and isopropanol, stirring for 3 hours, adding 4-6L of lower alcohol again, stirring for 3 hours, cooling to 10-30 ℃, for example, stirring for 1-3 hours after 20-30 ℃, and filtering to obtain a filter cake which is a crude product of R-norepinephrine D-tartrate;
according to the method disclosed by the invention, in the step (3), 2-2.5L of water is added into the crude R-norepinephrine D-tartrate.
According to the method of the invention, in the step (3), the temperature of the warm condition is 30-40 ℃.
According to the method of the present invention, in the step (3), the lower alcohol mixed solution is a mixed solution of two or three of methanol, ethanol and isopropanol, preferably two solutions in a volume ratio of 0.5 to 5:1 preferably 1 to 3: 1.
According to the method of the invention, in the step (3), the total addition amount of the lower alcohol mixed solution added per 6.51mol of the racemic norepinephrine feed is 14-18L.
The method according to the invention, wherein step (3) is performed according to the following operations: (3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2-2.5L of water, stirring at 30-40 ℃ for 0.5h to dissolve, then dropwise adding 14-18L of lower alcohol mixed solution into the reaction solution at a constant temperature, stirring at a constant temperature for 1h to react, cooling to 0-10 ℃, continuing stirring for 3h, and filtering.
In the present invention, the ethanol is absolute ethanol unless otherwise specified.
The process according to the invention, wherein in step (4) the lower alcohol is methanol or ethanol or isopropanol, preferably ethanol.
The process according to the invention, wherein in step (4) the lower alcohol is methanol or ethanol or isopropanol, preferably ethanol, added in an amount of 0.2 to 1L, e.g. 0.5L, per 6.51mol of racemic norepinephrine.
The process according to the invention, wherein in step (4), the amount of water added per 6.51mol of racemic norepinephrine feed is 3 to 6L, e.g. 4L.
The process according to the invention, wherein in step (4), water is added and stirred for 0.5 hours.
According to the method of the invention, in the step (4), ammonia water is added to adjust the pH to 8-11, and stirring is continued for 0.5 hour.
The process according to the invention, wherein in step (4), the filter cake obtained is washed with water (0.5L).
According to the method of the present invention, in the step (4), the obtained filter cake is washed with water and dried in vacuum at 30 to 40 ℃, for example 35 ℃ for 1 to 4 hours, for example 2 hours.
The method according to the invention, wherein step (4) is performed according to the following operations: (4) Washing the filter cake with 0.2-1L of absolute ethyl alcohol, adding 3-6L of water, stirring to dissolve, adding ammonia water to adjust the pH to 8-11 such as pH 9-10, continuously stirring, filtering, washing the filter cake with water, and vacuum drying at 30-40 ℃ such as 35 ℃ for 1-4 h to obtain R-norepinephrine.
The method according to the invention is carried out according to the following operations:
(1) Adding 6.73mol of D-tartaric acid, 0.2mol of sodium thiosulfate and 6.51mol of racemic norepinephrine into 2.75L of water and 0.4L of dimethyl sulfoxide, stirring for 0.5h at 30-40 ℃, then adding a mixed solution of 10L of methanol and 5L of ethanol into a reaction solution for Wen Di h, and continuing to stir for 3h after adding;
(2) Adding 0.33mol of potassium iodide into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding 5L of ethanol, stirring for 3 hours, adding 5L of ethanol again, stirring for 3 hours, cooling to 20-30 ℃, stirring for 3 hours, and filtering to obtain a filter cake which is a crude product of R-norepinephrine D-tartrate;
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2.25L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding a mixed solution of 10L of methanol and 5L of ethanol at a temperature of 1h, stirring for 1h at a temperature of 5+/-5 ℃, stirring for 3h at a temperature of 3h, and filtering;
(4) Washing a filter cake with 0.5L of absolute ethyl alcohol, adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with 0.5L of water, and drying in vacuum at 35 ℃ for 2 hours to obtain R-norepinephrine.
The method according to the invention is carried out according to the following operations:
(1) Adding 6.73mol of D-tartaric acid, 0.2mol of sodium thiosulfate and 6.51mol of racemic norepinephrine into 2.75L of water and 0.4L of dimethyl sulfoxide, stirring for 0.5h at 30-40 ℃, then adding a mixed solution of 12L of methanol and 4L of isopropanol into a reaction solution for Wen Di h, and keeping the temperature and stirring for 3h after adding;
(2) Adding 0.38mol of ammonium iodide into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding 4L of isopropanol, stirring for 3 hours, adding 4L of isopropanol again, stirring for 3 hours, cooling to 20-30 ℃, stirring for 1 hour, and filtering to obtain a filter cake which is a crude product of R-norepinephrine D-tartrate;
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2.25L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding a mixed solution of methanol 12L and isopropanol 4L at a temperature of 1h, stirring for 1h at a temperature of 5+/-5 ℃, stirring for 3h at a temperature of 3h, and filtering;
(4) Washing a filter cake with 0.5L of absolute ethyl alcohol, adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with 0.5L of water, and drying in vacuum at 35 ℃ for 2 hours to obtain R-norepinephrine.
