Preparation method of noradrenaline racemate

Abstract

The invention provides a preparation method of a noradrenaline racemate. The preparation method provided by the invention comprises the following step: carrying out hydrogenation reaction on norepinephrine hydrochloride and hydrogen under the action of a Pd-C catalyst and a benzene sulfonate gemini anionic surfactant as shown in a formula I to obtain the norepinephrine racemate. # imgabs0 #

Description

Technical Field

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

[0002] Norepinephrine, chemically known as 1-(3,4-dihydroxyphenyl)-2-aminoethanol, generally uses chloroacetylcatechol as the starting material, and undergoes amination and salt-forming reactions to obtain norepinephrine hydrochloride, and then obtains norepinephrine racemate through hydrogenation reduction reaction, and obtains L-norepinephrine after chiral resolution. The most critical step in the synthesis process of norepinephrine is the hydrogenation reduction reaction, which uses norepinephrine hydrochloride and hydrogen as reactants to prepare norepinephrine racemate through reduction reaction, and the efficiency of the hydrogenation reaction significantly affects the generation of impurities.

[0003] The document "Study on the Synthesis Process of (-)-Norepinephrine Bitartrate" reports the synthesis process of (±)-norepinephrine, and its synthesis process is a reduction reaction of norepinephrine hydrochloride and hydrogen under the catalytic action of Pd-C catalyst (10%). This process route is the mainstream process on the market, but the main problems are high reaction pressure (≥3MPa) and long reaction time (≥48h). The high reaction pressure poses a challenge to safe operation. In addition, under the conditions of high reaction pressure and long reaction time, the hydrogenation reaction process will produce more impurities, affecting the purity of norepinephrine racemate and product appearance, etc., and the long reaction time will also significantly affect production efficiency and increase production costs. Therefore, exploring a better hydrogenation reduction reaction process is an important research direction to improve the purity of norepinephrine racemate, increase yield, and reduce production costs. Summary of the invention

[0004] In order to solve one of the above-mentioned technical problems existing in the prior art, the present invention provides a method for preparing a norepinephrine racemate, which can react quickly under normal pressure and significantly shorten the reaction time. The process is simple and safe, the efficiency is high, the cost is low, and the prepared norepinephrine racemate has high purity.

[0005] The technical solution of the present invention is as follows:

[0006] A method for preparing a norepinephrine racemate comprises: subjecting norepinephrine hydrochloride and hydrogen to a hydrogenation reaction under the action of a Pd-C catalyst and a benzenesulfonate gemini anionic surfactant represented by the following formula I, to obtain a norepinephrine racemate;

[0007]

[0008] In formula I, R is selected from a C2-C6 straight chain or branched alkylene group;

[0009] R1 and R2 are the same or different and are each independently selected from a C10-C20 straight chain or branched alkyl group;

[0010] R3 and R4 are the same or different and are each independently selected from a sulfonate group.

[0011] The present invention has been found through research that adding a specific gemini anionic surfactant to the hydrogenation reaction system of noradrenaline hydrochloride can significantly accelerate the hydrogenation reaction process, shorten the reaction time, and even when the reaction pressure is as low as normal pressure, a rapid reaction can occur, the reaction efficiency is greatly improved, and the purity of the prepared noradrenaline racemate can be as high as 99.0% or more, which can effectively solve the problems of long hydrogenation reaction time, high reaction pressure and more impurities in the prior art of noradrenaline hydrochloride, and has unexpected effects.

[0012] In the above formula I of the present invention, R can be a straight chain alkylene of C2, C3, C4, C5 or C6; it can also be a branched alkylene of C2, C3, C4, C5 or C6. In some embodiments, in formula I, R is selected from C2-C4 straight chain or branched alkylene. In the above formula I of the present invention, R is preferably a C2-C4 straight chain alkylene, such as ethylene, propylene or butylene. In some embodiments, in the above formula I, R is ethylene.

