Method for preparing metaraminol bitartrate

Abstract

The present disclosure belongs to the technical field of drug synthesis, and specifically relates to a method for preparing metaraminol bitartrate. The preparation method comprises the following steps: using benzyloxycarbonyl-L-alanine as a raw material, reacting same with dimethylhydroxylamine hydrochloride, and then reacting with 3-benzyloxybromobenzene, then performing a one-step hydrogenation reaction to obtain metaraminol, and finally forming a salt to obtain metaraminol bitartrate.

Description

A preparation method of meta-hydroxylamine bitartrate Technical Field

[0001] The present disclosure belongs to the technical field of drug synthesis, and particularly relates to an improved preparation method of meta-hydroxylamine bitartrate. Background Art

[0002] Metaramyl Bitartrate (CAS: 33402-03-8) is the bitartrate salt of metaramyl. It is an α-adrenaline receptor agonist developed by Fresenius Kabi, USA. It mainly acts on α-receptors and is suitable for the early treatment of shock and the prevention and treatment of acute hypotension during spinal block anesthesia.

[0003] Due to the presence of two chiral carbon atoms in meta-hydroxylamine, it has four configurations: (R,S), (S,R), (R,R), and (S,S), among which (R,S) is the effective configuration, (S,R) is its enantiomer, and (R,R) and (S,S) are its diastereomers.

[0004] The current industrial method for producing meta-hydroxylamine bitartrate is biological fermentation, which has the disadvantages of low yield and high cost. Regarding the chemical synthesis of meta-hydroxylamine or meta-hydroxylamine bitartrate, there are two common methods:

[0005] One type uses m-hydroxybenzaldehyde as the starting material, and the contents disclosed in the literature are as follows:

[0006] CN 103739504 A, CN 106748818 A and CN 114835592 A respectively disclose using m-hydroxybenzaldehyde as the starting material, obtaining m-hydroxylamine through a two-step process, and finally salifying to obtain m-hydroxylamine bitartrate. Although the synthesis steps are relatively few, the experimental conditions and reaction control requirements are relatively high, the chiral purity and chromatographic purity of the intermediate and crude product are low, the purification pressure is relatively large, and the yield of the target product is low (7% to 26%). Secondly, the chiral catalyst and ligand are very expensive, and the production cost is very high. Currently, it is only used in the laboratory pilot research stage and cannot reach large-scale commercial production. In addition, this route uses nitroethane, which is a flammable and explosive chemical. Safety is difficult to ensure during the production process and is not suitable for scale-up production.

[0007] The other type uses benzyloxycarbonyl-L-alanine as the starting material, and the literature disclosed the following:

[0008] CN 107311875 A discloses a process using benzyloxycarbonyl-L-alanine as a raw material, undergoing a cyclization reaction, and reacting with a Grignard reagent to produce an intermediate. The intermediate undergoes a hydrolysis ring-opening reaction to produce a ketone, which is then reduced with sodium borohydride (NaBH4) to produce an alcohol, followed by hydrogenation and deprotection to produce meta-hydroxylamine, which is then salified to produce meta-hydroxylamine bitartrate. This route requires six reaction steps and numerous operational steps, resulting in a target product yield of only 31%, lacking chiral selectivity, and high chiral resolution costs. Furthermore, NaBH4 is a dangerous chemical that is easily explosive and generates a large amount of hydrogen upon addition, posing a certain risk. Furthermore, the preparation process contains large amounts of hazardous substances such as paraformaldehyde and toluene, making it unsuitable for industrial production.

