CN116675613B - Method for preparing norepinephrine bitartrate by chiral resolution - Google Patents
Method for preparing norepinephrine bitartrate by chiral resolution Download PDFInfo
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- 229960001695 norepinephrine bitartrate Drugs 0.000 title claims abstract description 145
- 238000000034 method Methods 0.000 title claims abstract description 74
- 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 title claims abstract 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 213
- 238000003756 stirring Methods 0.000 claims abstract description 145
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 90
- 238000001914 filtration Methods 0.000 claims abstract description 88
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims abstract description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 62
- 238000001816 cooling Methods 0.000 claims abstract description 59
- 229960002748 norepinephrine Drugs 0.000 claims abstract description 57
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims abstract description 56
- 239000012065 filter cake Substances 0.000 claims abstract description 49
- 239000000047 product Substances 0.000 claims abstract description 48
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 47
- 239000000706 filtrate Substances 0.000 claims abstract description 42
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 37
- 238000005406 washing Methods 0.000 claims abstract description 35
- 239000013078 crystal Substances 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 239000000243 solution Substances 0.000 claims abstract description 19
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 15
- 238000001035 drying Methods 0.000 claims abstract description 15
- 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 11
- 239000010413 mother solution Substances 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 189
- 235000019441 ethanol Nutrition 0.000 claims description 81
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 52
- 238000001291 vacuum drying Methods 0.000 claims description 28
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 23
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 23
- 238000010438 heat treatment Methods 0.000 claims description 21
- 239000011259 mixed solution Substances 0.000 claims description 17
- 239000012452 mother liquor Substances 0.000 claims description 16
- 238000004090 dissolution Methods 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims 1
- 239000012043 crude product Substances 0.000 abstract description 4
- 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 116
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 24
- 238000004321 preservation Methods 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 11
- 239000003814 drug Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 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 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 229930182836 (R)-noradrenaline Natural products 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000007689 inspection Methods 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- YCIMNLLNPGFGHC-UHFFFAOYSA-N o-dihydroxy-benzene Natural products OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 4
- 229940001584 sodium metabisulfite Drugs 0.000 description 4
- 235000010262 sodium metabisulphite Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000008901 benefit Effects 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
- 230000033228 biological regulation Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- -1 chloroacetyl catechol Chemical compound 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229960001270 d- tartaric acid Drugs 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- YLXIPWWIOISBDD-NDAAPVSOSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;4-[(1r)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CNC[C@H](O)C1=CC=C(O)C(O)=C1 YLXIPWWIOISBDD-NDAAPVSOSA-N 0.000 description 1
- SFLSHLFXELFNJZ-MRVPVSSYSA-N (S)-noradrenaline Chemical compound NC[C@@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-MRVPVSSYSA-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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000579895 Chlorostilbon Species 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
- 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 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229910052876 emerald Inorganic materials 0.000 description 1
- 239000010976 emerald Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000010977 unit operation 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
- 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
- C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to a method for preparing norepinephrine bitartrate by chiral resolution, which comprises the following steps: reacting L-tartaric acid with racemic norepinephrine in water, dropwise adding lower alcohol, and continuing to react; cooling the reaction solution to room temperature, continuing to keep the temperature and stirring, filtering, adding lower alcohol into the mother solution, then adding seed crystal, cooling to 0-10 ℃, keeping the temperature and standing, filtering, drying a filter cake, and obtaining a crude norepinephrine bitartrate product; adding the crude product into water, stirring under warm condition to dissolve, adding active carbon, decolorizing, and filtering; slowly adding lower alcohol into the filtrate under the protection of nitrogen, maintaining the temperature and stirring at proper time, reducing the temperature and stirring at proper time, filtering, washing the filter cake with lower alcohol, and drying to obtain norepinephrine bitartrate. The norepinephrine bitartrate obtained by the method has high yield, high purity and simple operation.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a method for preparing a norepinephrine bitartrate drug substance, and in particular relates to a method for preparing a norepinephrine bitartrate drug substance by chiral resolution. The prepared norepinephrine bitartrate medicinal raw material meets the requirements of pharmacopoeia quality standards, and has higher yield and higher purity.
Background
Norepinephrine bitartrate (Norepinephrine Bitartrate) is formed by R-norepinephrine, L-tartaric acid and water in a ratio of 1:1:1, and has a molecular formula of C8H11NO3.C4H6O6.H2O, a molecular weight of 337.28, and a chemical name of (R) -4- (2-amino-1-hydroxyethyl) -1, 2-benzenediol bitartrate monohydrate, and has a chemical structural formula as follows:
the Chinese pharmacopoeia records that the content of C8H11NO3.C4H6O6.H2O in the norepinephrine bitartrate bulk drug calculated by anhydrous substance is not less than 99.0%; the medicinal raw material medicine is white or white-like crystalline powder; no odor; is easy to deteriorate when meeting light and air; the medicinal raw materials are easily soluble in water, slightly soluble in ethanol, and insoluble in chloroform or diethyl ether.
The medicine is taken in pharmacopoeias of multiple nations current versions, and the Chinese pharmacopoeias of multiple versions also take the raw material medicine of the variety and the small-volume injection, so that the medicine is taken as a classical adrenergic receptor agonist, and is a very commonly used product in clinic.
It is well documented that norepinephrine bitartrate is prepared by the resolution of tartaric acid starting from racemic norepinephrine (i.e., a 1:1 mixture of S-norepinephrine and R-norepinephrine).
Liang Dawei (Liang Dawei, et al, (-) -norepinephrine bitartrate) describes chemical technology and development, 2014, 43 (08): 11) that, using chloroacetyl catechol as a raw material, a racemic norepinephrine is obtained by ammonification and catalytic hydrogenation in sequence, followed by resolution using L-tartaric acid, and (-) -norepinephrine bitartrate is successfully synthesized. According to the technical scheme, the feeding sequence, the reaction time, the reaction temperature and the chiral resolution condition are researched, and the result shows that the reaction condition for preparing norepinephrine by using 10% ammonia water ethanol solution and Pd/C catalysis under the hydrogen pressure of 3.0MPa is better, and the high-yield and purity (-) -norepinephrine bitartrate can be obtained through crystallization resolution and 2 times of refining of L-tartaric acid at the temperature of 5-10 ℃. The detailed splitting operation of this document is as follows: 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 ℃, 5.0g of (+ -) -norepinephrine is added after the solid is completely dissolved, stirring and reacting are carried out for 30min at the temperature of 60 ℃, 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 solid appears, stirring is stopped, and the temperature is slowly reduced to 5 ℃ to allow the system to crystallize naturally for 10h. And then carrying out suction filtration, washing a filter cake with a proper amount of ethanol, carrying out vacuum drying to obtain a crude product, and refining the crude product once again according to the method to obtain the final product (-) -norepinephrine bitartrate 0.4g. It can be seen that this document shows that in the final resolution work the molar yield is only 4% and that such a very low yield process is not industrially acceptable.