[0013] In the above formula I of the present invention, R1 and R2 may be the same or different, and are each independently selected from C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 straight chain alkyl, or, are each independently selected from C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 branched alkyl. In some embodiments, R1 and R2 are the same or different, and are each independently selected from C10-C18 straight chain alkyl, such as n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl or n-octadecyl. In the above formula I of the present invention, R1 and R2 are preferably the same. In some embodiments, R1 and R2 are each independently n-undecyl, n-tridecyl, n-pentadecyl or n-heptadecyl. In some embodiments, R1 and R2 are both n-undecyl. In some embodiments, R1 and R2 are both n-tridecyl. In some embodiments, R1 and R2 are both n-pentadecyl. In some embodiments, R1 and R2 are both n-heptadecyl.

[0014] In the above formula I of the present invention, R3 and R4 may be the same or different, and are independently selected from -SO3Na, -SO3K, -SO3Mg or -SO3Ca. In the above formula I of the present invention, R3 and R4 are preferably the same. In some embodiments, R3 and R4 are both -SO3Na.

[0015] In some embodiments, the benzenesulfonate gemini anionic surfactant represented by the above formula I has a structure represented by the following formula II:

[0016]

[0017] The symbols in formula II are defined the same as in formula I.

[0018] In some embodiments, the benzenesulfonate gemini anionic surfactant represented by the above formula I has a structure represented by the following formula I-1:

[0019]

[0020] In formula I-1, n is an integer selected from 10 to 16.

[0021] In some embodiments, in Formula I-1, n is selected from 10, 12, 14 or 16. In some embodiments, in Formula I-1, n is 10. In some embodiments, in Formula I-1, n is 12. In some embodiments, in Formula I-1, n is 14. In some embodiments, in Formula I-1, n is 16.

[0022] In some embodiments, the benzenesulfonate gemini anionic surfactant represented by the above formula I has a structure represented by the following formula I-2:

[0023]

[0024] The definition of n is the same as that in formula I-1.

[0025] In some embodiments, the benzenesulfonate-based gemini anionic surfactant is prepared by a method comprising the following steps:

[0026] (S1) reacting the compound NH2-R-NH2 with a halogenated benzene sulfonate solution to obtain an intermediate, wherein the halogenated benzene sulfonate comprises R, R3 and R4 are defined as in Formula I, X represents halogen (e.g., fluorine, chlorine, bromine, iodine, etc., preferably chlorine);

[0027] (S2) reacting the intermediate with a long-chain alkanoyl chloride, then cooling, concentrating and crystallizing to obtain the benzenesulfonate-based gemini anionic surfactant; wherein the long-chain alkanoyl chloride includes R1COCl and / or R2COCl, and the definitions of R1 and R2 are the same as those of Formula I.

[0028] In some embodiments, in the above step (S1), the molar ratio of the compound NH2-R-NH2 to the halobenzenesulfonate is 1:(2-3), preferably 1:(2.4-2.6).

[0029] In some embodiments, in the above step (S1), the halogenated benzene sulfonate comprises and / or Preferred include

[0030] In some embodiments, in the above step (S1), the reaction is carried out at a pH of 9.5 to 10.5, preferably 9.8 to 10.2.

[0031] In some embodiments, in the above step (S1), the reaction temperature is 40 to 50° C. In some embodiments, in the above step (S1), the reaction time is 4 to 12 hours, preferably 8 to 10 hours.

[0032] In some embodiments, in the above step (S2), the reaction is carried out in a mixed solvent of acetone and water. In some embodiments, the volume ratio of acetone to water in the mixed solvent is 1: (0.5-2), preferably 1: (0.8-1.2).

[0033] In some embodiments, in the above step (S2), the reaction is carried out at a pH of 7.5 to 9.5, preferably 7.8 to 8.2.

[0034] In some embodiments, in the above step (S2), the temperature for reacting the intermediate with the long-chain alkanoyl chloride is 40-50°C.

[0035] In some embodiments, in the above step (S2), the reaction time of the intermediate and the long-chain alkanoyl chloride is 3 to 8 hours, preferably 5 to 7 hours.

[0036] In some embodiments, the benzenesulfonate-based gemini anionic surfactant is prepared by a method comprising the following steps:

[0037] The ethylenediamine is reacted with a sodium p-chlorobenzenesulfonate solution to obtain an ethylenediamine-N,N′-sodium dibenzenesulfonate intermediate; the ethylenediamine-N,N′-sodium dibenzenesulfonate intermediate is reacted with a long carbon chain alkanoyl chloride CH3(CH2)nCOCl (n is selected from an integer between 10 and 16, such as 10, 12, 14, 16, etc.) to obtain the benzenesulfonate type anionic gemini surfactant.