[0009] CN 115960003 A discloses a method for synthesizing meta-hydroxylamine bitartrate. The synthetic route is as follows:

[0010] The reaction route uses benzyloxycarbonyl-L-alanine as the starting material, and a multi-step reaction process produces meta-hydroxylamine bitartrate. To prepare meta-hydroxylamine, the ketocarbonyl group must first be reduced with a reducing agent, followed by deprotection of the amino and phenolic hydroxyl groups. Finally, meta-hydroxylamine reacts with L-tartaric acid to produce the target product. This route has the following drawbacks: 1) The reaction process involves two mandatory steps: ketocarbonyl reduction and amino and phenolic hydroxyl deprotection. This lengthy reaction process results in a low overall yield (the total yield of meta-hydroxylamine bitartrate obtained from benzyloxycarbonyl-L-alanine via five steps: condensation, Grignard reaction, reduction, deprotection, and salt formation is 71% × 74% × 85% × 88% = 39.3%); 2) The key intermediate requires column chromatography purification, and the preparation process contains hazardous substances such as toluene, making it difficult to scale up production. Summary of the Invention

[0011] Problems to be solved by the invention

[0012] The purpose of the present disclosure is to provide an improved method for preparing meta-hydroxylamine bitartrate to solve the technical problems of low reaction yield, inconvenient operation and unsuitability for scale-up production in the prior art.

[0013] Solutions for solving problems

[0014] According to the first aspect of the present disclosure, the present disclosure provides a method for preparing meta-hydroxylamine bitartrate, comprising the following steps: using a compound of formula I as a raw material, reacting in an anhydrous solvent under the action of hydrogen and palladium on carbon to generate meta-hydroxylamine, which is then salified with L-tartaric acid to obtain a target product. The reaction equation is as follows:

[0015] Preferably, the solvent is an alcohol, preferably methanol, ethanol or isopropanol, more preferably methanol.

[0016] Preferably, the ratio of the solvent to the compound of formula I is 10-30 mL:1 g, more preferably 20 mL:1 g.

[0017] Preferably, the mass ratio of the palladium-carbon to the compound of formula I is 0.02:1-0.20:1, more preferably 0.04:1.

[0018] Preferably, the reaction pressure is 0.02-0.14 MPa, more preferably 0.10-0.14 MPa.

[0019] Preferably, the reaction temperature is 28-48°C, more preferably 33-38°C.

[0020] Preferably, the reaction time is 4-6 hours, more preferably 4 hours.

[0021] Preferably, the method further comprises the following purification steps: adding water and an organic solvent to the target product, heating to dissolve, cooling to crystallize, filtering, washing, and drying to obtain the target product.

[0022] Preferably, the organic solvent is a C2-C4 nitrile, a C1-C4 alkyl alcohol or a C3-C5 alkyl ketone; preferably, the C2-C4 nitrile is acetonitrile, the C1-C4 alkyl alcohol is methanol, ethanol or isopropanol, and the C3-C5 alkyl ketone is acetone.

[0023] More preferably, the organic solvent is acetone.

[0024] More preferably, the volume ratio of the organic solvent to water is 10:1-40:1, preferably 20:1.

[0025] Furthermore, the preparation method of the compound of formula I comprises the following steps:

[0026] 1) condensing benzyloxycarbonyl-L-alanine with dimethylhydroxylamine hydrochloride in the presence of a base and a condensing agent to obtain a compound of formula A;

[0027] 2) The compound of formula A reacts with 3-benzyloxybromobenzene in the presence of an initiator, magnesium metal and a Grignard reagent to obtain a compound of formula I. The reaction equation is as follows:

[0028] Preferably, the base in step 1) is an organic base, preferably an amine, more preferably DIEA.

[0029] Preferably, the condensing agent in step 1) is EDCI and HOBT.

[0030] Preferably, the solvent for the condensation reaction in step 1) is an ether, preferably a cyclic ether, more preferably tetrahydrofuran.

[0031] Preferably, the molar ratio of benzyloxycarbonyl-L-alanine to dimethylhydroxylamine hydrochloride in step 1) is 1:1-1:1.3, preferably 1:1.1-1:1.3, more preferably 1:1.2.

[0032] Preferably, in step 1), the molar ratio of benzyloxycarbonyl-L-alanine to EDCI is 1:1-1:1.3, preferably 1:1.1-1:1.3, more preferably 1:1.2.

[0033] Preferably, the molar ratio of benzyloxycarbonyl-L-alanine to HOBT in step 1) is 1:0-1:1.3, preferably 1:1.1-1:1.3, more preferably 1:1.2.