The method according to the invention is carried out according to the following operations:
(1) Adding 6.73mol of D-tartaric acid, 0.2mol of sodium thiosulfate and 6.51mol of racemic norepinephrine into 2.75L of water and 0.4L of dimethyl sulfoxide, stirring for 0.5h at 30-40 ℃, then dropwise adding a mixed solution of 10L of ethanol and 5L of isopropanol into the reaction solution at the temperature of 30-40 ℃ for 1h, and continuing to stir for 3h after adding;
(2) Adding 0.37mol of sodium iodide into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding 4L of isopropanol, stirring for 3 hours, adding 4L of isopropanol again, stirring for 3 hours, cooling to 20-30 ℃, stirring for 1 hour, and filtering to obtain a filter cake which is a crude product of R-norepinephrine D-tartrate;
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2.25L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding a mixed solution of ethanol 12L and isopropanol 4L at a temperature of 1h, stirring for 1h at a temperature of 5+/-5 ℃, stirring for 3h at a temperature of 3h, and filtering;
(4) Washing a filter cake with 0.5L of absolute ethyl alcohol, adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with 0.5L of water, and drying in vacuum at 35 ℃ for 2 hours to obtain R-norepinephrine.
The method according to the invention is carried out according to the following operations:
(1) 7.20mol of D-tartaric acid, 0.18mol of sodium thiosulfate and 6.51mol of racemic norepinephrine are added into 2.5L of water and 0.35L of dimethyl sulfoxide, stirred for 0.5h at 30-40 ℃, then a mixed solution of 5L of methanol and 10L of ethanol is added into a reaction solution for Wen Di h, and after the addition, the heat preservation and stirring are continued for 3h;
(2) Adding 0.30mol of potassium iodide into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding 4L of ethanol, stirring for 3 hours, adding 6L of ethanol again, stirring for 3 hours, cooling to 20-30 ℃, stirring for 3 hours, and filtering to obtain a filter cake which is a crude product of R-norepinephrine D-tartrate;
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2L of pure water, heating to 30-40 ℃, stirring for 0.5h, keeping the temperature, dropwise adding a mixed solution of methanol 7L and ethanol 7L for 1h, keeping the temperature, stirring for 1h, cooling to 5+/-5 ℃, keeping the temperature, stirring for 3h, and filtering;
(4) Washing a filter cake with 0.5L of absolute ethyl alcohol, adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with 0.5L of water, and drying in vacuum at 35 ℃ for 2 hours to obtain R-norepinephrine.
The method according to the invention is carried out according to the following operations:
(1) Adding 6.67mol of D-tartaric acid, 0.22mol of sodium thiosulfate and 6.51mol of racemic norepinephrine into 3L of water and 0.45L of dimethyl sulfoxide, stirring for 0.5h at 30-40 ℃, adding a mixed solution of 8L of methanol and 8L of ethanol into the reaction solution for Wen Di h, and keeping the temperature and stirring for 3h after adding;
(2) Adding 0.36mol of potassium iodide into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding 6L of ethanol, stirring for 3 hours, adding 4L of ethanol again, stirring for 3 hours, cooling to 20-30 ℃, stirring for 3 hours, and filtering to obtain a filter cake which is a crude product of R-norepinephrine D-tartrate;
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2.5L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding a mixed solution of methanol 6L and ethanol 12L at a temperature of 1h, stirring for 1h at a temperature of 5+/-5 ℃, stirring for 3h at a temperature of 3h, and filtering;
(4) Washing a filter cake with 0.5L of absolute ethyl alcohol, adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with 0.5L of water, and drying in vacuum at 35 ℃ for 2 hours to obtain R-norepinephrine.
Further, a second aspect of the present invention provides a process for preparing norepinephrine bitartrate comprising the steps of: preparing R-norepinephrine according to the method of the first aspect of the present invention; 950-1200 g of L-tartaric acid, such as 1000g, 3-5L of purified water, such as 3.8L, 0.5-2 g of sodium thiosulfate, such as 1g, and 950g of R-norepinephrine are added into a reaction kettle, reactants are heated to 30-40 ℃ such as 35 ℃, 15-30 g of medicinal active carbon, such as 20g, are added, stirring and heat preservation are carried out for 20-60 min, such as 30min, filtering is carried out, and filter paper is washed with 0.8-1.5L of water, such as 1L; controlling the temperature of the filtrate within the range of 35-40 ℃, dropwise adding 15-20L of absolute ethyl alcohol, such as 16L, into a reaction kettle, adding 1-3 g of norepinephrine bitartrate seed crystal, such as 2g, stirring for 0.5-2 h, such as 1h, cooling to 5+/-2 ℃, stirring for 1-3 h, such as 2h, filtering, leaching the filter cake with 1-3L of absolute ethyl alcohol, such as 2L, and vacuum drying at 30-50 ℃ such as 40 ℃ for 3-6 h, such as 4h, thereby obtaining the norepinephrine bitartrate.
The invention uses D-tartaric acid to split racemic norepinephrine, and achieves the purpose of dynamic kinetic resolution of norepinephrine by adding a catalyst, thereby greatly improving the resolution yield. After the racemized norepinephrine and D tartaric acid form salt, the R-configuration norepinephrine hydrochloride has smaller solubility in water/alcohol solvent, and is separated out, the S-configuration norepinephrine hydrochloride is catalyzed by iodide ions to generate racemized norepinephrine hydrochloride, and the racemized norepinephrine hydrochloride enters the next circulation, so that the purpose of splitting the norepinephrine by dynamic dynamics is achieved. It has been unexpectedly found that by using the process of the present invention, R-norepinephrine is obtained in high purity, in high yield, with low levels of isomeric impurities, and with a simple process.
Drawings
Fig. 1: a reaction scheme for dynamic kinetic resolution of racemic norepinephrine R.
Fig. 2: HPLC diagram of chemical purity after resolution.
Fig. 3: HPLC chart of the isomer of racemic norepinephrine of the starting material used in example 1.
Fig. 4: example 1 chiral purity isomer detection HPLC plot of R-norepinephrine pure obtained after resolution and D-tartaric acid removal.
Description of the embodiments
Various aspects of the invention will be described in detail below by way of examples, with the understanding that these example descriptions are illustrative only. In these examples, the operation and corresponding operating conditions are well known in the art, as not explicitly stated.