[0038] In some embodiments, the benzenesulfonate-based gemini anionic surfactant is prepared by a method comprising the following steps:

[0039] Mix ethylenediamine and water and heat to 40-50°C, add a saturated aqueous solution of sodium p-chlorobenzenesulfonate dropwise and adjust the pH to 9.5-10.5, and keep the reaction warm for 8-10 hours; vacuum concentrate, add anhydrous ethanol to the concentrate until it becomes turbid, and cool and crystallize to obtain an intermediate;

[0040] The intermediate is dissolved in a mixed solution of acetone and water in a volume ratio of 1:(1-2), heated at 40-50° C. to dissolve, long-chain alkanoyl chloride CH3(CH2)nCOCl is added dropwise, and the pH is adjusted to 7.8-8.5, and the reaction is carried out for 5-7 hours; the temperature is lowered, concentrated and crystallized to obtain a benzenesulfonate anionic gemini surfactant.

[0041] In some embodiments, the benzenesulfonate-based gemini anionic surfactant is prepared by a method comprising the following steps:

[0042] 1) Add ethylenediamine and water to a reactor, heat to 45°C with stirring, and slowly drop a saturated aqueous solution of sodium p-chlorobenzenesulfonate; after the dropwise addition is completed, adjust the pH to 10.0, keep warm and stir to react for 9 hours; vacuum concentrate, add anhydrous ethanol to the remaining concentrated solution until it becomes turbid, cool and crystallize to obtain an intermediate containing two hydrophilic groups;

[0043] 2) The intermediate containing two hydrophilic groups is dissolved in a 1:1 acetone-water mixed solution, stirred at 50°C until completely dissolved, and long-chain alkanoyl chloride CH3(CH2)nCOCl is added dropwise. After the addition is complete, the pH is adjusted to 8 and the reaction is carried out for 6 hours; the temperature is lowered, and the mixture is concentrated and crystallized to obtain a benzenesulfonate-type anionic gemini surfactant.

[0044] In some embodiments, the amount of the gemini surfactant is 0.01 to 0.03 times the weight of norepinephrine hydrochloride, for example, 0.01 times, 0.012 times, 0.015 times, 0.018 times, 0.020 times, 0.022 times, 0.025 times, 0.028 times, 0.030 times or any value therebetween, preferably 0.015 to 0.025 times.

[0045] In some embodiments, the loading amount of Pd in ​​the Pd-C catalyst is 1 to 10%, preferably 3 to 8%. In some embodiments, the loading amount of Pd in ​​the Pd-C catalyst is 5%. In the present invention, the Pd-C catalyst and the surfactant must exist at the same time, and neither is indispensable. The Pd-C catalyst is a hydrogenation reaction catalyst, which can realize a reduction reaction on the Pd-C surface by adsorbing hydrogen, and the addition of the surfactant can synergistically catalyze with the Pd-C catalyst to achieve an efficient reduction reaction. The possible reason is that the addition of the surfactant significantly increases the solubility of noradrenaline hydrochloride in anhydrous solvents, from noradrenaline hydrochloride needing to be completely dissolved in 12 to 15 times alcohol solvents to being dissolved in 7 to 8 times alcohol solvents, thereby increasing the concentration of the reaction substrate, thereby accelerating the reaction rate; on the other hand, the surfactant used in the present invention has a lower critical micelle concentration, which is equivalent to forming many microreactors, increasing the probability of contact and collision between reactants, thereby forming a synergistic catalytic effect with the Pd-C catalyst.

[0046] In the present invention, the Pd-C catalyst can be used on a dry basis or on a wet basis. In some embodiments, the amount of the Pd-C catalyst is 0.025 to 0.3 times, preferably 0.03 to 0.06 times, of the weight of the adrenaline hydrochloride, on a dry basis. In some embodiments, the Pd loading in the Pd-C catalyst is 5%, and the amount of Pd-C (5%) on a dry basis is 0.05 to 0.08 times, preferably 0.06 times, of the weight of the adrenaline hydrochloride. In some embodiments, the Pd loading in the Pd-C catalyst is 10%, and the amount of Pd-C (10%) on a dry basis is 0.025 to 0.04 times, preferably 0.03 times, of the weight of the adrenaline hydrochloride.