[0034] Preferably, in step 1), the molar ratio of the benzyloxycarbonyl-L-alanine to the base is 1:1-1:3, preferably 1:1.5-1:2, more preferably 1:1.5.

[0035] Preferably, the temperature of the condensation reaction in step 1) is 15-45°C, more preferably 25-35°C.

[0036] Preferably, the condensation reaction time in step 1) is 1-3 hours, more preferably 1 hour.

[0037] Preferably, the initiator in step 2) is 1,2-dibromoethane or iodine, more preferably iodine.

[0038] Preferably, the Grignard reagent in step 2) is ethylmagnesium chloride, ethylmagnesium bromide, propylmagnesium chloride, propylmagnesium bromide, isopropylmagnesium bromide or isopropylmagnesium chloride, more preferably isopropylmagnesium chloride.

[0039] Preferably, the solvent for the Grignard reaction in step 2) is an ether, preferably a cyclic ether, more preferably tetrahydrofuran.

[0040] Preferably, in step 2), the mass ratio of the initiator to the compound of formula A is 0.01:1-0.1:1, more preferably 0.02:1.

[0041] Preferably, in step 2), the molar ratio of the 3-benzyloxybromobenzene to the compound of formula A is 1.1:1-1.4:1, more preferably 1.2:1.

[0042] Preferably, in step 2), the molar ratio of the magnesium metal to the compound of formula A is 1.1:1-1.4:1, more preferably 1.3:1.

[0043] Preferably, in step 2), the molar ratio of the Grignard reagent to the compound of formula A is 0.8:1-1.5:1, more preferably 1.3:1.

[0044] Preferably, the temperature of the Grignard reaction in step 2) is 25-65°C, more preferably 25-35°C.

[0045] Preferably, the Grignard reaction in step 2) is carried out for 1-4 h, more preferably 2 h.

[0046] Effects of the Invention

[0047] Compared with the prior art, the synthesis method of meta-hydroxylamine bitartrate disclosed in the present invention has the following advantages:

[0048] 1) The present disclosure avoids the use of expensive chiral catalysts, greatly reducing costs;

[0049] 2) The present invention adopts a one-step hydrogenation method to achieve the dual effects of reduction and deprotection simultaneously, changing the two-step reaction of "sodium borohydride reduction and palladium carbon deprotection" in the prior art to "one-step hydrogenation", eliminating the trouble of adding sodium borohydride in batches, achieving continuous operation, reducing operating steps and material consumption, saving material costs, and reducing the generation of reaction waste;

[0050] 3) The disclosed method has readily available raw materials, fewer synthesis steps, mild reaction conditions, easy-to-control operation, and is safe and reliable. It achieves a significant increase in the yield of the target product (the yield of the product from the two-step hydrogenation and salt formation reactions reaches 85%), with an overall yield of 67.8% (i.e., 92.4% × 86.3% × 85%), which can lay the foundation for subsequent industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] FIG1 is an HPLC spectrogram of the hydrogenated liquid in Example 1;

[0052] FIG2 is an HPLC spectrogram of meta-hydroxylamine bitartrate (crude product) in Example 1;

[0053] FIG3 is an HPLC spectrum of meta-hydroxylamine bitartrate (after purification) in Example 3. DETAILED DESCRIPTION

[0054] purity

[0055] The "purity" in this disclosure refers to the HPLC purity determined by the peak area normalization method.

[0056] The abbreviations in this disclosure have the following meanings:

[0057] Example

[0058] The embodiments of the present disclosure will be described in detail below with reference to the examples. However, those skilled in the art will appreciate that the following examples are intended only to illustrate the present disclosure and should not be construed as limiting the scope of the present disclosure. Where specific conditions are not specified in the examples, the experiments were performed under conventional conditions or the conditions recommended by the manufacturer. Where the manufacturer of the reagents or instruments is not specified, all are commercially available conventional products.