In the examples below, the starting material, racemic norepinephrine, was prepared by resolution from starting material, which, if not specified, was obtained by crystallization purification from ethanol and 2% hydrochloric acid solution after drying the crude product according to the methods described in sections 1.2.1 and 1.2.2 of the Liang Dawei document, the starting material racemic norepinephrine (50:50 ratio of the two isomers) had a chromatographic purity of >95% as measured by reference to the method under the pharmacopoeia 2020 p.954 norepinephrine bitartrate.
In the course of carrying out the dynamic kinetic resolution method of racemic norepinephrine according to the invention, a racemisation catalyst selected from the group consisting of: potassium iodide, sodium iodide, ammonium iodide, which can provide iodide anions for the racemization catalytic reaction.
Example 1: dynamic kinetic resolution of racemic norepinephrine for the preparation of R-norepinephrine
Splitting:
(1) D-tartaric acid (1010 g,6.73 mol), sodium thiosulfate (32 g,0.2 mol) and racemic norepinephrine (1100 g,6.51 mol) are added into 2.75L of water and 0.4L of dimethyl sulfoxide, stirred for 0.5h at 30-40 ℃, then a mixed solution of methanol (10L) and ethanol (5L) is dropwise added into the reaction solution at a temperature of 30-40 ℃ for heat preservation, and the heat preservation and stirring are continued for 3h after the addition;
(2) Adding potassium iodide (55 g,0.33 mol) into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding ethanol (5L), stirring for 3h, adding ethanol (5L) again, stirring for 3h, cooling to 20-30 ℃, stirring for 3h again, and filtering to obtain a filter cake which is the crude product of R-norepinephrine D-tartrate;
d-tartaric acid removal:
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2.25L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding (1 h) a mixed solution of methanol (10L) and ethanol (5L) at a constant temperature, stirring for 1h at a constant temperature, cooling to 5+/-5 ℃, stirring for 3h at a constant temperature, and filtering;
(4) Washing the filter cake with absolute ethyl alcohol (0.5L), adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with water (0.5L), and drying in vacuum at 35 ℃ for 2 hours to obtain 711g of R-norepinephrine pure product with the yield of 64.6%.
The above-mentioned yield of 64.6% is calculated based on 6.51mol of the RS racemic norepinephrine, and the yield is 129.2% based on 3.255mol of R norepinephrine which is half of 6.51mol of the racemic norepinephrine. In calculating the yield of this pure R-norepinephrine product herein, all are calculated on the basis of the total amount of racemic norepinephrine, unless otherwise specified.
The norepinephrine bitartrate carried by the pharmacopoeia is a salt formed by R-norepinephrine and L-tartaric acid, so that the D-tartrate is removed from the crude product of the D-tartrate of the R-norepinephrine obtained in the step (1) to prepare the R-norepinephrine, and then the R-norepinephrine can be further prepared into the norepinephrine bitartrate medicinal bulk drug meeting the pharmacopoeia standard.
Example 2: dynamic kinetic resolution of racemic norepinephrine for the preparation of R-norepinephrine
Splitting:
(1) D-tartaric acid (1010 g,6.73 mol), sodium thiosulfate (32 g,0.2 mol) and racemic norepinephrine (1100 g,6.51 mol) are added into 2.75L of water and 0.4L of dimethyl sulfoxide, stirred for 0.5h at 30-40 ℃, then a mixed solution of methanol (12L) and isopropanol (4L) is dropwise added into the reaction solution at a temperature of 30-40 ℃ for heat preservation, and the heat preservation and stirring are continued for 3h after the addition;
(2) Adding ammonium iodide (55 g,0.38 mol) into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding isopropanol (4L), stirring for 3h, adding isopropanol (4L) again, stirring for 3h, cooling to 20-30 ℃, stirring for 1h again, and filtering to obtain a filter cake which is the crude product of R-norepinephrine D-tartrate;
d-tartaric acid removal:
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2.25L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding (1 h) a mixed solution of methanol (12L) and isopropanol (4L) at a constant temperature, stirring for 1h at a constant temperature, cooling to 5+/-5 ℃, stirring for 3h at a constant temperature, and filtering;
(4) Washing the filter cake with absolute ethyl alcohol (0.5L), adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with water (0.5L), and drying in vacuum at 35 ℃ for 2 hours to obtain 724g of R-norepinephrine pure product with the yield of 65.8%.
Example 3: dynamic kinetic resolution of racemic norepinephrine for the preparation of R-norepinephrine
Splitting:
(1) D-tartaric acid (1010 g,6.73 mol), sodium thiosulfate (32 g,0.2 mol) and racemic norepinephrine (1100 g,6.51 mol) are added into 2.75L of water and 0.4L of dimethyl sulfoxide, stirred for 0.5h at 30-40 ℃, then a mixed solution of ethanol (10L) and isopropanol (5L) is dropwise added into the reaction solution at a temperature of 30-40 ℃ for heat preservation, and the heat preservation and stirring are continued for 3h after the addition;
(2) Adding sodium iodide (55 g,0.37 mol) into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding isopropanol (4L), stirring for 3h, adding isopropanol (4L) again, stirring for 3h, cooling to 20-30 ℃, stirring for 1h again, and filtering to obtain a filter cake which is the crude product of R-norepinephrine D-tartrate;
d-tartaric acid removal:
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2.25L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding (1 h) a mixed solution of ethanol (12L) and isopropanol (4L) at a constant temperature, stirring for 1h at a constant temperature, cooling to 5+/-5 ℃, stirring for 3h at a constant temperature, and filtering;
(4) Washing the filter cake with absolute ethyl alcohol (0.5L), adding the filter cake into 4L of purified water, stirring for 0.5h, adding ammonia water to adjust the pH to 9-10, stirring for 0.5h, filtering, washing the filter cake with water (0.5L), and vacuum drying at 35 ℃ for 2h to obtain 703g of pure R-norepinephrine with the yield of 63.9%.
