Refining method of norepinephrine bitartrate intermediate

Abstract

The invention discloses a refining method of a norepinephrine bitartrate intermediate. The refining method of the norepinephrine bitartrate intermediate comprises the following steps: S1, reacting a crude product of the norepinephrine bitartrate intermediate 3 with inorganic acid in an organic solvent to obtain inorganic acid salt of the norepinephrine bitartrate intermediate 3; s2, in the presence of an antioxidant, enabling the inorganic acid salt of the norepinephrine bitartrate intermediate 3 to react with inorganic alkali in water to obtain a refined product of the norepinephrine bitartrate intermediate 3; the structural formula of the norepinephrine bitartrate intermediate 3 is as shown in formula I in the specification. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the technical field of chemical drug synthesis, and in particular to a method for refining a norepinephrine bitartrate intermediate. Background Art

[0002] Norepinephrine bitartrate (structural formula see Figure 1 ), chemical name: (R)-4-(2-amino-1-hydroxyethyl)-l,2-benzenediol bitartrate monohydrate, English name: Norepinephrine Bitartrate, molecular formula: C8H 11 NO3·C4H6O6·H2O is both a neurotransmitter and a substance formed by removing the N-methyl group from adrenaline. It belongs to catecholamines in chemical structure and was formerly known as "norepinephrine". It is used to treat hypotension caused by acute myocardial infarction, extracorporeal circulation, pheochromocytoma resection, etc. It is often used as a pressor in emergency treatment and is a commonly used emergency medicine in clinical practice.

[0003] The synthetic routes of norepinephrine bitartrate are mainly as follows:

[0004] Route 1: J. Am. Parm. Association, 1946, 35: 306-309 reported the reaction of chloroacetylcatechol with dibenzylamine, followed by palladium-carbon catalytic hydrogenation reduction deprotection to obtain racemic norepinephrine. J. Am. Chem. Soc, 1948, 70 (6): 2067-2068 reported a method for resolving racemic norepinephrine to obtain L-norepinephrine. The two reports combined to form a complete route 1.

[0005] Route 2: Chemical Technology and Research, 2014, 43(8): 11-12, Liang Dawei et al. reported the preparation of norepinephrine bitartrate from chloroacetylcatechol by ammonia solution ammoniation, hydrochloride formation, catalytic hydrogenation, and L-tartaric acid splitting.

[0006] Route 3: WO2013008247 utilizes chloroacetylcatechol to react with urotropine and then hydrolyze to generate noradrenaline, which is then catalytically hydrogenated to obtain racemic noradrenaline.

[0007] Route 4: CN108069863A introduces a chiral reduction method, using (-)-diisopinocampheyl chloroborane as a reducing agent at -25°C to directly reduce noradrenaline ketone to L-noradrenaline.

[0008] Route 2 requires the use of ammonia, which is a dangerous gas and is not suitable for large-scale production. Route 3 uses the urotropine method to introduce amine groups, which requires hydrolysis with hydrochloric acid / methanol at high temperature and is prone to produce by-products. Route 4 chiral reagents are expensive and the reaction conditions are harsh, which is not conducive to industrial production. The starting materials and intermediates of Route 1 are all solids in good condition, no dangerous or highly toxic reagents are used, and there are no ultra-high temperature or ultra-low temperature reaction conditions, which is suitable for industrial production. At present, most domestic manufacturers use this route to produce norepinephrine bitartrate.

[0009] Impurities (related substances) are important factors affecting drug safety and are CQA of drugs. If the drug contains impurities exceeding the limit, the content will be significantly lower or the activity will be reduced, and the toxic and side effects will increase significantly, which will cause a series of adverse reactions, endanger patient safety and affect the efficacy of the drug. According to the requirements of ICH Q3A and the quality standards of norepinephrine bitartrate included in ChP2020, EP10.0, unknown impurities shall not exceed 0.1%.