CN115073312a (application No. 202210831097.5, modern halsen) discloses a method for synthesizing norepinephrine bitartrate, comprising: 1) Under the protection of inert gas, catechol and N-benzyl glycine or N, N-dibenzyl glycine are subjected to condensation reaction in a reaction solvent under the action of an auxiliary reagent to obtain N-benzyl norepinephrine ketone hydrochloride or N, N-dibenzyl norepinephrine ketone hydrochloride; 2) In the presence of inert atmosphere and purified water, N-benzyl norepinephrine ketone or N, N-dibenzyl norepinephrine ketone hydrochloride is catalyzed to hydrogenate and deprotect to obtain racemized norepinephrine; 3) Splitting: under the protection of nitrogen, adding racemic norepinephrine, L-tartaric acid and purified water into a 500ml reaction bottle, heating to 50-55 ℃ and stirring for dissolution; adding activated carbon, and decolorizing for 30min; filtering while the mixture is hot, slowly cooling the filtrate to 0-5 ℃ under the protection of nitrogen, stirring to separate out a large amount of solids, and continuously stirring for 4-6 hours; filtering to obtain a filter cake and a norepinephrine bitartrate mother solution, and washing the filter cake with absolute ethyl alcohol to obtain a wet product of the norepinephrine bitartrate split product; under the protection of nitrogen, adding wet norepinephrine bitartrate resolution product and purified water into a 250ml reaction bottle, heating to 50-55 ℃ and stirring for dissolution; adding activated carbon, and decolorizing for 30min; filtering while the mixture is hot, slowly cooling the filtrate to 0-5 ℃ under the protection of nitrogen, stirring to separate out solid, and then continuing stirring for 4-6 hours; filtering to obtain a filter cake and norepinephrine bitartrate mother solution, and washing the filter cake with absolute ethyl alcohol; and (3) obtaining a wet norepinephrine bitartrate product, and carrying out vacuum drying for 4-5 hours at the temperature of 40-45 ℃ to obtain a pure norepinephrine bitartrate product. However, the inventor discovers that the yield of R-norepinephrine obtained by the method is only 22%, the water has very good solubility to epinephrine tartrate, the solvent is used in large quantity, the yield is low, the materials are viscous, the stirring is difficult, and the scale-up is difficult.
CN112225665a (application No. 202011174131.3, yifeng) discloses a process for the preparation of norepinephrine bitartrate, comprising the steps of: s1, taking chloroacetyl catechol as a starting material, and carrying out a coupling reaction with dibenzylamine in a reaction solvent to obtain 2- (benzhydryl amino) -3',4' -dihydroxyacetophenone hydrochloride; s2, reducing 2- (benzhydryl amino) -3',4' -dihydroxyacetophenone hydrochloride in a solvent through hydrogenation catalysis to obtain racemic norepinephrine; s3, resolving racemic norepinephrine in an alcohol water solution through D-tartaric acid to obtain L-norepinephrine D-tartrate; s4, neutralizing the L-norepinephrine D-tartrate in water by alkali to obtain L-norepinephrine; compared with the existing preparation method, the preparation method disclosed by the invention uses easily available starting materials, ensures good reproducibility of a synthetic route, is simple in unit operation and economical in calculation, is easy to purify in each step of reaction, is controllable in quality, and greatly improves the reaction yield. However, it is apparent that this document uses D tartaric acid for resolution, requiring a resolution substitution to L tartaric acid, which is cumbersome.
Therefore, a simple and easy method for preparing high-purity norepinephrine bitartrate drug substance with high yield is still expected by those skilled in the art.
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. It has been found that at least one of the above-mentioned benefits is obtained by using the method of the present invention.
To this end, the present invention provides a process for the preparation of norepinephrine bitartrate comprising the steps of:
(1) Dissolving L-tartaric acid and racemic norepinephrine in water, reacting under warm condition, filtering, dripping lower alcohol into filtrate, and keeping warm and stirring;
(2) Cooling the reaction solution to room temperature, continuing to keep the temperature and stirring at proper time, filtering, adding lower alcohol into the mother solution, then adding norepinephrine bitartrate seed crystal to disperse, cooling to 0-10 ℃, keeping the temperature and standing, filtering, and drying a filter cake to obtain a crude norepinephrine bitartrate product;
(3) Adding the crude norepinephrine bitartrate into water under the protection of nitrogen, stirring under warm condition to dissolve, adding active carbon, decolorizing, and filtering;
(4) Slowly adding lower alcohol into the filtrate under the protection of nitrogen, maintaining the temperature, stirring, cooling to 0-15 ℃, maintaining the temperature, stirring, filtering, washing the filter cake with lower alcohol, and drying to obtain norepinephrine bitartrate.
According to the method disclosed by the invention, in the step (1), the molar ratio of L-tartaric acid to racemic norepinephrine is 1-1.1: 1.
the process according to the invention, wherein in step (1), sodium thiosulfate is added together with L-tartaric acid.
According to the method disclosed by the invention, in the step (1), sodium thiosulfate is also added together with L-tartaric acid, and the molar ratio of the racemized norepinephrine to the sodium thiosulfate is 108-163: 1.
the process according to the invention, wherein in step (1), the amount of water added per 1mol of racemic norepinephrine is 0.4l to 1l, e.g. 0.4l to 0.9l.
According to the method of the invention, in the step (1), dimethyl sulfoxide is also added, and the amount of dimethyl sulfoxide is 15-25% (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 is a mixed solution of methanol and ethanol, for example, the volume ratio of methanol to ethanol is 1.5-2.5: 1.
The method according to the invention, wherein step (1) is performed according to the following operations: adding 6.7-7.2 mol of L-tartaric acid and 0.04-0.06 mol of sodium thiosulfate into 2.5-6L of water to dissolve, adding 0.55-1L of dimethyl sulfoxide, adding 6.5mol of racemized norepinephrine under the condition of stirring at 30-40 ℃, stirring for 0.5h, filtering, and dropwise adding methanol and ethanol into the filtrate at the temperature of 35-40 ℃ in a volume ratio of 1.5-2.5: 1, and stirring for 1h at a constant temperature.