Example 4: dynamic kinetic resolution of racemic norepinephrine for the preparation of R-norepinephrine
Splitting:
(1) D-tartaric acid (1080 g,7.20 mol), sodium thiosulfate (28 g,0.18 mol) and racemic norepinephrine (1100 g,6.51 mol) are added into 2.5L of water and 0.35L of dimethyl sulfoxide, stirred for 0.5h at 30-40 ℃, then a mixed solution of methanol (5L) and ethanol (10L) is dropwise added into the reaction solution at a temperature of 30-40 ℃ for heat preservation, and the heat preservation and stirring are continued for 3h after the addition;
(2) Adding potassium iodide (50 g,0.30 mol) into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding ethanol (4L), stirring for 3h, adding ethanol (6L) again, stirring for 3h, cooling to 20-30 ℃, stirring for 3h again, and filtering to obtain a filter cake which is the crude product of R-norepinephrine D-tartrate;
d-tartaric acid removal:
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding (1 h) a mixed solution of methanol (7L) and ethanol (7L) at a constant temperature, stirring for 1h at a constant temperature, cooling to 5+/-5 ℃, stirring for 3h at a constant temperature, and filtering;
(4) Washing the filter cake with absolute ethyl alcohol (0.5L), adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with water (0.5L), and vacuum drying at 35 ℃ for 2 hours to obtain 709g of pure R-norepinephrine with the yield of 64.4%.
Example 5: dynamic kinetic resolution of racemic norepinephrine for the preparation of R-norepinephrine
Splitting:
(1) D-tartaric acid (1000 g,6.67 mol), sodium thiosulfate (35 g,0.22 mol) and racemic norepinephrine (1100 g,6.51 mol) are added into 3L of water and 0.45L of dimethyl sulfoxide, stirred for 0.5h at 30-40 ℃, then a mixed solution of methanol (8L) and ethanol (8L) is dropwise added into the reaction solution at a temperature of 30-40 ℃ for heat preservation, and the heat preservation and stirring are continued for 3h after the addition;
(2) Adding potassium iodide (60 g,0.36 mol) into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding ethanol (6L), stirring for 3h, adding ethanol (4L) again, stirring for 3h, cooling to 20-30 ℃, stirring for 3h again, and filtering to obtain a filter cake which is the crude product of R-norepinephrine D-tartrate;
d-tartaric acid removal:
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2.5L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding (1 h) a mixed solution of methanol (6L) and ethanol (12L) at a constant temperature, stirring for 1h at a constant temperature, cooling to 5+/-5 ℃, stirring for 3h at a constant temperature, and filtering;
(4) Washing the filter cake with absolute ethyl alcohol (0.5L), adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with water (0.5L), and vacuum drying at 35 ℃ for 2 hours to obtain 716g of pure R-norepinephrine with the yield of 65.1%.
Example 6: dynamic kinetic resolution of racemic norepinephrine for the preparation of R-norepinephrine
Referring to the operations of examples 1-3, respectively, except that sodium thiosulfate was changed to 0.2mol of sodium metabisulfite, and the rest of the operations were the same, three batches of R-norepinephrine yields of 44.2%, 43.5% and 45.0% were obtained, respectively, indicating that the effect of changing to sodium metabisulfite was significantly poorer.
Example 7: dynamic kinetic resolution of racemic norepinephrine for the preparation of R-norepinephrine
Referring to the operations of examples 1-3, except that the amount of sodium thiosulfate was changed to 0.05mol, and the remaining operations were the same, three batches of R-norepinephrine yields of 40.4%, 38.1% and 39.8%, respectively, were obtained, indicating that the effect of reducing the amount of sodium thiosulfate by changing to sodium thiosulfate was poor.
Referring to the operations of examples 1-3, except that the amount of sodium thiosulfate was changed to 0.1mol, and the remaining operations were the same, three batches of R-norepinephrine yields of 45.8%, 44.2% and 46.3% were obtained, respectively, indicating that the effect of reducing the amount of sodium thiosulfate by changing to sodium thiosulfate was poor.
It has also been found that the R-norepinephrine yield also drops below 52% when increasing the amount of sodium thiosulfate to 0.3mol and above in the operations of examples 1-3, so that an amount of sodium thiosulfate of 0.18-0.22 mol is preferred as in examples 1-5.
Example 8: dynamic kinetic resolution of racemic norepinephrine for the preparation of R-norepinephrine
With reference to the operations of examples 1-3, except that sodium thiosulfate was not used, the remaining operations were identical, and three batches of R-norepinephrine yields of 23.6%, 25.3%, 24.2%, respectively, were obtained.
Referring to the operations of examples 1-3, except that dimethyl sulfoxide (whose volume was made up with water) was not used, the remaining operations were identical, and three batches of R-norepinephrine yields were 34.5%, 33.7%, 35.4%, respectively.
With reference to the operations of examples 1 to 3, the differences were that sodium thiosulfate was not used and dimethyl sulfoxide was not used (its volume was made up with water), and the remaining operations were the same, giving three batches of R-norepinephrine yields of 18.2%, 20.3% and 19.5%, respectively.
Referring to the operations of examples 1-3, the only difference was that the D-tartaric acid used therein was changed to an equivalent amount of L-tartaric acid, and the remaining operations were the same, resulting in three batches of R-norepinephrine yields of 4.4%, 6.3%, 5.8%, respectively.