[0010] The inventors have found that the production of norepinephrine bitartrate according to route 1 is carried out by using intermediate 2 (structural formula: Figure 2 ) to prepare intermediate 3 (structural formula see Figure 3 ) process, palladium carbon was used for hydrogenation reduction reaction, there were two steps of hydrogenation of benzyl and keto groups, and there was a transition state after debenzylation (structural formula see Figure 4 ), this transition state can undergo polymerization and cyclization reaction under the action of palladium carbon to generate impurity 23 (HPLC retention time is about 23.2min, structural formula is shown in Figure 5 ). Impurity 23 cannot be removed by conventional solvent beating or refining methods. Once this impurity is produced, it cannot be removed in subsequent splitting, refining and purification processes. Instead, the product output is halved and doubled after splitting. If this impurity cannot be well controlled, it will be impossible to obtain subsequent qualified intermediates and finished products, which will have a serious impact on product quality.

[0011] Therefore, developing a method for refining the norepinephrine bitartrate intermediate by removing the impurity 23 is an urgent problem to be solved in order to ensure product quality and obtain a high-purity product. Summary of the invention

[0012] The purpose of the present invention is to provide a method for refining a noradrenaline bitartrate intermediate, which effectively solves the problem that impurity 23 generated by a hydrogenation reaction cannot be effectively removed, is simple to operate, has a high yield, and is suitable for industrial production. The content of impurity 23 in the noradrenaline bitartrate intermediate 3 (4-(2-amino-1-hydroxyethyl)-1,2-benzenediol) obtained by the method is ≤0.05%, and the purity can reach ≥99%.

[0013] To achieve the above object, the present invention adopts the following technical solution:

[0014] The present invention provides a method for refining a norepinephrine bitartrate intermediate, comprising the following steps:

[0015] S1, reacting the crude product of norepinephrine bitartrate intermediate 3 with an inorganic acid in an organic solvent to obtain an inorganic acid salt of norepinephrine bitartrate intermediate 3;

[0016] S2. In the presence of an antioxidant, the inorganic acid salt of the noradrenaline bitartrate intermediate 3 reacts with an inorganic base in water to obtain a refined product of the noradrenaline bitartrate intermediate 3;

[0017] The structural formula of the norepinephrine bitartrate intermediate 3 is shown in Formula I:

[0018]

[0019] In the present invention, the chemical name of the noradrenaline bitartrate intermediate 3 is 4-(2-amino-1-hydroxyethyl)-1,2-benzenediol. The synthesis route of the noradrenaline bitartrate intermediate 3 is as follows: catechol is used as a starting material, and under the catalysis of aluminum chloride, a Friedel-Crafts acylation reaction is carried out with chloroacetyl chloride to obtain 2-chloro-3',4'-dihydroxyacetophenone (intermediate 1), intermediate 1 reacts with dibenzylamine to obtain 2-(diphenylmethylamino)-3',4'-dihydroxyacetophenone hydrochloride (intermediate 2), and intermediate 2 is hydrogenated under the catalysis of palladium carbon to obtain 4-(2-amino-1-hydroxyethyl)-1,2-benzenediol (intermediate 3).

[0020] Based on the above technical scheme, the purification method of the present invention can reduce the impurity 23 in the noradrenaline bitartrate intermediate 3 to ≤0.05%, and other impurities are also largely removed, and the purity of the noradrenaline bitartrate intermediate 3 can reach 99%.

[0021] The conception of the present invention is as follows: the solubility of the crude product of the intermediate 3 of bitartrate of noradrenaline is very low in various organic solvents, and it is almost insoluble in common solvents such as water, ethanol, acetone, methanol, isopropanol, etc. Therefore, according to the conventional refining and purification method, the purpose of removing impurities cannot be achieved by simply refining with a solvent. In the present invention, the crude product of the intermediate 3 of bitartrate of noradrenaline is mixed with an organic solvent, and hydrochloric acid is then dripped therein to make it a hydrochloride with good solubility. During the process of dripping hydrochloric acid, the intermediate 3 gradually dissolves, but as the acidity increases, the intermediate 3 precipitates crystals again. During the process of dissolving and crystallizing, the impurity 23 gradually dissolves into the solvent and is removed by filtering (removal rate is about 90% or more). The hydrochloride obtained is then dissociated by ammonia water, filtered and dried, thereby obtaining a high-purity intermediate 3 of bitartrate of noradrenaline.