[0047] In some embodiments, the pressure of the hydrogenation reaction is 0.1-3 MPa, for example, 0.1 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.8 MPa, 1.0 MPa, 1.5 MPa, 2.0 MPa, 2.5 MPa, 3.0 MPa or any value therebetween, preferably 0.1-0.5 MPa, more preferably 0.2-0.4 MPa.

[0048] In some embodiments, the temperature of the hydrogenation reaction is 25-50°C, for example, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C or any value therebetween, preferably 25-35°C.

[0049] In some embodiments, the hydrogenation reaction is carried out in an alcohol solvent. The alcohol solvent of the present invention includes a C1-C4 alcohol solvent, such as one or more of methanol, ethanol, and isopropanol. In the hydrogenation reaction system of the present invention, the solvent used does not contain water, and the addition of water will reduce the activity of the Pd-C catalyst and inhibit the reaction process.

[0050] In some embodiments, the alcohol solvent includes anhydrous ethanol. In some embodiments, the alcohol solvent includes methanol. In some embodiments, the amount of the alcohol solvent is 7 to 10 times the weight of noradrenaline hydrochloride, such as 7 times, 8 times, 9 times or 10 times.

[0051] In some embodiments, the method for preparing the norepinephrine racemate further comprises:

[0052] The reaction liquid obtained after the reaction is subjected to solid-liquid separation to obtain a liquid phase; the liquid phase is concentrated in vacuo and then mixed with water, and an alkali solution is added to adjust the pH to 8-9, and the reaction liquid is crystallized and dried to obtain norepinephrine racemate crystals.

[0053] Compared with the prior art, the present invention has the following beneficial technical effects:

[0054] The method of the present invention increases the solubility of adrenaline hydrochloride in a solvent by adding a specific gemini surfactant into the reaction system, and cooperates with a Pd-C catalyst for catalysis, so that noradrenaline hydrochloride is efficiently reduced at a relatively low temperature and a relatively low pressure. The reaction conditions are mild, the reaction rate is fast, the reaction efficiency is high, and no refining is required. High-purity and high-yield noradrenaline racemate can be prepared once in a short time, with a purity (HPLC normalization) of ≥99.0% and a yield of ≥90.0%, thereby providing a high-quality intermediate for the preparation of L-noradrenaline. DETAILED DESCRIPTION

[0055] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation to the present invention.

[0056] In the hydrogenation reduction reaction system of noradrenaline hydrochloride, the classic process is to use Pd-C catalyst to carry out reduction reaction in alcohol solvent, and the hydrogenation reaction generally requires a certain pressure and temperature. The existing reduction process parameters of noradrenaline hydrochloride are reaction pressure 3MPa, reaction time 48h, and reaction temperature room temperature. The significant disadvantages of this process are high reaction pressure, long reaction time, and many impurities in the product.

[0057] The invention finds in the process of studying the reduction reaction of noradrenaline hydrochloride that adding a specific surfactant into the reaction system can significantly improve the efficiency of the reduction reaction, not only can realize low pressure or normal pressure reaction (0.1-0.5MPa), but also can significantly shorten the reaction time (≤8h), significantly reduce the generation of impurities, and efficiently realize the hydrogenation reduction of noradrenaline hydrochloride to prepare the noradrenaline racemate. By determining a reasonable reaction system and optimizing process parameters, the purity (HPLC normalization) of the noradrenaline racemate is ≥99.0%, and the yield is ≥90.0%. Under mild reaction conditions, the preparation of the noradrenaline racemate with high yield and high purity is realized in a relatively short time.

[0058] In the present invention, "racemate" is an equimolar mixture of an optically active chiral molecule and its enantiomer. It is formed by mixing equal amounts of molecules with opposite optical rotation directions and the same optical rotation ability. The optical rotation of the molecules cancels each other due to the interaction between these molecules, so it is optically inactive.