For each of the batches of R-norepinephrine pure obtained in examples 1-5 above, the HPLC purity and isomer content of each of the batches were measured, and the results showed that the HPLC purity of 5 batches of samples was greater than 99% and the isomer content was less than 1%. The measurement method is described below.
Example 9: HPLC chromatographic purity detection
According to high performance liquid chromatography (four general rules 0512 in the 2020 edition of Chinese pharmacopoeia);
test solution: taking a test sample, adding the mobile phase A to dissolve and dilute the test sample to prepare a solution containing about 5mg of the mobile phase A in each 1ml of the solution, wherein the solution is used as the test sample solution;
control solution: precisely measuring a proper amount of sample solution, quantitatively diluting with a mobile phase A to prepare a solution with the concentration of about 15 mug in each 1ml, and taking the solution as a control solution;
system applicability solution: taking 10mg of norepinephrine bitartrate (which dissociates in the solution, so the method is suitable for measuring norepinephrine and norepinephrine bitartrate), adding 5ml of 0.1mol/L hydrochloric acid solution to dissolve, taking 1ml of concentrated hydrogen peroxide solution and 0.1ml of concentrated hydrogen peroxide solution, shaking up, irradiating for 90 minutes under an ultraviolet lamp (254 nm), adding 9ml of mobile phase A, shaking up, and taking the solution as a system applicability solution;
chromatographic conditions: octadecylsilane chemically bonded silica is used as a filler, a 0.05% sodium heptanesulfonate solution (pH value is regulated to 2.2 by phosphoric acid) is used as a mobile phase A, an acetonitrile-0.05% sodium heptanesulfonate solution (1:1) (pH value is regulated to 2.4 by phosphoric acid) is used as a mobile phase B, gradient elution is carried out according to the following table, the detection wavelength is 280nm, the flow rate is 1.5ml per minute, and the sample injection volume is 20 mu l;
System applicability requirements: in the system applicability solution chromatogram, the retention time of the main component peak is about 11 minutes, an unknown degradation product peak and a norepinephrine peak should appear after the main component peak, the relative retention time of the norepinephrine peak is about 1.27, and the separation degree of the main component peak and the adjacent impurity peak is more than 3.8.
And (3) measuring: precisely measuring 20 mu l of each of the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording a chromatogram.
Limit: the pharmacopoeia standard prescribes that the limit requirement of the norepinephrine bitartrate pharmaceutical bulk drug has a chromatographic peak with the retention time consistent with that of norepinephrine peak in a chromatogram of a test solution, the peak area is multiplied by 0.3 and then is not more than 1/3 (0.1%) of the main peak area of a control solution, the peak area of other single impurities is not more than 1/3 (0.1%) of the main peak area of the control solution, and the total amount of impurities is not more than 0.3%.
The HPLC chromatographic purity was calculated by subtracting the solvent peak from the chromatogram of the test solution and using the hundred product normalization method.
Results: the purity of the five batches of R-norepinephrine obtained in examples 1-5 is in the range of 99.2% -99.6%, for example, the chromatographic purity of R-norepinephrine in example 1 is 99.5%, and the chromatogram of the sample in typical example 1 is shown in FIG. 2.
Example 10: HPLC method for determining S isomer content in R norepinephrine
According to high performance liquid chromatography (four general rules 0512 in the 2020 edition of Chinese pharmacopoeia);
solvent: methanesulfonic acid-absolute ethanol (0.1:100);
control solution: taking a proper amount of isomer reference substance, precisely weighing, adding a solvent to dissolve and dilute the isomer reference substance to prepare a solution containing about 0.1mg of isomer reference substance per 1ml, and taking the isomer reference substance as a reference substance solution;
test solution: taking a proper amount of a test sample, precisely weighing, adding a solvent to dissolve and dilute the test sample into a solution containing about 2mg per 1ml, and taking the solution as a test sample solution;
chromatographic conditions: chromatographic column (Chiralpak AD-H4.6x250 mm,5 μm) packed with amylose-tris (3, 5-dimethylphenylcarbamate); n-hexane: absolute ethyl alcohol: methane sulfonic acid: ethanolamine (60:40:0.1:0.02) is a mobile phase, the flow rate is 0.8ml per minute, the column temperature is 30 ℃, and the detection wavelength is 280nm;
assay: precisely measuring 20 μl of each of the solvent, the reference solution and the sample solution, injecting into a liquid chromatograph, and recording the chromatogram;
in the chromatogram of the sample solution, the peak sequence is the chromatographic peak of isomer (S-norepinephrine) and main component (R-norepinephrine) in sequence, and the separation degree between the two should be more than 1.2.
FIG. 3 is an HPLC plot of the isomer of racemic norepinephrine of the starting material used in example 1 showing a peak at 9.56min for S-norepinephrine and a peak at 12.41min for R-norepinephrine, showing, in aggregate, that the two isomer ratios are approximately 50:50 (peak areas of the two peaks were 5822515 and 6028624, respectively), and the degree of separation of the two isomers was 2.08.
FIG. 4 is a chiral purity isomer detection HPLC chart of the pure R-norepinephrine product obtained after resolution and D-tartaric acid removal of example 1, showing an area normalized content of 0.751% for S-norepinephrine (peak areas of the two peaks 84904 and 11214214, respectively).
According to measurement, the S-norepinephrine content as impurities in the five batches of R-norepinephrine pure products obtained in examples 1-5 is in the range of 0.41% -0.87%.