[0022] In the above-mentioned method for refining the noradrenaline bitartrate intermediate, the inorganic acid can be any inorganic acid that can dissolve the impurity 23 in the organic solvent during the dissolution and crystallization of the inorganic acid salt of the generated noradrenaline bitartrate intermediate 3 in the organic solvent, such as hydrochloric acid;

[0023] The molar ratio of the inorganic acid to the crude norepinephrine bitartrate intermediate 3 is (1.0-1.4):1, preferably (1.2-1.4):1, and more preferably 1.2:1;

[0024] The inorganic acid is added dropwise to the crude norepinephrine bitartrate intermediate 3;

[0025] The temperature of the inorganic acid during the dropwise addition is controlled to be 10 to 30°C, preferably 15 to 25°C;

[0026] As an example, the organic solvent is mixed with the crude norepinephrine bitartrate intermediate 3, and then the inorganic acid is added dropwise to the mixed system.

[0027] In the above-mentioned method for purifying the intermediate of bitartrate of noradrenaline, every 1g of the crude intermediate of bitartrate of noradrenaline 3 is mixed with (4-12)mL of the organic solvent, preferably 1g: 8mL;

[0028] The organic solvent is any one of methanol, ethanol, isopropanol and acetone, preferably isopropanol.

[0029] In the above-mentioned method for purifying the intermediate of norepinephrine bitartrate, the reaction temperature in step S1 is 10-30° C., preferably 15-25° C., and the reaction time is 0.5-2 h, such as 0.5 h, 1 h.

[0030] In the above-mentioned method for purifying the intermediate of norepinephrine bitartrate, after the reaction in step S1 is completed, the following steps are also included: cooling the system after the reaction to -5 to 10°C (preferably 0 to 5°C) for crystallization for 1 to 3 hours (such as 1 hour or 2 hours), and then filtering, washing and drying in sequence.

[0031] In the above-mentioned method for purifying the intermediate of norepinephrine bitartrate, the inorganic base is a weak base, preferably aqueous ammonia;

[0032] The molar ratio of the inorganic base to the norepinephrine bitartrate intermediate 3 hydrochloride is (1.6-2.0):1, preferably 1.8:1;

[0033] The inorganic base is added dropwise to the noradrenaline bitartrate intermediate 3 hydrochloride; specifically, the inorganic base is added dropwise to a mixed system consisting of water, noradrenaline bitartrate intermediate 3 hydrochloride and an antioxidant;

[0034] The temperature of the inorganic base is controlled at 10-30°C, preferably 15-25°C during the dropping process.

[0035] In the above-mentioned method for refining the intermediate of norepinephrine bitartrate, the antioxidant is sodium pyrosulfite or sodium bisulfite;

[0036] The mass ratio of the antioxidant to the crude product of the norepinephrine bitartrate intermediate 3 is (0.005-0.015):1, such as 0.01:1.

[0037] In the above-mentioned method for purifying the intermediate of bitartrate of norepinephrine, the reaction temperature in step S2 is 10-30° C., preferably 15-25° C., and the reaction time is 0.5-1 h, such as 0.5 h.

[0038] In the above-mentioned method for purifying the intermediate of norepinephrine bitartrate, after the reaction in step S2 is completed, the following steps are further included: filtering, washing and drying the system after the reaction is completed at 35-45° C. under reduced pressure in sequence.

[0039] In the above-mentioned purification method of norepinephrine bitartrate intermediate, the purification method can remove the impurity 23 in the crude norepinephrine bitartrate intermediate 3, and the structural formula of the impurity 23 is shown in Formula II:

[0040]

[0041] The present invention has the following beneficial effects:

[0042] The purification method of the norepinephrine bitartrate intermediate of the present invention is simple to operate and has a high yield. The impurity 23 can be reduced to ≤0.05%, and other impurities are also largely removed. The purity of the norepinephrine bitartrate intermediate 3 can reach 99%, thereby ensuring the quality of subsequent products. The preparation of subsequent products can specifically refer to the synthesis route disclosed in the patent "A Preparation Method of Norepinephrine Bitartrate" (CN112225665A) or the document "Research on the Synthesis of (-)-Norepinephrine Bitartrate" (Chemical Technology and Research and Development, 2014, 43(8):11-12, reported by Liang Dawei et al.), and the norepinephrine bitartrate intermediate 3 is used to further prepare norepinephrine bitartrate, thereby solving the problem that the impurity 23 is difficult to remove during production. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 It is the structural formula of norepinephrine bitartrate.

[0044] Figure 2 The structural formula of the intermediate 2 of norepinephrine heavy tartrate in the synthesis route 1 in the background technology is shown in FIG.