[0059] The reagents used in the following experiments of the present invention, unless otherwise specified, are all conventional commercial products or reagents prepared by conventional methods, and the methods used in the experiments, unless otherwise specified, are all conventional experimental methods. The instruments used in the experiments, unless otherwise specified, can all be obtained through commercial channels.

[0060] The specific structures of the surfactants used in the following embodiments of the present invention are as follows:

[0061]

[0062] Wherein, when n=10, the chemical name is: ethylenebis(N-benzenesulfonic acid-lauramide) sodium salt;

[0063] When n=12, the chemical name is: ethylenebis(N-benzenesulfonic acid-n-tetradecanoic acid amide) sodium salt, abbreviated as FY-2C14;

[0064] When n=14, the chemical name is: ethylenebis(N-benzenesulfonic acid-n-hexadecanoic acid amide) sodium salt;

[0065] When n=16, the chemical name is: ethylenebis(N-benzenesulfonic acid-n-octadecylamide) sodium salt;

[0066] For the specific preparation method of the surfactant, please refer to the synthesis method disclosed in Example 3, Example 4, Example 5 and Example 6 of document CN102351749A.

[0067] Comparative Example 1

[0068] This comparative example relates to a method for preparing a norepinephrine racemate, comprising the following steps:

[0069] 1) Add 20.4g (0.1mol) of noradrenaline hydrochloride and 265.2g of ethanol to a 500mL stainless steel hydrogenation reactor, stir until completely dissolved, then add 1.2g of 5% palladium carbon (dry basis), stir evenly. After nitrogen replaces the air, introduce hydrogen, maintain the pressure at 3MPa, and stir the reaction at 25°C. Monitor the reaction process in the liquid phase, and the reaction is complete after 48h.

[0070] 2) After the reaction is complete, the palladium carbon is filtered off, and the solvent is concentrated under vacuum at -0.09MPa to -0.1MPa and 40-50°C to remove about 200g, and 400g of water is added, and the pH is adjusted to 8-9 with ammonia water to precipitate the norepinephrine racemate crystals, which are filtered and vacuum dried at a vacuum degree of -0.08 to -0.1MPa, a drying temperature of 45-50°C, and dried for 4h. The material is collected to obtain the norepinephrine racemate, with a weight of 13.8g, a molar yield of 81.6%, and a HPLC normalized purity of 95.6%.

[0071] Comparative Example 2

[0072] Compared with Comparative Example 1, the difference is that the reaction pressure of step 1) is maintained at 0.5 MPa, and the other conditions remain unchanged. The reaction is completed in 96 hours, and the weight of the obtained product is 11.2 g, the molar yield is 66.2%, and the HPLC normalized purity is 88.5%.

[0073] Example 1

[0074] This embodiment relates to a method for preparing a racemic norepinephrine by hydrogenation reduction reaction of norepinephrine hydrochloride in an optimized reaction system, comprising the following steps:

[0075] 1) Add 20.4g (0.1mol) of noradrenaline hydrochloride, 163.2g of anhydrous ethanol, and 0.4g of FY-2C14 surfactant to a 500mL stainless steel hydrogenation reactor, stir until completely dissolved, then add 1.2g of 5wt% palladium carbon (dry basis), and stir evenly. After nitrogen replaces the air, introduce hydrogen, maintain the pressure at 3MPa, and stir the reaction at 25°C. Monitor the reaction process in the liquid phase until the reaction is complete after 4 hours.

[0076] 2) After the reaction is complete, the palladium carbon is filtered off, and the solvent is concentrated under vacuum at -0.09MPa to -0.1MPa and 40 to 50°C to remove about 200g, and 400g of water is added, and the pH is adjusted to 8 to 9 with ammonia water to precipitate the norepinephrine racemate crystals, which are filtered and vacuum dried at a vacuum degree of -0.08 to -0.1MPa, a drying temperature of 45 to 50°C, and dried for 4h. The material is collected to obtain the norepinephrine racemate, with a weight of 15.5g, a molar yield of 91.6%, and a HPLC normalized purity of 99.2%.

[0077] Example 2

[0078] The difference from Example 1 is that the reaction pressure of step 1) is maintained at 0.5 MPa, and the other conditions remain unchanged. The reaction completion time is 6 hours, the weight of the obtained product is 15.8 g, the molar yield is 93.4%, and the HPLC normalized purity is 99.4%.