Example 11: preparation of norepinephrine bitartrate
Adding L-tartaric acid (1000 g), purified water (3.8L), sodium thiosulfate (1 g) and norepinephrine (950 g) obtained in example 1 into a reaction kettle, heating the reactant to 35 ℃, adding medicinal active carbon (20 g), stirring and preserving heat for 30min, filtering, and washing filter paper with water (1L); the temperature of the filtrate is controlled within the range of 35-40 ℃, absolute ethyl alcohol (16L) is dropwise added into a reaction kettle, after that, norepinephrine bitartrate seed crystal (2 g) is added, the mixture is stirred for 1h under heat preservation, the temperature is reduced to 5+/-2 ℃, the mixture is stirred for 2h under heat preservation, the mixture is filtered, the filter cake is leached by the absolute ethyl alcohol (2L) and then is dried for 4h under vacuum at 40 ℃, and 1684g of norepinephrine bitartrate which can be used as a medicinal raw material medicine is obtained, and the molar yield is 88.9%.
In addition, norepinephrine bitartrate prepared by the method according to the method by taking norepinephrine obtained in examples 2-5 as a starting material respectively, and 4 batches of norepinephrine bitartrate which can be used as a medicinal raw material medicine are obtained, and the molar yield is 87.2% -89.4%.
Example 12: quality inspection of norepinephrine bitartrate
The norepinephrine bitartrate loaded by the second edition of Chinese pharmacopoeia 2020 provides a certain quality standard and a detection method, and the embodiment examines whether the five batches of norepinephrine bitartrate obtained in the embodiment 11 meet the pharmacopoeia standard regulation or not and whether the five batches of norepinephrine bitartrate meet the medicinal requirements or not.
1. Traits (3)
The five batches obtained in example 11, all of which were white crystalline powders, were odorless; each sample was readily soluble in water, slightly soluble in ethanol, and insoluble in chloroform or diethyl ether.
Melting point: the melting points of the five batches of samples are all in the range of 102-106 ℃, and the samples are decomposed and cloudy at the same time when melted, for example, the melting point of the samples prepared from norepinephrine obtained in example 1 is 102.8-103.6 ℃.
Specific rotation: the specific rotations of the five samples were all in the range of-10.0 ° to-12.0 ° as determined by the method, for example, the specific rotations of the samples prepared with norepinephrine obtained in example 1 were-11.3 °.
2. Authentication
And (3) identifying a ferric trichloride test solution: and checking according to law, wherein five batches of samples all meet the pharmacopoeia standard.
And (3) iodine test solution identification: and checking according to law, wherein five batches of samples all meet the pharmacopoeia standard.
And (3) potassium chloride identification: and checking according to law, wherein five batches of samples all meet the pharmacopoeia standard.
3. Inspection of
Clarity and color of the solution: the solution was clear and colorless as examined by law for all five batches.
Ketone body: according to the law, the absorbance of each of the five batches of samples is less than 0.04, for example, the absorbance of the sample of example 1 is 0.021.
Related substances: the system applicability test is carried out according to related substance inspection methods recorded in pharmacopoeia standards, and meets the standard regulation; limit results: the norepinephrine content of the five samples is less than 0.05%, for example, the norepinephrine content of the sample obtained in example 1 is 0.018%, the other single impurities are less than 0.05%, the total impurity content of the five samples is less than 0.18%, for example, the total impurity content of the sample obtained in example 1 is 0.010%; five batches of samples for inspection of the related substances all meet the standard rules.
Moisture content: according to the legal examination, the moisture content of the five batches of samples is in the range of 5.0% -6.0%, for example, the moisture content of the samples prepared by using norepinephrine obtained in example 1 is 5.34%.
Glowing residues: the legal inspection is carried out, and the standard regulation is less than 0.1 percent; the burning residues of the five batches of samples are not more than 0.1 percent.
4. Content determination
The perchloric acid titration method is adopted, the measurement is carried out according to the method, and calculated according to anhydrous matters, the content of C8H11NO3.C4H6O6 in five batches of samples is greater than 99.0 percent and is in the range of 99.4% -100.2%, for example, the content of C8H11NO3.C4H6O6 in the samples prepared by norepinephrine obtained in the example 1 is 99.86 percent, and all the samples accord with the standard regulation.
The present invention is described in detail by the above examples, but the present invention is not limited to the above detailed methods, i.e., it does not mean that the present invention must be practiced depending on the above detailed methods. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (10)
1. A process for preparing norepinephrine bitartrate using racemic norepinephrine, comprising the steps of:
(1) Adding D-tartaric acid, sodium thiosulfate and racemic norepinephrine into water and dimethyl sulfoxide, stirring under warm condition to dissolve, then dropwise adding a lower alcohol mixed solution into the reaction solution at a certain temperature, and stirring under a certain temperature to react;
(2) Adding a racemization catalyst into the reaction solution to dissolve, heating the reaction solution to 50-80 ℃, for example, 60-70 ℃, adding lower alcohol, continuing stirring, adding lower alcohol again, continuing stirring, cooling to 10-30 ℃, for example, 20-30 ℃, continuing stirring, and filtering to obtain a filter cake which is the crude product of R-norepinephrine D-tartrate;
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into water, stirring under warm condition to dissolve, then dropwise adding lower alcohol mixed solution into the reaction solution at a constant temperature, stirring under a constant temperature to react, cooling to below 10deg.C, continuing stirring, and filtering;
(4) Washing the filter cake with lower alcohol, adding into water, stirring to dissolve, adding ammonia water to adjust the pH to 8-11, continuously stirring, filtering, washing the filter cake with water, and drying to obtain R-norepinephrine.