The method according to the present invention, wherein in step (2), the room temperature is a temperature of 25±3 ℃.
According to the method disclosed by the invention, in the step (2), the reaction solution is cooled to room temperature and then is continuously stirred for 1-2 hours under heat preservation.
The process according to the present invention, wherein in step (2), the lower alcohol is ethanol,
according to the method of the present invention, in the step (2), the lower alcohol is ethanol, and the amount of the lower alcohol added per 6.5mol of racemic norepinephrine is 2L to 4L.
The process according to the invention, wherein in step (2), the amount of the seed crystals of norepinephrine bitartrate added per 6.5mol of racemic norepinephrine is 1 to 3g, e.g. 2g.
According to the method of the invention, in the step (2), after the norepinephrine bitartrate seed crystal is added, the reaction solution is cooled to 5+/-3 ℃ and kept stand for 3-5 hours, for example, 4 hours.
According to the process of the present invention, wherein in step (2) the obtained filter cake is washed with lower alcohol, for example 0.6 to 1L of methanol per 6.5mol of racemic norepinephrine.
According to the method of the present invention, in the step (2), the cake is dried at 40 ℃ for 1 to 3 hours, for example, 2 hours.
The method according to the invention, wherein step (2) is performed according to the following operations: cooling the reaction solution to 25+/-3 ℃, preserving heat, stirring for 1-2 h, filtering, adding 2L-4L of ethanol into the mother solution, adding 1-3 g of norepinephrine bitartrate seed crystal, cooling to 5+/-3 ℃ and preserving heat for 3-5 h, washing a filter cake with 0.6-1L of methanol, and vacuum drying at 40 ℃ for 1-3 h to obtain a crude norepinephrine bitartrate.
According to the method disclosed by the invention, in the step (3), the crude norepinephrine bitartrate is added into 1.5-2.5L of water.
According to the method of the invention, in the step (3), the temperature of the warm condition is 35-40 ℃.
The method according to the present invention, wherein in the step (3), the amount of activated carbon added is 15g.
The method according to the invention, wherein in step (3), the decoloring time is 30min.
The method according to the invention, wherein step (3) is performed according to the following operations: under the protection of nitrogen, adding the crude norepinephrine bitartrate into 1.5-2.5L of water, heating to 35-40 ℃, stirring and dissolving. Adding 15g of active carbon, decolorizing for 30min, and filtering.
The process according to the present invention, wherein in step (4), the lower alcohol is methanol or ethanol.
The method according to the present invention, wherein in the step (4), the lower alcohol is methanol or ethanol, and the lower alcohol is added in an amount of 10 to 15L, for example, 10 to 14L per 6.5mol of racemic norepinephrine.
According to the method of the present invention, in the step (4), the lower alcohol is added, and then the mixture is stirred for 1 hour with heat preservation, and then the mixture is cooled to 0 to 15 ℃, for example, 0 to 5 ℃ or 10 to 15 ℃.
According to the method disclosed by the invention, in the step (4), the temperature is reduced to 0-15 ℃ and then the mixture is stirred for 3 hours.
The process according to the invention, wherein in step (4), the lower alcohol used to wash the filter cake is methanol or absolute ethanol, the lower alcohol being used in an amount of 0.5L per 6.5mol of racemic norepinephrine.
According to the method disclosed by the invention, in the step (4), the wet norepinephrine bitartrate obtained by washing is dried in vacuum for 4-5 hours at the temperature of 40-45 ℃.
The method according to the invention, wherein step (4) is performed according to the following operations: slowly adding 10-14L of lower alcohol ethanol or methanol into the filtrate under the protection of nitrogen, preserving heat, stirring for 1h, then cooling to 0-15 ℃, stirring for 3h, filtering, washing the filter cake with 0.5L of absolute ethanol or methanol to obtain a norepinephrine bitartrate wet product, and vacuum drying for 4-5 h at 40-45 ℃.
The method according to the invention is carried out according to the following operations:
(1) Adding 6.7mol of L-tartaric acid and 0.05mol of sodium thiosulfate into 2.75L of water to dissolve, adding 0.55L of dimethyl sulfoxide, adding 6.5mol of racemic norepinephrine under the condition of stirring at 30-40 ℃, stirring for 0.5h, filtering, continuously preserving the temperature of the filtrate at 35-40 ℃ for 1h, dropwise adding a mixed solution of 8L of methanol and 4) of ethanol, and preserving the temperature and stirring for 1h;
(2) Cooling the reaction to 25+/-3 ℃, preserving heat, stirring for 2 hours, filtering, adding 2L of ethanol into the mother liquor, adding 2g of norepinephrine bitartrate seed crystal, cooling to 5+/-3 ℃, preserving heat for 4 hours, washing a filter cake with 0.8L of methanol, and drying in vacuum at 40 ℃ for 2 hours to obtain a crude norepinephrine bitartrate;
(3) Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 2L of water, heating to 35-40 ℃, stirring for dissolution, adding 15g of activated carbon, decoloring for 30min, and filtering;
(4) And (3) slowly adding 10L of ethanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 10-15 ℃, stirring for 3h, filtering, washing a filter cake with 0.5L of absolute ethyl alcohol to obtain a norepinephrine bitartrate wet product, and carrying out vacuum drying for 4-5 h at 40-45 ℃ to obtain a pure norepinephrine bitartrate product.
The method according to the invention is carried out according to the following operations:
(1) Adding 6.7mol of L-tartaric acid and 0.05mol of sodium thiosulfate into 5L of water to dissolve, adding 1L of dimethyl sulfoxide, adding 6.5mol of racemic norepinephrine under stirring at 30-40 ℃, stirring for 0.5h, filtering, continuously maintaining the temperature of the filtrate at 35-40 ℃ for 1h, dropwise adding a mixed solution of 12L of methanol and 8L of ethanol, and maintaining the temperature and stirring for 1h;
(2) Cooling the reaction to 25+/-3 ℃, preserving heat, stirring for 2 hours, filtering, adding ethanol 4L into the mother liquor, adding 2g of norepinephrine bitartrate seed crystal, cooling to 5+/-3 ℃, preserving heat for 4 hours, washing a filter cake with 0.8L of methanol, and drying in vacuum at 40 ℃ for 2 hours to obtain a crude norepinephrine bitartrate;
(3) Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 1.5L of water, heating to 35-40 ℃, stirring for dissolution, adding 15g of activated carbon, decoloring for 30min, and filtering;
(4) Slowly adding 10L of methanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 0-5 ℃, stirring for 3h, filtering, washing the filter cake with 0.5L of methanol to obtain a wet norepinephrine bitartrate product, and vacuum drying at 40-45 ℃ for 4-5 h to obtain a pure norepinephrine bitartrate product.