[0045] Figure 3 The structural formula of the intermediate 3 of norepinephrine heavy tartrate in the synthesis route 1 in the background technology is shown in FIG.

[0046] Figure 4 The present invention is a structural formula of the transition state of the hydrogenation reaction of norepinephrine heavy tartrate in the synthesis route one in the background technology.

[0047] Figure 5 It is the structural formula of impurity 23 in the synthetic route 1 in the background technology.

[0048] Figure 6 This is the mass spectrum of impurity 23.

[0049] FIG. 7( a ) and FIG. 7( b ) are liquid phase spectra of the crude product (1) of the intermediate 3 of noradrenaline bitartrate used in Examples 1 to 6 of the present invention.

[0050] FIG8(a) and FIG8(b) are liquid phase spectra of the refined product of norepinephrine bitartrate intermediate 3 obtained in Example 1 of the present invention.

[0051] 9(a) and 9(b) are liquid phase spectra of the refined product of norepinephrine bitartrate intermediate 3 obtained in Example 2 of the present invention.

[0052] 10( a ) and 10( b ) are liquid phase spectra of the refined product of the intermediate 3 of norepinephrine bitartrate obtained in Example 3 of the present invention.

[0053] FIG. 11( a ) and FIG. 11( b ) are liquid phase spectra of the refined product of the intermediate 3 of norepinephrine bitartrate obtained in Example 4 of the present invention.

[0054] Figures 12(a) and 12(b) are liquid phase spectra of the refined product of norepinephrine bitartrate intermediate 3 obtained in Example 5 of the present invention.

[0055] 13(a) and 13(b) are liquid phase spectra of the refined product of norepinephrine bitartrate intermediate 3 obtained in Example 6 of the present invention.

[0056] Fig.14 It is the liquid phase spectrum of the crude product (2) of the intermediate 3 of noradrenaline bitartrate used in Comparative Examples 1 and 2 of the present invention.

[0057] Fig.15 It is a liquid phase spectrum of the refined product of norepinephrine bitartrate intermediate 3 obtained by single solvent refining in Comparative Example 1 of the present invention.

[0058] 16(a) and 16(b) are liquid phase spectra of the refined product of norepinephrine bitartrate intermediate 3 obtained by single solvent refining in Comparative Example 2 of the present invention. DETAILED DESCRIPTION

[0059] The present invention is further described in detail below in conjunction with specific embodiments, and the examples provided are only for illustrating the present invention, rather than for limiting the scope of the present invention. The examples provided below can be used as a guide for further improvements by those of ordinary skill in the art, and do not constitute a limitation of the present invention in any way.

[0060] The methods used in the following examples, unless otherwise specified, are all conventional methods, carried out according to the techniques or conditions described in the literature in the art or according to the product instructions. The materials, reagents, etc. used in the following examples, unless otherwise specified, can all be obtained from commercial sources.

[0061] The crude product of norepinephrine bitartrate intermediate 3 in the following example was prepared according to the following steps:

[0062] Add 1200g of dichloromethane, 48g of catechol, 174g of aluminum chloride, and 49g of chloroacetyl chloride to the reaction kettle, control the temperature at 35-45°C, reflux and keep warm for 4h, and cool to 0-10°C. Slowly add dilute hydrochloric acid (960g of water + 113g of concentrated hydrochloric acid) to quench, control the temperature at 20-30°C, stir for 0.5h, filter and wash to obtain intermediate 1 (56g). The structural formula of intermediate 1 is shown in formula III:

[0063]

[0064] The obtained 56g intermediate 1 and 300g butanone were added to a reaction bottle, and then 134g dibenzylamine was added, and the temperature was controlled at 75-85°C for 12h, and the temperature was lowered to 30-40°C, and 9g hydrochloric acid was added dropwise, and the mixture was stirred for 15-20min after the addition was completed, filtered and washed, and the filtrate and washing liquid were transferred to another reaction bottle, and 36g hydrochloric acid was added dropwise to the filtrate, and the temperature was controlled at 40-50°C for 1h after the addition was completed, and the mixture was cooled to 0-10°C and stirred for 3h, and filtered, washed, and dried to obtain intermediate 2 (82g). The structural formula of the intermediate 2 is shown in Formula IV:

[0065]

[0066] Add 82g of the intermediate 2, 900g of ethanol and 2.1g of palladium on carbon into a hydrogenation reactor, control the temperature at 55-65°C and the pressure at 0.6-0.8MPa, and allow hydrogen to react for 3h. After the reaction is completed, filter and collect the filtrate in a reaction bottle. Add 0.9g of sodium metabisulfite, stir at 20-30°C for 2h, cool to 0-10°C, add 33g of aqueous ammonia dropwise, control the temperature at 0-10°C and stir for 0.5h after the addition is completed, filter, wash and dry to obtain 34g of a crude intermediate 3.