[0079] Example 3

[0080] The difference from Example 1 is that the reaction pressure of step 1) is maintained at 0.3 MPa, and the other conditions remain unchanged. The reaction completion time is 7 hours, the weight of the obtained product is 15.8 g, the molar yield is 93.4%, and the HPLC normalized purity is 99.6%.

[0081] Example 4

[0082] The difference from Example 1 is that the reaction pressure of step 1) is maintained at 0.1 MPa (normal pressure), and the other conditions remain unchanged. The reaction completion time is 8 hours, the weight of the obtained product is 15.6 g, the molar yield is 92.2%, and the HPLC normalized purity is 99.5%.

[0083] Example 5

[0084] The difference from Example 1 is that the reaction pressure of step 1) is maintained at 0.3 MPa, the reaction temperature is 30° C., and the other conditions remain unchanged. The reaction completion time is 6.5 h, the weight of the obtained product is 15.8 g, the molar yield is 93.4%, and the HPLC normalized purity is 99.7%.

[0085] Example 6

[0086] The difference from Example 1 is that the reaction pressure of step 1) is maintained at 0.3 MPa, the reaction temperature is 50° C., and the other conditions remain unchanged. The reaction completion time is 3 h, the weight of the obtained product is 15.3 g, the molar yield is 90.4%, and the HPLC normalized purity is 99.2%.

[0087] Example 7

[0088] The difference from Example 1 is that the amount of FY-2C14 surfactant used in step 1) is 0.2 g, and the other conditions remain unchanged. The reaction completion time is 8 hours, the weight of the obtained product is 15.0 g, the molar yield is 88.7%, and the HPLC normalized purity is 99.1%.

[0089] Example 8

[0090] The difference from Example 1 is that the alcohol solvent in step 1) is changed to methanol, and the other conditions remain unchanged. The reaction completion time is 6.5 hours, the weight of the obtained product is 15.6 g, the molar yield is 93.4%, and the HPLC normalized purity is 99.7%.

[0091] Example 9

[0092] The difference from Example 1 is that the FY-2C14 surfactant in step 1) is replaced by "ethylene bis(N-benzenesulfonic acid-lauramide) sodium salt", and the other conditions remain unchanged. The reaction completion time is 4.5 hours, the weight of the obtained product is 15.0 g, the molar yield is 88.6%, and the HPLC normalization purity is 99.4%.

[0093] Example 10

[0094] The difference from Example 1 is that the FY-2C14 surfactant in step 1) is replaced by "ethylene bis (N-benzenesulfonic acid-hexadecanoic acid amide) sodium salt", and the other conditions remain unchanged. The reaction completion time is 4 hours, the weight of the obtained product is 15.8 g, the molar yield is 93.4%, and the HPLC normalization purity is 99.5%.

[0095] Embodiment 11

[0096] The difference from Example 1 is that the FY-2C14 surfactant in step 1) is replaced by "ethylene bis (N-benzenesulfonic acid-octadecylamide) sodium salt", and the other conditions remain unchanged. The reaction completion time is 4.5h, the weight of the obtained product is 15.2g, the molar yield is 89.8%, and the HPLC normalization purity is 99.4%.

[0097] Comparative Example 3

[0098] The difference from Example 1 is that the FY-2C14 surfactant in step 1) is replaced by "sodium dodecylbenzene sulfonate", and the other conditions remain unchanged. The reaction completion time is 16 hours, the weight of the obtained product is 14.0 g, the molar yield is 82.7%, and the HPLC normalized purity is 96.5%.

[0099] The results of the above examples and comparative examples show that the present invention significantly improves the molar yield and purity of the racemic form of norepinephrine by using a specific gemini surfactant, and can react under relatively low pressure or normal pressure, and can also significantly shorten the reaction time.

[0100] The technical solution of the present invention is not limited to the above-mentioned specific embodiments. All technical variations made according to the technical solution of the present invention fall within the protection scope of the present invention.