The method according to the invention is carried out according to the following operations:
(1) Adding 7mol of L-tartaric acid and 0.04mol of sodium thiosulfate into 2.5L of water to dissolve, adding 0.62L of dimethyl sulfoxide, adding 6.5mol of racemic norepinephrine under stirring at 30-40 ℃, stirring for 0.5h, filtering, continuously preserving the temperature of the filtrate at 35-40 ℃ for 1h, dropwise adding a mixed solution of 10L of methanol and 6L of ethanol, and preserving the temperature and stirring for 1h;
(2) Cooling the reaction to 25+/-3 ℃, preserving heat, stirring for 2 hours, filtering, adding 3L of ethanol into the mother liquor, adding 2g of norepinephrine bitartrate seed crystal, cooling to 5+/-3 ℃, preserving heat for 4 hours, washing a filter cake with 1L of methanol, and drying in vacuum at 40 ℃ for 2 hours to obtain a crude norepinephrine bitartrate;
(3) Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 2.5L of water, heating to 35-40 ℃, stirring for dissolution, adding 15g of activated carbon, decoloring for 30min, and filtering;
(4) And (3) slowly adding ethanol into the filtrate under the protection of nitrogen for 14L, stirring for 1h, cooling to 10-15 ℃, stirring for 3h, filtering, washing a filter cake with 0.5L of absolute ethyl alcohol to obtain a norepinephrine bitartrate wet product, and carrying out vacuum drying at 40-45 ℃ for 4-5 h to obtain a pure norepinephrine bitartrate product.
The method according to the invention is carried out according to the following operations:
(1) Adding 7.2mol of L-tartaric acid and 0.06mol of sodium thiosulfate into 6L of water to dissolve, adding 0.9L of dimethyl sulfoxide, adding racemic norepinephrine (1.10 kg,6.5 mol) under stirring at 30-40 ℃, stirring for 0.5h, filtering, continuously preserving the temperature of the filtrate at 35-40 ℃ for 1h, dropwise adding a mixed solution of 10L of methanol and 4L of ethanol, and preserving the temperature and stirring for 1h after adding;
(2) Cooling the reaction to 25+/-3 ℃, preserving heat, stirring for 2 hours, filtering, adding 3L of ethanol into the mother liquor, adding 2g of norepinephrine bitartrate seed crystal, cooling to 5+/-3 ℃ and preserving heat for 4 hours, washing a filter cake with 0.6L of methanol, and drying in vacuum at 40 ℃ for 2 hours to obtain a crude norepinephrine bitartrate;
(3) Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 2L of water, heating to 35-40 ℃, stirring for dissolution, adding 15g of activated carbon, decoloring for 30min, and filtering;
(4) Slowly adding 12L of methanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 0-5 ℃, stirring for 3h, filtering, washing the filter cake with 0.5L of methanol to obtain a wet norepinephrine bitartrate product, and vacuum drying at 40-45 ℃ for 4-5 h to obtain a pure norepinephrine bitartrate product.
The invention directly splits and salifies the racemic norepinephrine by using L-tartaric acid, and then refines the product to obtain the product, wherein the quality of the product meets the pharmacopoeia requirement. It has been unexpectedly found that by using the process of the present invention, norepinephrine bitartrate is obtained in high purity, in high yield, and in a simple process.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of norepinephrine bitartrate.
FIG. 2 is a nuclear magnetic resonance carbon spectrum of norepinephrine bitartrate.
Detailed Description
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.
Example 1: preparation of norepinephrine bitartrate
L-tartaric acid (1.01 kg,6.7 mol) and sodium thiosulfate (8 g,0.05 mol) are added into 2.75L of water to be dissolved, 0.55L of dimethyl sulfoxide is added, racemic norepinephrine (1.10 kg,6.5 mol) is added under stirring at 30-40 ℃, stirring is carried out for 0.5h, filtration is carried out, a mixed solution of methanol (8L) and ethanol (4L) is dropwise added into filtrate at 35-40 ℃ under heat preservation (continuously for 1 h), stirring is carried out for 1h under heat preservation, cooling is carried out to 25+/-3 ℃ under heat preservation, stirring is carried out for 2h, filtration is carried out, ethanol (2L) is added into mother liquor, 2g of norepinephrine bitartrate crystal seed crystal (note dispersion) is added, cooling is carried out to 5+/-3 ℃ under heat preservation for 4h, filter cake is washed by methanol (0.8L), and vacuum drying is carried out at 40 ℃ for 2h, thus obtaining a crude norepinephrine bitartrate.
Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 2L of water, heating to 35-40 ℃, and stirring for dissolution. Adding 15g of active carbon, decolorizing for 30min, and filtering. Adding ethanol 10L into the filtrate slowly under the protection of nitrogen, stirring for 1h, cooling to 10-15 ℃, stirring for 3h, filtering, washing the filter cake with absolute ethyl alcohol 0.5L to obtain a wet norepinephrine bitartrate product, and vacuum drying at 40-45 ℃ for 4-5 h to obtain 0.71kg of pure norepinephrine bitartrate product with a yield of 64.8% (in the invention, if not otherwise stated, the yield is calculated according to the R configuration amount in the racemic norepinephrine).
Example 2: preparation of norepinephrine bitartrate
L-tartaric acid (1.01 kg,6.7 mol) and sodium thiosulfate (8 g,0.05 mol) are added into 5L of water to dissolve, 1L of dimethyl sulfoxide is added, racemic norepinephrine (1.10 kg,6.5 mol) is added under stirring at 30-40 ℃, stirring is carried out for 0.5h, filtering is carried out, a mixed solution of methanol (12L) and ethanol (8L) is dropwise added into filtrate at 35-40 ℃ under heat preservation (for 1 h), the mixture is heated and stirred for 1h after the adding, the temperature is reduced to 25+/-3 ℃ under heat preservation and stirring for 2h, filtering is carried out, ethanol (4L) is added into mother liquor, 2g (note dispersion) of norepinephrine seed crystals of bitartrate is added, the mixture is cooled to 5+/-3 ℃ under heat preservation for 4h, filter cake is washed by methanol (0.8L) and vacuum-dried at 40 ℃ for 2h, and thus a crude norepinephrine bitartrate is obtained.
Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 1.5L of water, heating to 35-40 ℃, stirring and dissolving. Adding 15g of active carbon, decolorizing for 30min, and filtering. Slowly adding 10L of methanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 0-5 ℃, stirring for 3h, filtering, washing the filter cake with 0.5L of methanol to obtain a wet norepinephrine bitartrate product, and vacuum drying at 40-45 ℃ for 4-5 h to obtain 0.68kg of pure norepinephrine bitartrate product with the yield of 62.1%.
Example 3: preparation of norepinephrine bitartrate
L-tartaric acid (1.05 kg,7 mol) and sodium thiosulfate (6.3 g,0.04 mol) are added into 2.5L of water to dissolve, 0.62L of dimethyl sulfoxide is added, racemic norepinephrine (1.10 kg,6.5 mol) is added under stirring at 30-40 ℃ and stirred for 0.5h, filtration is carried out, a mixed solution of methanol (10L) and ethanol (6L) is dropwise added into filtrate at 35-40 ℃ under heat preservation (continuously for 1 h), after addition, heat preservation and stirring are carried out for 1h, cooling is carried out to 25+/-3 ℃ under heat preservation and stirring for 2h, filtration is carried out, ethanol (3L) is added into mother liquor, 2g of norepinephrine bitartrate seed crystal (note dispersion) is added, cooling is carried out to 5+/-3 ℃ and heat preservation is carried out for 4h, filter cake is washed by methanol (1L) and vacuum drying is carried out at 40 ℃ for 2h, and thus crude norepinephrine bitartrate is obtained.
Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 2.5L of water, heating to 35-40 ℃, stirring and dissolving. Adding 15g of active carbon, decolorizing for 30min, and filtering. And (3) slowly adding ethanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 10-15 ℃, stirring for 3h, filtering, washing a filter cake with 0.5L absolute ethyl alcohol to obtain a wet norepinephrine bitartrate product, and vacuum drying at 40-45 ℃ for 4-5 h to obtain 0.69kg of pure norepinephrine bitartrate product with the yield of 63.1%.
Example 4: preparation of norepinephrine bitartrate
L-tartaric acid (1.08 kg,7.2 mol) and sodium thiosulfate (9.5 g,0.06 mol) are added into 6L of water to dissolve, 0.9L of dimethyl sulfoxide is added, racemic norepinephrine (1.10 kg,6.5 mol) is added under stirring at 30-40 ℃, stirring is carried out for 0.5h, filtration is carried out, the filtrate is dropwise added (continuously added for 1 h) with a mixed solution of methanol (10L) and ethanol (4L) at 35-40 ℃ under heat preservation, stirring is carried out for 1h under heat preservation, cooling to 25+/-3 ℃ under heat preservation, stirring is carried out for 2h, filtration is carried out, ethanol (3L) is added into mother liquor, 2g of norepinephrine seed crystal bitartrate is added, cooling to 5+/-3 ℃ is carried out for 4h under heat preservation, filter cake is washed with methanol (0.6L) and vacuum drying is carried out at 40 ℃ for 2h, and thus crude norepinephrine bitartrate is obtained.
Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 2L of water, heating to 35-40 ℃, and stirring for dissolution. Adding 15g of active carbon, decolorizing for 30min, and filtering. Slowly adding 12L of methanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 0-5 ℃, stirring for 3h, filtering, washing the filter cake with 0.5L of methanol to obtain a wet norepinephrine bitartrate product, and vacuum drying at 40-45 ℃ for 4-5 h to obtain 0.70kg of pure norepinephrine bitartrate product with the yield of 63.9%.
Example 5: preparation of norepinephrine bitartrate
L-tartaric acid (1.01 kg,6.7 mol) and sodium metabisulfite (9.5 g,0.05 mol) are added into 2.75L of water to be dissolved, 0.55L of dimethyl sulfoxide is added, racemic norepinephrine (1.10 kg,6.5 mol) is added under stirring at 30-40 ℃ and is stirred for 0.5h, filtration is carried out, a mixed solution of methanol (8L) and ethanol (4L) is dropwise added (continuously for 1 h) at 35-40 ℃ under heat preservation, after addition, heat preservation and stirring are carried out for 1h, the temperature is reduced to 25+/-3 ℃ and is stirred for 2h, filtration is carried out, ethanol (2L) is added into mother liquor, 2g of norepinephrine bitartrate crystal seeds (note dispersion) is added, the temperature is reduced to 5+/-3 ℃ and is kept for 4h, filter cake is washed with methanol (0.8L) and is dried under vacuum at 40 ℃ for 2h, and thus a crude norepinephrine bitartrate.
Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 2L of water, heating to 35-40 ℃, and stirring for dissolution. Adding 15g of active carbon, and decoloring for 30min. And (3) slowly adding 10L of ethanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 10-15 ℃, stirring for 3h, filtering, washing a filter cake with 0.5L of absolute ethyl alcohol to obtain a wet norepinephrine bitartrate product, and carrying out vacuum drying at 40-45 ℃ for 4-5 h to obtain 0.48kg of pure norepinephrine bitartrate product with the yield of 43.8%.
Example 6: preparation of norepinephrine bitartrate
L-tartaric acid (1.01 kg,6.7 mol) and sodium metabisulfite (9.5 g,0.05 mol) are added into 5L of water to dissolve, 1L of dimethyl sulfoxide is added, racemic norepinephrine (1.10 kg,6.5 mol) is added under stirring at 30-40 ℃, stirring is carried out for 0.5h, filtering is carried out, a mixed solution of methanol (12L) and ethanol (8L) is dropwise added into filtrate at 35-40 ℃ under heat preservation (for 1 h), the mixture is stirred for 1h under heat preservation, the temperature is reduced to 25+/-3 ℃ under heat preservation, stirring is carried out for 2h under heat preservation, filtering is carried out, ethanol (4L) is added into mother liquor, 2g (note dispersion) of norepinephrine seed crystal of bitartrate is added, the mixture is cooled to 5+/-3 ℃ under heat preservation for 4h, filter cake is washed by methanol (0.8L) and vacuum drying is carried out at 40 ℃ for 2h, and thus crude norepinephrine bitartrate is obtained.
Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 1.5L of water, heating to 35-40 ℃, stirring and dissolving. Adding 15g of active carbon, and decoloring for 30min. Slowly adding 10L of methanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 0-5 ℃, stirring for 3h, filtering, washing the filter cake with 0.5L of methanol to obtain a wet norepinephrine bitartrate product, and vacuum drying at 40-45 ℃ for 4-5 h to obtain 0.46kg of pure norepinephrine bitartrate product with the yield of 42.0%.