[0067] The HPLC purity, impurity 23 content and the maximum single impurity detection steps, chromatographic conditions and calculation formulas of the crude and refined products of the noradrenaline bitartrate intermediate 3 in the following examples are as follows:

[0068] Method basis: High performance liquid chromatography (ChP 2020 edition four general rules 0512)

[0069] Chromatographic conditions:

[0070] Chromatographic column: C18 column (Welch Ultimate XB-C18 4.6×150mm, 5μm or column with equivalent performance);

[0071] Mobile phase A: 0.12% sodium heptane sulfonate solution (pH adjusted to 2.2 with phosphoric acid);

[0072] Mobile phase B: acetonitrile;

[0073] Flow rate: 1.5 mL / min;

[0074] Detection wavelength: 280nm;

[0075] Injection volume: 20 μL;

[0076] Column temperature: 40°C;

[0077] Sample concentration: 2.5 mg / mL

[0078] Solution preparation:

[0079] Solvent: mobile phase A: mobile phase B (95:5);

[0080] Test solution Take an appropriate amount of the product, weigh accurately, dissolve in solvent and dilute to make a solution containing about 2.5 mg per 1 mL.

[0081] Reference solution: Take an appropriate amount of norepinephrine bitartrate reference substance, dissolve it in solvent and dilute it to make a solution containing about 15 μg per 1 mL.

[0082] Determination method:

[0083] (1) Blank solvent: Accurately measure 20 μL of blank solvent, inject it into the liquid chromatograph, and record the chromatogram.

[0084] (2) Accurately measure 20 μL of the control solution and the test solution, inject them into the liquid chromatograph, and record the chromatogram.

[0085] The calculation method is as follows:

[0086] ①Unknown single impurity: calculated by the main component external standard method, the calculation formula is as follows:

[0087]

[0088] A 杂质 : Peak area of ​​impurities in the test solution;

[0089] m 供试品 : Sample weight of the test sample (mg);

[0090] V 供试品 : dilution volume of test solution (mL);

[0091] m 对照品 : The weight of the reference substance of norepinephrine bitartrate (mg);

[0092] V 对照品 : dilution volume of norepinephrine bitartrate reference substance (mL);

[0093] A STD : The main peak area of ​​the norepinephrine bitartrate reference solution;

[0094] 0.5296: Conversion factor of norepinephrine and norepinephrine bitartrate anhydrate;

[0095] W: Purity of norepinephrine bitartrate reference substance (according to C8H 11 NO3·C4H6O6);

[0096] ②Total impurities: Total impurities (%) = sum of all impurities.

[0097] Example 1: Refining of norepinephrine bitartrate intermediate 3

[0098] 5.0 g of crude norepinephrine bitartrate intermediate 3 (HPLC purity 97.30%, impurity 23 content 0.28%, mass spectrum of impurity 23 see Figure 6 , maximum single impurity 0.41%, the detection spectrum is shown in Figure 7) and 20mL of acetone, start stirring, control the temperature at 10-20°C and add 3mL of hydrochloric acid (36-38%) (the molar ratio of hydrochloric acid to norepinephrine bitartrate intermediate 3 is 1.2:1), after the addition is completed, control the temperature at 10-20°C and stir for 0.5h, then cool to -5-0°C and stir for 1h, filter, wash and dry to obtain norepinephrine bitartrate intermediate 3 hydrochloride. Add the hydrochloride into the reaction flask, add 40 mL of purified water and 0.05 g of sodium pyrosulfite, control the temperature at 15-25° C. and add 3.6 g of ammonia water (ammonia water concentration is 25-28%, and the molar ratio of ammonia water to norepinephrine bitartrate intermediate 3 hydrochloride is 1.8:1). After the addition is completed, keep stirring at 15-25° C. for 0.5 h, filter and wash, and dry under reduced pressure at 35-45° C. to obtain 4.2 g of a refined product of norepinephrine bitartrate intermediate 3, with a yield of 84% (HPLC purity is 98.91%, impurity 23 content is 0.04%, maximum single impurity content is 0.18%, and the detection spectrum is shown in Figure 8).