[0059] Example 1: Preparation of meta-hydroxylamine bitartrate

[0060] To a 400mL hydrogenation flask, add 5.0g of the compound of Formula I, 0.2g of palladium on carbon, and 100mL of anhydrous methanol and stir to dissolve. Replace the atmosphere with nitrogen three times, evacuate, and introduce hydrogen at a pressure of 0.10-0.14MPa. Stir at 33-38°C for 4h. Close the hydrogen valve. If the system pressure remains constant for 15min, the reaction is complete. Remove the reaction solution, filter it, and sample it for HPLC testing of the purity and impurity content of the intermediate hydroxylamine in the hydrogenation reaction mixture (see Figure 1). Concentrate the filtrate to obtain an oil. Add 25mL of anhydrous ethanol and stir to dissolve. Then, add a solution of L-tartaric acid (1.92g) in anhydrous ethanol (25mL) dropwise and stir for 2h. Filter, wash the filter cake with a small amount of ethanol, and dry it at 50-60°C for 2h to obtain 3.48g of meta-hydroxylamine bitartrate (see Figure 2), with a yield of 85%, as a yellow to white solid.

[0061] Table 1. Screening of hydrogenation reaction solvents

[0062] The results in Table 1 show that when isopropanol is used as the reaction solvent, the purity of the obtained meta-hydroxylamine is low (less than 70%) and the impurity content is high. When methanol and ethanol are used as the reaction solvent, the purity of the obtained meta-hydroxylamine is high (reaching over 90%). However, considering the selectivity of meta-hydroxylamine, methanol is preferably used as the hydrogenation reaction solvent.

[0063] Example 2: Screening of hydrogenation reaction conditions

[0064] The methanol with the highest purity in Example 1 was used as the reaction solvent. Referring to the experimental operation process of Example 1, the reaction conditions were screened by detecting the purity and impurity content of the intermediate hydroxylamine in the hydrogenation reaction mixture. The results are shown below.

[0065] (1) Screening of the amount of hydrogenation solvent:

[0066] Referring to the experimental operation process of Example 1, methanol was used as the hydrogenation reaction solvent, and the solvent dosage was screened. The results are shown in Table 2.

[0067] Table 2. Screening of solvent dosage for hydrogenation reaction

[0068] The results in Table 2 show that as the amount of reaction solvent increases from 10 v / w to 20 v / w, the purity of meta-hydroxylamine gradually increases and the impurity content significantly decreases. However, when the amount of solvent is 20 v / w-30 v / w, the purity of meta-hydroxylamine does not change significantly. Therefore, from the perspective of saving materials, methanol is preferably used as the reaction solvent in an amount of 20 v / w in the hydrogenation reaction.

[0069] (2) Screening of the amount of palladium carbon used in hydrogenation reaction:

[0070] Referring to the experimental operation process of Example 1, the amount of palladium carbon was screened using 20 v / w of methanol as the reaction solvent. The results are shown in Table 3.

[0071] Table 3. Screening of palladium carbon dosage for hydrogenation reaction

[0072] The results in Table 3 show that as the amount of palladium on carbon increases from 2% to 8%, the purity of meta-hydroxylamine gradually increases and the impurity content decreases. However, when the amount of palladium on carbon further increases from 8% to 20%, the purity of meta-hydroxylamine decreases. Specifically, when the amount of palladium on carbon is within the range of 4% to 8%, the purity of meta-hydroxylamine can reach over 92%, which is a relatively ideal result. Therefore, from the perspective of saving materials, the amount of palladium on carbon used in the hydrogenation reaction is preferably 4%.

[0073] (3) Screening of hydrogenation reaction pressure:

[0074] Referring to the experimental operation process of Example 1, the hydrogenation reaction pressure was screened using 20 v / w methanol as the reaction solvent and 4% palladium carbon. The results are shown in Table 4.

[0075] Table 4. Screening of hydrogenation reaction pressure

[0076] The results in Table 4 show that the pressure of the hydrogenation reaction has little effect on the purity of meta-hydroxylamine, but when the system pressure is 0.10-0.14 MPa, the selectivity of meta-hydroxylamine is the highest (94%). Therefore, the system pressure in the hydrogenation reaction is preferably 0.10-0.14 MPa.