Example 7: preparation of norepinephrine bitartrate
L-tartaric acid (1.05 kg,7 mol) and sodium metabisulfite (7.6 g,0.04 mol) are added into 2.5L of water to dissolve, 0.62L of dimethyl sulfoxide is added, racemic norepinephrine (1.10 kg,6.5 mol) is added under stirring at 30-40 ℃, stirring is carried out for 0.5h, filtration is carried out, filtrate is dropwise added (continuously carried out for 1 h) at 35-40 ℃ in a mixed solution of methanol (10L) and ethanol (6L), stirring is carried out for 1h at the same time, cooling to 25+/-3 ℃ in a heat-preserving way, stirring is carried out for 2h, filtration is carried out, mother liquor is added with ethanol (3L), 2g of norepinephrine seed crystal of bitartrate is added, cooling is carried out to 5+/-3 ℃ in a heat-preserving way for 4h, filter cake is washed with methanol (1L), and vacuum drying is carried out at 40 ℃ for 2h, thus obtaining crude norepinephrine bitartrate.
Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 2.5L of water, heating to 35-40 ℃, stirring and dissolving. Adding 15g of active carbon, decolorizing for 30min, and filtering. And (3) slowly adding ethanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 10-15 ℃, stirring for 3h, filtering, washing a filter cake with 0.5L absolute ethyl alcohol to obtain a wet norepinephrine bitartrate product, and vacuum drying at 40-45 ℃ for 4-5 h to obtain 0.50kg of pure norepinephrine bitartrate product with a yield of 45.7%.
Example 8: preparation of norepinephrine bitartrate
L-tartaric acid (1.08 kg,7.2 mol) and sodium metabisulfite (11.4 g,0.06 mol) are added into 6L of water to dissolve, 0.9L of dimethyl sulfoxide is added, racemic norepinephrine (1.10 kg,6.5 mol) is added under stirring at 30-40 ℃, stirring is carried out for 0.5h, filtering is carried out, the filtrate is dropwise added (continuously carried out for 1 h) at 35-40 ℃ for a mixed solution of methanol (10L) and ethanol (4L), stirring is carried out for 1h at a constant temperature, cooling to 25+/-3 ℃ for 2h, filtering is carried out, ethanol (3L) is added into mother liquor, 2g (note dispersion) of norepinephrine seed crystal of bitartrate is added, cooling to 5+/-3 ℃ for 4h is carried out, filter cake is washed by methanol (0.6L), and vacuum drying is carried out at 40 ℃ for 2h, thus obtaining crude norepinephrine bitartrate.
Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 2L of water, heating to 35-40 ℃, and stirring for dissolution. Adding 15g of active carbon, decolorizing for 30min, and filtering. Slowly adding 12L of methanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 0-5 ℃, stirring for 3h, filtering, washing the filter cake with 0.5L of methanol to obtain a wet norepinephrine bitartrate product, and vacuum drying at 40-45 ℃ for 4-5 h to obtain 0.45kg of pure norepinephrine bitartrate product with the yield of 41.1%.
Example 9: preparation of norepinephrine bitartrate
The difference between the methods of examples 1 to 4 was that sodium thiosulfate was not added, and four batches of pure norepinephrine bitartrate was produced in a yield ranging from 24 to 27%, for example, 25.3% when referring to example 1, which indicates that the yield of sodium thiosulfate was significantly reduced in the production steps and conditions of examples 1 to 4.
The difference between the methods of examples 1 to 4 was that no dimethyl sulfoxide (the volume of which was made up with water) was added, and four batches of pure norepinephrine bitartrate were produced in a range of 35 to 38%, for example, 36.4% in the case of example 1, which showed a significant decrease in the yield without dimethyl sulfoxide under the production steps and conditions of examples 1 to 4.
The difference between the methods of examples 1 to 4 is that sodium thiosulfate and dimethyl sulfoxide (the volumes of which are made up with water) are not added, and four batches of pure norepinephrine bitartrate are produced in a yield ranging from 14% to 19%, for example, 15.2% when referring to example 1, which shows that the yields of sodium thiosulfate and dimethyl sulfoxide are significantly reduced in the production steps and conditions of examples 1 to 4.
Example 10: quality inspection of norepinephrine bitartrate
In this example, referring to the method under the norepinephrine bitartrate item of the 2020 edition of chinese pharmacopoeia, it is examined whether the four batches of norepinephrine bitartrates obtained in examples 1 to 4 meet the pharmacopoeia standard specification, and whether they meet the pharmaceutical requirements.
1. Traits (3)
The four batches of norepinephrine bitartrate obtained in examples 1-4 all present white crystalline powder, are odorless, and are easy to deteriorate (change color) in light and air; all four samples appeared to be readily soluble in water, slightly soluble in ethanol, and insoluble in chloroform or diethyl ether.
Melting point: the melting points of the four batches of samples are all in the range of 102-105 ℃, and the samples are decomposed simultaneously during melting and are turbid, for example, the melting point of the sample in example 1 is 103.3-104.2 ℃.
Specific rotation: the specific rotations of the four samples were all in the range of-10.0 ° to-12.0 °, as measured by the method, for example 1 with a specific rotation of-10.9 °.
2. Authentication
And (3) identifying a ferric trichloride test solution: according to the method, the four batches of samples are emerald after being added with ferric trichloride test solution, are blue after being added with sodium bicarbonate test solution, and finally are red.
And (3) iodine test solution identification: according to the legal examination, all four sample examination liquids are colorless or only reddish or light purple.
And (3) potassium chloride identification: according to the legal examination, four samples all precipitated crystalline precipitate within 10 minutes.
3. Inspection of
Clarity and color of the solution: the solution was clear and colorless as examined by law for all four samples.
Ketone body: norepinephrine bitartrate is taken, dissolved in water and diluted to a solution of about 2.0mg per 1ml, and the four batches of samples each have an absorbance of less than 0.04, as measured by ultraviolet-visible spectrophotometry at a wavelength of 310nm, e.g., the absorbance of example 1 sample 0.016.
Related substances: according to the related substance inspection method recorded in pharmacopoeia standards, in a system applicability solution chromatogram, the retention time of a main component peak is 11.3 minutes, an unknown degradation product peak and a norepinephrine peak 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 an adjacent impurity peak is more than 3.8; limit results: the norepinephrine content of the four samples is less than 0.06%, such as example 1 sample content is 0.024%, the other single impurities are less than 0.05%, the total impurity content of the four samples is less than 0.18%, such as example 1 sample impurity content is 0.011%; four samples of the related substance examination all meet the standard.