[0099] Example 2

[0100] 5.0 g of crude norepinephrine bitartrate intermediate 3 (HPLC purity 97.30%, impurity 23 content 0.28%, mass spectrum of impurity 23 see Figure 6 , maximum single impurity 0.41%, detection spectrum see Figure 7) and isopropanol 40mL, start stirring, control the temperature at 15-25°C and add 3mL of hydrochloric acid (36-38%) (the molar ratio of hydrochloric acid to norepinephrine bitartrate intermediate 3 is 1.2:1), after the addition is completed, control the temperature at 15-25°C and stir for 1h, then cool to 0-5°C and stir to crystallize for 2h, filter, wash and dry to obtain norepinephrine bitartrate intermediate 3 hydrochloride. Add the hydrochloride into the reaction flask, add 40 mL of purified water and 0.05 g of sodium pyrosulfite, control the temperature at 15-25° C. and add 3.6 g of ammonia water (ammonia water concentration 25-28%, molar ratio of ammonia water to norepinephrine bitartrate intermediate 3 hydrochloride 1.8:1), after the addition is complete, keep warm and stir at 15-25° C. for 0.5 h, then filter and wash, and dry under reduced pressure at 35-45° C. to obtain 4.1 g of a refined product of norepinephrine bitartrate intermediate 3, with a yield of 82% (HPLC purity of 99.25%, impurity 23 content of 0.01%, maximum single impurity 0.17%, detection spectrum see Figure 9).

[0101] Example 3

[0102] 5.0 g of crude norepinephrine bitartrate intermediate 3 (HPLC purity 97.30%, impurity 23 content 0.28%, mass spectrum of impurity 23 see Figure 6 , maximum single impurity 0.41%, the detection spectrum is shown in Figure 7) and 60mL of ethanol, start stirring, control the temperature at 10-20°C and add 2.5mL of hydrochloric acid (36-38%) (the molar ratio of hydrochloric acid to norepinephrine bitartrate intermediate 3 is 1.0:1), after the addition is completed, control the temperature at 10-20°C and stir for 1.5h, then cool to 5-10°C and stir for 3h, filter, wash and dry to obtain norepinephrine bitartrate intermediate 3 hydrochloride. Add the hydrochloride into the reaction flask, add 40 mL of purified water and 0.05 g of sodium pyrosulfite, control the temperature at 15-25° C. and add 3.6 g of aqueous ammonia (ammonia concentration 25-28%, molar ratio of aqueous ammonia to norepinephrine bitartrate intermediate 3 hydrochloride 1.8:1), after the addition is complete, keep warm and stir at 15-25° C. for 0.5 h, then filter and wash, and dry under reduced pressure at 35-45° C. to obtain 3.8 g of refined product of norepinephrine bitartrate intermediate 3, with a yield of 76% (HPLC purity of 99.31%, impurity 23 content of 0.01%, maximum single impurity of 0.17%, detection spectrum see Figure 10).

[0103] Example 4

[0104] 5.0 g of crude norepinephrine bitartrate intermediate 3 (HPLC purity 97.30%, impurity 23 content 0.28%, mass spectrum of impurity 23 see Figure 6 , maximum single impurity 0.41%, the detection spectrum is shown in Figure 7) and methanol 40mL, start stirring, control the temperature at 15-25°C and add 3.5mL of hydrochloric acid (36-38%) (the molar ratio of hydrochloric acid to norepinephrine bitartrate intermediate 3 is 1.4:1), after the addition is completed, control the temperature at 15-25°C and stir for 1h, then cool to 0-5°C and stir for 2h, filter, wash and dry to obtain norepinephrine bitartrate intermediate 3 hydrochloride. Add the hydrochloride into the reaction flask, add 40 mL of purified water and 0.05 g of sodium pyrosulfite, control the temperature at 15-25° C., add 3.6 g of ammonia water (ammonia water concentration 25-28%, molar ratio of ammonia water to norepinephrine bitartrate intermediate 3 hydrochloride 1.8:1), and after the addition is complete, keep stirring at 15-25° C. for 0.5 h, filter and wash, and dry under reduced pressure at 35-45° C. to obtain 3.9 g of refined norepinephrine bitartrate intermediate 3, with a yield of 78% (HPLC purity of 99.04%, impurity 23 content of 0.01%, maximum single impurity of 0.18%, and the detection spectrum is shown in Figure 11).