2. The method according to claim 1, wherein in step (1):
the molar ratio of the D-tartaric acid to the racemic norepinephrine is 1-1.2: 1, a step of;
the molar ratio of the racemized norepinephrine to the sodium thiosulfate is 25-40: 1, a step of;
the amount of water added into each 1mol of racemic norepinephrine is 0.2L-1L;
the dimethyl sulfoxide content is 10-25% (v/v) of water;
the temperature of the warming condition is 30-40 ℃;
The lower alcohol mixed solution is two of methanol, ethanol and isopropanol in a volume ratio of 0.5-5: 1, mixing the liquid in proportion; or (b)
The total addition amount of the lower alcohol mixed solution added by adding every 6.51mol of racemic norepinephrine is 14-18L.
3. The method of claim 1, wherein step (1) is performed as follows: adding 6.6-7.2 mol of D-tartaric acid, 0.18-0.22 mol of sodium thiosulfate and 6.51mol of racemic norepinephrine into 2.5-3L of water and 0.35-0.45L of dimethyl sulfoxide, stirring at 30-40 ℃ for 0.5h to dissolve, dropwise adding 15-16L of lower alcohol mixed solution at a constant temperature, and stirring at a constant temperature for 3h.
4. The method according to claim 1, wherein in step (2):
the racemization catalyst is selected from potassium iodide, sodium iodide and ammonium iodide, and the amount of the racemization catalyst added per 6.51mol of racemization norepinephrine is 0.2-0.5 mol, for example 0.30-0.38 mol;
the lower alcohol is selected from methanol, ethanol and isopropanol, and the amount of the lower alcohol added for two times is 3-8L independently based on the addition of each 6.51mol of racemic norepinephrine; or,
the step (2) is carried out according to the following operation: adding 0.30-0.38 mol of racemization catalyst into the reaction liquid to dissolve, heating the reaction liquid to 50-80 ℃, for example, 60-70 ℃, adding 4-6L of lower alcohol selected from methanol, ethanol and isopropanol, stirring for 3 hours, adding 4-6L of lower alcohol again, stirring for 3 hours, cooling to 10-30 ℃, for example, stirring for 1-3 hours after 20-30 ℃, and filtering to obtain a filter cake which is the crude product of R-norepinephrine D-tartrate.
5. The method according to claim 1, wherein in step (3):
adding 2-2.5L of water into the crude product of the R-norepinephrine D-tartrate;
the temperature of the warm condition is 30-40 ℃;
the lower alcohol mixed solution is two of methanol, ethanol and isopropanol in a volume ratio of 0.5-5: 1, mixing the liquid in proportion;
the total addition amount of the lower alcohol mixed solution added by adding each 6.51mol of racemic norepinephrine is 14-18L; or,
the step (3) is carried out according to the following operation: (3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2-2.5L of water, stirring at 30-40 ℃ for 0.5h to dissolve, then dropwise adding 14-18L of lower alcohol mixed solution into the reaction solution at a constant temperature, stirring at a constant temperature for 1h to react, cooling to 0-10 ℃, continuing stirring for 3h, and filtering.
6. The method according to claim 1, wherein in step (4):
the lower alcohol is methanol or ethanol or isopropanol, and the addition amount of the lower alcohol is 0.2-1L calculated by each 6.51mol of racemic norepinephrine;
the amount of water added into each 6.51mol of racemic norepinephrine feed is 3-6L;
adding water and stirring for 0.5 hour;
adding ammonia water to adjust the pH to 8-11, and continuously stirring for 0.5 hour;
the filter cake obtained was washed with water (0.5L); or alternatively, the first and second heat exchangers may be,
The obtained filter cake is washed by water and then dried in vacuum at 30-40 ℃ such as 35 ℃ for 1-4 hours such as 2 hours.
7. The method of claim 1, wherein step (4) is performed as follows: (4) Washing the filter cake with 0.2-1L of absolute ethyl alcohol, adding 3-6L of water, stirring to dissolve, adding ammonia water to adjust the pH to 8-11 such as pH 9-10, continuously stirring, filtering, washing the filter cake with water, and vacuum drying at 30-40 ℃ such as 35 ℃ for 1-4 h to obtain R-norepinephrine.
8. The method according to claim 1, which is performed according to the following operations:
(1) Adding 6.73mol of D-tartaric acid, 0.2mol of sodium thiosulfate and 6.51mol of racemic norepinephrine into 2.75L of water and 0.4L of dimethyl sulfoxide, stirring for 0.5h at 30-40 ℃, then adding a mixed solution of 10L of methanol and 5L of ethanol into a reaction solution for Wen Di h, and continuing to stir for 3h after adding;
(2) Adding 0.33mol of potassium iodide into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding 5L of ethanol, stirring for 3 hours, adding 5L of ethanol again, stirring for 3 hours, cooling to 20-30 ℃, stirring for 3 hours, and filtering to obtain a filter cake which is a crude product of R-norepinephrine D-tartrate;
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2.25L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding a mixed solution of 10L of methanol and 5L of ethanol at a temperature of 1h, stirring for 1h at a temperature of 5+/-5 ℃, stirring for 3h at a temperature of 3h, and filtering;
(4) Washing a filter cake with 0.5L of absolute ethyl alcohol, adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with 0.5L of absolute ethyl alcohol, and vacuum drying at 35 ℃ for 2 hours to obtain R-norepinephrine;
alternatively, it is performed as follows:
(1) Adding 6.73mol of D-tartaric acid, 0.2mol of sodium thiosulfate and 6.51mol of racemic norepinephrine into 2.75L of water and 0.4L of dimethyl sulfoxide, stirring for 0.5h at 30-40 ℃, then adding a mixed solution of 12L of methanol and 4L of isopropanol into a reaction solution for Wen Di h, and keeping the temperature and stirring for 3h after adding;