Moisture content: 50mg of norepinephrine bitartrate is taken and measured according to a moisture measurement method (the first method 1 of the four general rules 0832 of Chinese pharmacopoeia of 2020 edition), and the standard prescribes that the moisture is in the range of 5.0% -6.0%; the moisture content of the four samples is determined to be in the range of 5.0% -6.0%, for example, the moisture content of the sample of example 1 is 5.47%.
Glowing residues: the legal inspection is carried out, and the standard regulation is less than 0.1 percent; the burning residues of the four batches of samples are not more than 0.1 percent.
4. Content determination
0.2g of norepinephrine bitartrate is precisely weighed, 10ml of glacial acetic acid is added, 1 drop of crystal violet indicator solution is added after shaking (micro temperature is needed) for dissolution, the solution is titrated with perchloric acid titration solution (0.1 mol/L) until the solution is blue-green, and the titration result is corrected by a blank test. Each 1ml of the perchloric acid titration solution (0.1 mol/L) corresponds to 31.93mg of C8H11NO3.C4H6O6. The contents of the four batches of samples are respectively 99.73%, 100.27%, 99.48% and 99.87% according with the standard regulation after measurement.
In addition, the nuclear magnetic resonance hydrogen spectrum (figure 1) and the carbon spectrum (figure 2) of the norepinephrine bitartrate sample obtained in example 1 are tested, and the analysis result shows that the norepinephrine bitartrate sample is matched with the norepinephrine bitartrate.
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 comprising the steps of:
(1) Dissolving L-tartaric acid, sodium thiosulfate and racemic norepinephrine in water and dimethyl sulfoxide, reacting under warm condition, filtering, dripping lower alcohol into the filtrate, and continuing to keep temperature and stir at proper time; the lower alcohol is methanol and ethanol in a volume ratio of 1.5-2.5: 1;
(2) Cooling the reaction solution to room temperature, continuing to keep the temperature and stirring at proper time, filtering, adding lower alcohol into the mother solution, then adding norepinephrine bitartrate seed crystal to disperse, cooling to 0-10 ℃, keeping the temperature and standing, filtering, and drying a filter cake to obtain a crude norepinephrine bitartrate product;
(3) Adding the crude norepinephrine bitartrate into water under the protection of nitrogen, stirring under warm condition to dissolve, adding active carbon, decolorizing, and filtering;
(4) Slowly adding lower alcohol into the filtrate under the protection of nitrogen, maintaining the temperature, stirring, cooling to 0-15 ℃, maintaining the temperature, stirring, filtering, washing the filter cake with lower alcohol, and drying to obtain norepinephrine bitartrate.
2. The method according to claim 1, wherein in the step (1), the molar ratio of L-tartaric acid to racemic norepinephrine is 1 to 1.1:1.
3. the method according to claim 1, wherein in the step (1), the molar ratio of the racemic norepinephrine to the sodium thiosulfate is 108 to 163:1.
4. the method according to claim 1, wherein in step (1), the amount of dimethyl sulfoxide is 15 to 25% (v/v) of water.
5. The method according to claim 1, wherein in step (1), the amount of water added per 1mol of racemic norepinephrine is 0.4l to 1l; the temperature of the warming condition is 30-40 ℃.
6. The method according to claim 1, wherein step (1) is performed as follows: adding 6.7-7.2 mol of L-tartaric acid and 0.04-0.06 mol of sodium thiosulfate into 2.5-6L of water to dissolve, adding 0.55-1L of dimethyl sulfoxide, adding 6.5mol of racemized norepinephrine under the condition of stirring at 30-40 ℃, stirring for 0.5h, filtering, and dropwise adding methanol and ethanol into the filtrate at the temperature of 35-40 ℃ in a volume ratio of 1.5-2.5: 1, and stirring for 1h at a constant temperature.
7. The method of claim 1, wherein step (2) is performed as follows: cooling the reaction solution to 25+/-3 ℃, preserving heat, stirring for 1-2 h, filtering, adding 2L-4L of ethanol into the mother solution, adding 1-3 g of norepinephrine bitartrate seed crystal, cooling to 5+/-3 ℃ and preserving heat for 3-5 h, washing a filter cake with 0.6-1L of methanol, and vacuum drying at 40 ℃ for 1-3 h to obtain a crude norepinephrine bitartrate.
8. The method according to claim 1, wherein step (3) is performed as follows: under the protection of nitrogen, adding the crude norepinephrine bitartrate into 1.5-2.5L of water, heating to 35-40 ℃, stirring and dissolving; adding 15g of active carbon, decolorizing for 30min, and filtering.
9. The method according to claim 1, wherein step (4) is performed as follows: slowly adding 10-14L of lower alcohol ethanol or methanol into the filtrate under the protection of nitrogen, preserving heat, stirring for 1h, then cooling to 0-15 ℃, stirring for 3h, filtering, washing the filter cake with 0.5L of absolute ethanol or methanol to obtain a norepinephrine bitartrate wet product, and vacuum drying for 4-5 h at 40-45 ℃.