[0105] Example 5

[0106] 5.0 g of crude norepinephrine bitartrate intermediate 3 (HPLC purity 97.30%, impurity 23 content 0.28%, mass spectrum of impurity 23 see Figure 6 , maximum single impurity 0.41%, detection spectrum see Figure 7) and 40mL of acetone, start stirring, control the temperature at 15-25°C and add 3mL of hydrochloric acid (36-38%) (the molar ratio of hydrochloric acid to norepinephrine bitartrate intermediate 3 is 1.2:1), after the addition is completed, control the temperature at 15-25°C and stir for 1h, then cool to 0-5°C and stir for 2h, filter, wash and dry to obtain norepinephrine bitartrate intermediate 3 hydrochloride. Add the hydrochloride into the reaction flask, add 40 mL of purified water and 0.05 g of sodium pyrosulfite, control the temperature at 15-25°C, add 3.6 g of ammonia water (ammonia water concentration 25-28%, ammonia water to norepinephrine bitartrate intermediate 3 hydrochloride molar ratio of 1.8:1), after the addition is complete, keep stirring at 15-25°C for 0.5 h, then filter and wash, and dry under reduced pressure at 35-45°C to obtain 3.9 g of refined norepinephrine bitartrate intermediate 3, with a yield of 78% (HPLC purity of 98.95%, impurity 23 not detected, maximum single impurity 0.18%, detection spectrum see Figure 12).

[0107] Example 6

[0108] 5.0 g of crude norepinephrine bitartrate intermediate 3 (HPLC purity 97.30%, impurity 23 content 0.28%, mass spectrum of impurity 23 see Figure 6 , maximum single impurity 0.41%, the detection spectrum is shown in Figure 7) and 40mL of isopropanol, start stirring, control the temperature at 10-20°C and add 3.2mL of hydrochloric acid (36-38%) (the molar ratio of hydrochloric acid to norepinephrine bitartrate intermediate 3 is 1.3:1), after the addition is completed, control the temperature at 10-20°C and stir for 0.5h, then cool to 0-5°C and stir for 1h, filter, wash and dry to obtain norepinephrine bitartrate intermediate 3 hydrochloride. Add the hydrochloride into the reaction flask, add 40 mL of purified water and 0.05 g of sodium pyrosulfite, control the temperature at 15-25°C, add 3.6 g of ammonia water (ammonia water concentration 25-28%, ammonia water to norepinephrine bitartrate intermediate 3 hydrochloride molar ratio of 1.8:1), after the addition is complete, keep stirring at 15-25°C for 0.5 h, then filter and wash, and dry under reduced pressure at 35-45°C to obtain 3.8 g of refined norepinephrine bitartrate intermediate 3, with a yield of 76% (HPLC purity of 99.11%, impurity 23 not detected, maximum single impurity 0.18%, detection spectrum see Figure 13).

[0109] Comparative Example 1

[0110] 5.0 g of crude norepinephrine bitartrate intermediate 3 (HPLC purity 97.16%, impurity 23 content 0.10%, maximum single impurity 0.62%, detection spectrum see Fig.14 ) and 40 mL of ethanol, start stirring, control the temperature at 15-25 ° C, stir and beat for 1 h, then cool to 0-5 ° C, stir and beat for 2 h, filter, wash and dry to obtain 4.5 g of refined product of norepinephrine bitartrate intermediate 3, with a yield of 90% (HPLC purity of 98.07%, impurity 23 content of 0.09%, maximum single impurity 0.44%, detection spectrum see Fig.15 ). The content of impurity 23 hardly changed. This shows that refining with ethanol alone has no impurity removal effect.