(2) Adding 0.38mol of ammonium iodide into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding 4L of isopropanol, stirring for 3 hours, adding 4L of isopropanol again, stirring for 3 hours, cooling to 20-30 ℃, stirring for 1 hour, and filtering to obtain a filter cake which is a crude product of R-norepinephrine D-tartrate;
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2.25L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding a mixed solution of methanol 12L and isopropanol 4L at a temperature of 1h, stirring for 1h at a temperature of 5+/-5 ℃, stirring for 3h at a temperature of 3h, and filtering;
(4) Washing a filter cake with 0.5L of absolute ethyl alcohol, adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with 0.5L of absolute ethyl alcohol, and vacuum drying at 35 ℃ for 2 hours to obtain R-norepinephrine;
alternatively, it is performed as follows:
(1) Adding 6.73mol of D-tartaric acid, 0.2mol of sodium thiosulfate and 6.51mol of racemic norepinephrine into 2.75L of water and 0.4L of dimethyl sulfoxide, stirring for 0.5h at 30-40 ℃, then dropwise adding a mixed solution of 10L of ethanol and 5L of isopropanol into the reaction solution at the temperature of 30-40 ℃ for 1h, and continuing to stir for 3h after adding;
(2) Adding 0.37mol of sodium iodide into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding 4L of isopropanol, stirring for 3 hours, adding 4L of isopropanol again, stirring for 3 hours, cooling to 20-30 ℃, stirring for 1 hour, and filtering to obtain a filter cake which is a crude product of R-norepinephrine D-tartrate;
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2.25L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding a mixed solution of ethanol 12L and isopropanol 4L at a temperature of 1h, stirring for 1h at a temperature of 5+/-5 ℃, stirring for 3h at a temperature of 3h, and filtering;
(4) Washing a filter cake with 0.5L of absolute ethyl alcohol, adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with 0.5L of water, and drying in vacuum at 35 ℃ for 2 hours to obtain R-norepinephrine.
9. The method according to claim 1, which is performed according to the following operations:
(1) 7.20mol of D-tartaric acid, 0.18mol of sodium thiosulfate and 6.51mol of racemic norepinephrine are added into 2.5L of water and 0.35L of dimethyl sulfoxide, stirred for 0.5h at 30-40 ℃, then a mixed solution of 5L of methanol and 10L of ethanol is added into a reaction solution for Wen Di h, and after the addition, the heat preservation and stirring are continued for 3h;
(2) Adding 0.30mol of potassium iodide into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding 4L of ethanol, stirring for 3 hours, adding 6L of ethanol again, stirring for 3 hours, cooling to 20-30 ℃, stirring for 3 hours, and filtering to obtain a filter cake which is a crude product of R-norepinephrine D-tartrate;
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2L of pure water, heating to 30-40 ℃, stirring for 0.5h, keeping the temperature, dropwise adding a mixed solution of methanol 7L and ethanol 7L for 1h, keeping the temperature, stirring for 1h, cooling to 5+/-5 ℃, keeping the temperature, stirring for 3h, and filtering;
(4) Washing a filter cake with 0.5L of absolute ethyl alcohol, adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with 0.5L of absolute ethyl alcohol, and vacuum drying at 35 ℃ for 2 hours to obtain R-norepinephrine;
alternatively, it is performed as follows:
(1) Adding 6.67mol of D-tartaric acid, 0.22mol of sodium thiosulfate and 6.51mol of racemic norepinephrine into 3L of water and 0.45L of dimethyl sulfoxide, stirring for 0.5h at 30-40 ℃, adding a mixed solution of 8L of methanol and 8L of ethanol into the reaction solution for Wen Di h, and keeping the temperature and stirring for 3h after adding;
(2) Adding 0.36mol of potassium iodide into the reaction solution to dissolve, heating the reaction solution to 60-70 ℃, adding 6L of ethanol, stirring for 3 hours, adding 4L of ethanol again, stirring for 3 hours, cooling to 20-30 ℃, stirring for 3 hours, and filtering to obtain a filter cake which is a crude product of R-norepinephrine D-tartrate;
(3) Adding the crude R-norepinephrine D-tartrate product obtained in the last step into 2.5L of pure water, heating to 30-40 ℃, stirring for 0.5h, dropwise adding a mixed solution of methanol 6L and ethanol 12L at a temperature of 1h, stirring for 1h at a temperature of 5+/-5 ℃, stirring for 3h at a temperature of 3h, and filtering;
(4) Washing a filter cake with 0.5L of absolute ethyl alcohol, adding the filter cake into 4L of purified water, stirring for 0.5 hour, adding ammonia water to adjust the pH to 9-10, stirring for 0.5 hour, filtering, washing the filter cake with 0.5L of water, and drying in vacuum at 35 ℃ for 2 hours to obtain R-norepinephrine.
10. A process for preparing norepinephrine bitartrate comprising the steps of: preparing R-norepinephrine according to the method of any one of claims 1-9; adding 950-1200 g of L-tartaric acid, 3-5L of purified water, 0.5-2 g of sodium thiosulfate and 950g of R-norepinephrine into a reaction kettle, heating reactants to 30-40 ℃, adding 15-30 g of medicinal active carbon, stirring and preserving heat for 20-60 min, filtering, and washing filter paper with 0.8-1.5L of water; and controlling the temperature of the filtrate within a range of 35-40 ℃, dropwise adding 15-20L of absolute ethyl alcohol into a reaction kettle, adding 1-3 g of norepinephrine bitartrate seed crystal, stirring for 0.5-2 h at a constant temperature, cooling to 5+/-2 ℃, stirring for 1-3 h at a constant temperature, filtering, leaching the filter cake with 1-3L of absolute ethyl alcohol, and vacuum-drying for 3-6 h at 30-50 ℃ to obtain the norepinephrine bitartrate.
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