10. The method according to claim 1, which is performed according to the following operations:
(1) Adding 6.7mol of L-tartaric acid and 0.05mol of sodium thiosulfate into 2.75L of water to dissolve, adding 0.55L of dimethyl sulfoxide, adding 6.5mol of racemic norepinephrine under stirring at 30-40 ℃, stirring for 0.5h, filtering, continuously preserving the temperature of the filtrate at 35-40 ℃ for 1h, dropwise adding a mixed solution of 8L of methanol and 4L of ethanol, and preserving the temperature and stirring for 1h;
(2) Cooling the reaction to 25+/-3 ℃, preserving heat, stirring for 2 hours, filtering, adding 2L of ethanol into the mother liquor, adding 2g of norepinephrine bitartrate seed crystal, cooling to 5+/-3 ℃, preserving heat for 4 hours, washing a filter cake with 0.8L of methanol, and drying in vacuum at 40 ℃ for 2 hours to obtain a crude norepinephrine bitartrate;
(3) Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 2L of water, heating to 35-40 ℃, stirring for dissolution, adding 15g of activated carbon, decoloring for 30min, and filtering;
(4) Slowly adding 10L of ethanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 10-15 ℃, stirring for 3h, filtering, washing a filter cake with 0.5L of absolute ethyl alcohol to obtain a norepinephrine bitartrate wet product, and carrying out vacuum drying at 40-45 ℃ for 4-5 h to obtain a pure norepinephrine bitartrate product; or alternatively, the process may be performed,
which is carried out according to the following operations:
(1) Adding 6.7mol of L-tartaric acid and 0.05mol of sodium thiosulfate into 5L of water to dissolve, adding 1L of dimethyl sulfoxide, adding 6.5mol of racemic norepinephrine under stirring at 30-40 ℃, stirring for 0.5h, filtering, continuously maintaining the temperature of the filtrate at 35-40 ℃ for 1h, dropwise adding a mixed solution of 12L of methanol and 8L of ethanol, and maintaining the temperature and stirring for 1h;
(2) Cooling the reaction to 25+/-3 ℃, preserving heat, stirring for 2 hours, filtering, adding ethanol 4L into the mother liquor, adding 2g of norepinephrine bitartrate seed crystal, cooling to 5+/-3 ℃, preserving heat for 4 hours, washing a filter cake with 0.8L of methanol, and drying in vacuum at 40 ℃ for 2 hours to obtain a crude norepinephrine bitartrate;
(3) Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 1.5L of water, heating to 35-40 ℃, stirring for dissolution, adding 15g of activated carbon, decoloring for 30min, and filtering;
(4) Slowly adding 10L of methanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 0-5 ℃, stirring for 3h, filtering, washing a filter cake with 0.5L of methanol to obtain a wet norepinephrine bitartrate product, and vacuum drying at 40-45 ℃ for 4-5 h to obtain a pure norepinephrine bitartrate product; or alternatively, the process may be performed,
which is carried out according to the following operations:
(1) Adding 7mol of L-tartaric acid and 0.04mol of sodium thiosulfate into 2.5L of water to dissolve, adding 0.62L of dimethyl sulfoxide, adding 6.5mol of racemic norepinephrine under stirring at 30-40 ℃, stirring for 0.5h, filtering, continuously preserving the temperature of the filtrate at 35-40 ℃ for 1h, dropwise adding a mixed solution of 10L of methanol and 6L of ethanol, and preserving the temperature and stirring for 1h;
(2) Cooling the reaction to 25+/-3 ℃, preserving heat, stirring for 2 hours, filtering, adding 3L of ethanol into the mother liquor, adding 2g of norepinephrine bitartrate seed crystal, cooling to 5+/-3 ℃, preserving heat for 4 hours, washing a filter cake with 1L of methanol, and drying in vacuum at 40 ℃ for 2 hours to obtain a crude norepinephrine bitartrate;
(3) Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 2.5L of water, heating to 35-40 ℃, stirring for dissolution, adding 15g of activated carbon, decoloring for 30min, and filtering;
(4) Slowly adding ethanol into the filtrate under the protection of nitrogen for 14L, stirring for 1h, cooling to 10-15 ℃, stirring for 3h, filtering, washing a filter cake with 0.5L of absolute ethyl alcohol to obtain a norepinephrine bitartrate wet product, and carrying out vacuum drying at 40-45 ℃ for 4-5 h to obtain a pure norepinephrine bitartrate product; or alternatively, the process may be performed,
which is carried out according to the following operations:
(1) Adding 7.2mol of L-tartaric acid and 0.06mol of sodium thiosulfate into 6L of water to dissolve, adding 0.9L of dimethyl sulfoxide, adding racemic norepinephrine (1.10 kg,6.5 mol) under stirring at 30-40 ℃, stirring for 0.5h, filtering, continuously preserving the temperature of the filtrate at 35-40 ℃ for 1h, dropwise adding a mixed solution of 10L of methanol and 4L of ethanol, and preserving the temperature and stirring for 1h after adding;
(2) Cooling the reaction to 25+/-3 ℃, preserving heat, stirring for 2 hours, filtering, adding 3L of ethanol into the mother liquor, adding 2g of norepinephrine bitartrate seed crystal, cooling to 5+/-3 ℃ and preserving heat for 4 hours, washing a filter cake with 0.6L of methanol, and drying in vacuum at 40 ℃ for 2 hours to obtain a crude norepinephrine bitartrate;
(3) Under the protection of nitrogen, adding the crude norepinephrine bitartrate into 2L of water, heating to 35-40 ℃, stirring for dissolution, adding 15g of activated carbon, decoloring for 30min, and filtering;
(4) Slowly adding 12L of methanol into the filtrate under the protection of nitrogen, stirring for 1h, cooling to 0-5 ℃, stirring for 3h, filtering, washing the filter cake with 0.5L of methanol to obtain a wet norepinephrine bitartrate product, and vacuum drying at 40-45 ℃ for 4-5 h to obtain a pure norepinephrine bitartrate product.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5831117A (en) * | 1995-01-20 | 1998-11-03 | G. D. Searle & Co. | Method of preparing retroviral protease inhibitor intermediates |
| CN112225665A (en) * | 2020-10-28 | 2021-01-15 | 合肥亿帆生物制药有限公司 | Preparation method of noradrenaline bitartrate |
| CN115073312A (en) * | 2022-07-15 | 2022-09-20 | 上海现代哈森（商丘）药业有限公司 | Novel synthesis method of noradrenaline bitartrate |
| CN115850095A (en) * | 2022-12-27 | 2023-03-28 | 武汉嘉诺康医药技术有限公司 | Preparation method of noradrenaline bitartrate |
| CN116162034A (en) * | 2022-12-23 | 2023-05-26 | 蚌埠丰原医药科技发展有限公司 | Chiral resolution method of racemic norepinephrine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10865180B2 (en) * | 2018-08-10 | 2020-12-15 | Harman Finochem Limited | Process for the preparation of l-Norepinephrine bitartrate monohydrate having high enantiomeric purity |
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- 2023-08-03 CN CN202310968645.3A patent/CN116675613B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5831117A (en) * | 1995-01-20 | 1998-11-03 | G. D. Searle & Co. | Method of preparing retroviral protease inhibitor intermediates |
| CN112225665A (en) * | 2020-10-28 | 2021-01-15 | 合肥亿帆生物制药有限公司 | Preparation method of noradrenaline bitartrate |
| CN115073312A (en) * | 2022-07-15 | 2022-09-20 | 上海现代哈森（商丘）药业有限公司 | Novel synthesis method of noradrenaline bitartrate |
| CN116162034A (en) * | 2022-12-23 | 2023-05-26 | 蚌埠丰原医药科技发展有限公司 | Chiral resolution method of racemic norepinephrine |
| CN115850095A (en) * | 2022-12-27 | 2023-03-28 | 武汉嘉诺康医药技术有限公司 | Preparation method of noradrenaline bitartrate |
Non-Patent Citations (1)
| Title |
|---|
| 梁大伟.（-）-重酒石酸去甲肾上腺素的合成研究.《化工技术与开发》.2014,第43卷(第8期),11-12. * |
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