Claims

1. A method for preparing a norepinephrine racemate, comprising: Noradrenaline hydrochloride and hydrogen are subjected to a hydrogenation reaction under the action of a Pd-C catalyst and a benzenesulfonate gemini anionic surfactant represented by formula I to obtain a racemic noradrenaline; In formula I, R is selected from a C2-C6 straight chain or branched alkylene group; R1 and R2 are the same or different and are each independently selected from a C10-C20 straight chain or branched alkyl group; R3 and R4 are the same or different and are each independently selected from a sulfonate group.

2. The preparation method according to claim 1, characterized in that: In formula I, R is selected from C2-C4 straight or branched alkylene, preferably ethylene, propylene or butylene, more preferably ethylene; R1 and R2 are the same or different and are each independently selected from a C10-C18 straight chain alkyl group; preferably n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl or n-octadecyl; more preferably n-undecyl, n-tridecyl, n-pentadecyl or n-heptadecyl; Preferably, R1 and R2 are the same; R3 and R4 are the same or different and are each independently selected from -SO3Na, -SO3K, -SO3Mg or -SO3Ca, Preferably, R3 and R4 are the same; More preferably, R3 and R4 are both -SO3Na.

3. The preparation method according to claim 1 or 2, characterized in that: The benzenesulfonate gemini anionic surfactant shown in Formula I has a structure shown in the following Formula I-1: In formula I-1, n is selected from an integer between 10 and 16; Preferably, n is selected from 10, 12, 14 or 16; Preferably, the benzenesulfonate gemini anionic surfactant shown in Formula I has a structure shown in the following Formula I-2: Wherein, n is defined the same as in formula I-1.

4. The preparation method according to claim 1, characterized in that: The benzenesulfonate-based gemini anionic surfactant is prepared by a method comprising the following steps: (S1) reacting the compound NH2-R-NH2 with a halogenated benzene sulfonate solution to obtain an intermediate, wherein the halogenated benzene sulfonate comprises and / or R, R3 and R4 are as defined in formula I, X represents halogen, preferably chlorine; (S2) reacting the intermediate with a long-chain alkanoyl chloride, then cooling, concentrating and crystallizing to obtain the benzenesulfonate-based gemini anionic surfactant; wherein the long-chain alkanoyl chloride includes R1COCl and / or R2COCl, and the definitions of R1 and R2 are the same as those in Formula I.

5. The preparation method according to claim 4, characterized in that: In step (S1), the molar ratio of the compound NH2-R-NH2 to the halobenzenesulfonate is 1:(2-3), preferably 1:(2.4-2.6); and / or, In step (S1), the reaction is carried out at a pH of 9.5 to 10.5, preferably 9.8 to 10.2; and / or, In step (S1), the reaction temperature is 40 to 50° C. and the reaction time is 4 to 12 hours.

6. The preparation method according to claim 4 or 5, characterized in that: In step (S2), the reaction is carried out in a mixed solvent of acetone and water; and / or, In step (S2), the reaction is carried out at a pH of 7.5 to 9.5, preferably 7.8 to 8.2; and / or, In step (S2), the temperature for the reaction of the intermediate with the long-chain alkanoyl chloride is 40 to 50° C., and the reaction time is 3 to 8 hours.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The amount of the gemini surfactant used is 0.01 to 0.03 times the weight of noradrenaline hydrochloride, preferably 0.015 to 0.025 times.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The loading amount of Pd in ​​the Pd-C catalyst is 1-10%, preferably 3-8%; and / or, on a dry basis, the amount of the Pd-C catalyst is 0.025-0.3 times, preferably 0.03-0.06 times, the weight of the adrenaline hydrochloride.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The pressure of the hydrogenation reaction is 0.1-3 MPa, preferably 0.1-0.5 MPa, more preferably 0.2-0.4 MPa; and / or the temperature of the hydrogenation reaction is 25-50°C, preferably 25-35°C.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The hydrogenation reaction is carried out in an alcohol solvent; Preferably, the alcohol solvent comprises a C1-C4 alcohol solvent, preferably comprises one or more of methanol, ethanol, isopropanol, preferably comprises methanol and / or anhydrous ethanol; Preferably, the amount of the alcohol solvent used is 7 to 10 times, preferably 7 to 9 times, the weight of noradrenaline hydrochloride.

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