[0111] Comparative Example 2

[0112] 5.0 g of crude norepinephrine bitartrate intermediate 3 (HPLC purity 97.16%, impurity 23 content 0.10%, maximum single impurity 0.62%, detection spectrum see Fig.14 ) and 40 mL of methanol, start stirring, control the temperature at 40-50°C, stir and beat for 1 hour, then cool to 0-5°C, stir and beat for 2 hours, filter, wash and dry to obtain 4.4 g of refined product of norepinephrine bitartrate intermediate 3, with a yield of 88% (HPLC purity of 98.11%, impurity 23 content of 0.09%, maximum single impurity of 0.53%, detection spectrum see Figure 16). The content of impurity 23 has almost no change. It shows that the refining with methanol alone has no impurity removal effect.

[0113] The present invention has been described in detail above. For those skilled in the art, without departing from the purpose and scope of the present invention, can implement the present invention in a wider range under equivalent parameters, concentrations and conditions. Although the present invention provides specific embodiments, it should be understood that the present invention can be further improved. In a word, according to the principle of the present invention, the application is intended to include any changes, uses or improvements to the present invention, including departing from the disclosed scope in the application and the changes made with conventional techniques known in the art.

Claims

1. A method for refining a norepinephrine bitartrate intermediate, characterized in that: The steps include: S1, reacting the crude product of norepinephrine bitartrate intermediate 3 with an inorganic acid in an organic solvent to obtain an inorganic acid salt of norepinephrine bitartrate intermediate 3; S2. In the presence of an antioxidant, the inorganic acid salt of the noradrenaline bitartrate intermediate 3 reacts with an inorganic base in water to obtain a refined product of the noradrenaline bitartrate intermediate 3; The structural formula of the norepinephrine bitartrate intermediate 3 is shown in Formula I:

2. The method for purifying the norepinephrine bitartrate intermediate according to claim 1, wherein: The inorganic acid is hydrochloric acid; The molar ratio of the inorganic acid to the crude product of the norepinephrine bitartrate intermediate 3 is (1.0-1.4):1; The inorganic acid is added dropwise to the crude norepinephrine bitartrate intermediate 3; The temperature of the inorganic acid is controlled at 10-30° C. during the dropwise addition process.

3. The method for refining the norepinephrine bitartrate intermediate according to any one of claims 1-2, characterized in that: Each 1 g of the crude norepinephrine bitartrate intermediate 3 is mixed with (4-12) mL of the organic solvent; The organic solvent is any one of methanol, ethanol, isopropanol and acetone.

4. The method for refining the norepinephrine bitartrate intermediate according to any one of claims 1 to 3, characterized in that: The reaction temperature in step S1 is 10-30° C. and the reaction time is 0.5-2 h.

5. The method for refining the norepinephrine bitartrate intermediate according to any one of claims 1 to 4, characterized in that: After the reaction in step S1 is completed, the following steps are further included: cooling the system after the reaction to -5 to 10°C for crystallization for 1 to 3 hours, and then filtering, washing and drying in sequence.

6. The method for refining the norepinephrine bitartrate intermediate according to any one of claims 1 to 5, characterized in that: The inorganic base is a weak base, preferably aqueous ammonia; The molar ratio of the inorganic base to the inorganic acid salt of the norepinephrine bitartrate intermediate 3 is (1.6-2.0):1; The inorganic base is added dropwise to the inorganic acid salt of the norepinephrine bitartrate intermediate 3; The temperature of the inorganic base is controlled at 10-30° C. during the dropping process.

7. The method for refining the norepinephrine bitartrate intermediate according to any one of claims 1 to 6, characterized in that: The antioxidant is sodium pyrosulfite or sodium bisulfite; The mass ratio of the antioxidant to the crude product of the norepinephrine bitartrate intermediate 3 is (0.005-0.015):

1.

8. The method for refining the norepinephrine bitartrate intermediate according to any one of claims 1 to 7, characterized in that: The reaction temperature in step S2 is 10-30° C. and the reaction time is 0.5-1 h.

9. The method for refining the norepinephrine bitartrate intermediate according to any one of claims 1 to 8, characterized in that: After the reaction in step S2 is completed, the following steps are further included: filtering, washing and drying the system after the reaction under reduced pressure at 35-45° C. in sequence.

10. The method for refining the norepinephrine bitartrate intermediate according to any one of claims 1 to 9, characterized in that: The purification method can remove the impurity 23 in the crude product of the intermediate 3 of bitartrate of noradrenaline, and the structural formula of the impurity 23 is shown in Formula II:

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