[0077] (4) Screening of hydrogenation reaction temperature:

[0078] Referring to the experimental operation process of Example 1, 20 v / w of methanol was used as the reaction solvent, 4% of palladium carbon was used, and the reaction pressure was 0.10-0.14 MPa. The hydrogenation reaction temperature was screened. The results are shown in Table 5.

[0079] Table 5. Screening of hydrogenation reaction temperature

[0080] The results in Table 5 show that as the reaction temperature increases, the purity of meta-hydroxylamine increases and the impurity content decreases. However, as the reaction temperature increases further, the purity of meta-hydroxylamine gradually decreases and the impurity content gradually increases. Within the temperature range of 33-38°C, the purity of meta-hydroxylamine can reach over 90%, which is a relatively ideal result. Therefore, the reaction temperature in the hydrogenation reaction is preferably 33-38°C.

[0081] (5) Screening of hydrogenation reaction time:

[0082] Referring to the experimental operation process of Example 1, 20 v / w of methanol was used as the reaction solvent, 4% palladium carbon was used, the reaction pressure was 0.10-0.14 MPa, the reaction temperature was 33-38° C., and the hydrogenation reaction time was screened. The results are shown in Table 6.

[0083] Table 6. Screening of hydrogenation reaction time

[0084] The results in Table 6 show that when the reaction time is further increased from 4 h, the purity of m-hydroxylamine decreases and the impurity content increases. Therefore, the reaction time in the hydrogenation reaction is preferably 4 h.

[0085] Example 3: Removal of specific impurities in meta-hydroxylamine bitartrate

[0086] An equal amount of purified water was added to 3.48 g of meta-hydroxylamine bitartrate prepared in Example 1, and the mixture was heated to 50° C. to dissolve. 69.6 mL of acetone was slowly added, and the mixture was cooled to 0-10° C. to crystallize for 2 h. The mixture was filtered, and the filter cake was washed with a small amount of acetone and dried at 80-90° C. for 2 h to obtain 3.31 g of refined meta-hydroxylamine bitartrate (see Figure 3), with a yield of 95.2%, as a white solid.

[0087] Example 4: Screening of specific impurity removal conditions

[0088] During the experiment, the inventors found that there was a specific impurity peak in the liquid chromatogram at around 13 minutes, with a content of 0.14%-0.16% in the hydrogenated liquid and 0.06%-0.10% in the crude product. Referring to the experimental operation process of Example 3, the reaction conditions were screened by detecting the purity and impurity content of the refined meta-hydroxylamine bitartrate. The results are shown below.

[0089] (1) Screening of organic solvents:

[0090] Referring to the experimental operation process of Example 3, the volume ratio of the organic solvent to purified water was controlled to 10:1, and the organic solvent was screened. The results are shown in Table 7.

[0091] Table 7. Screening of organic solvents

[0092] The results in Table 7 show that for 5 different organic solvents, the yield of meta-hydroxylamine bitartrate can reach more than 75%, which meets the most basic requirements; when acetonitrile, ethanol and isopropanol are used as organic solvents, the yield of meta-hydroxylamine bitartrate is higher (up to more than 85%), but the solvent systems of ethanol / water and isopropanol / water have little effect on the removal of specific impurities, and the content of specific impurities is basically around 0.05%-0.10%. The solvent system of acetonitrile / water is too viscous, making stirring extremely difficult; when acetone is used as the organic solvent, although the yield of meta-hydroxylamine bitartrate after purification in the acetone / water system is not high, the removal of specific impurities is relatively complete. According to the drug registration and approval standards, unknown impurities should not be higher than 0.10%. In order to facilitate subsequent scale-up production and avoid product unqualified problems, unknown impurities will be required to be less than 0.03% in the pilot stage. Therefore, acetone is selected as the organic solvent for removing specific impurities in meta-hydroxylamine bitartrate after comprehensive consideration.

[0093] (2) Screening of organic solvent volume:

[0094] Referring to the experimental operation process of Example 3, acetone was used as the organic solvent to screen the volume of the organic solvent. The results are shown in Table 8.

[0095] Table 8. Screening of organic solvent volumes

[0096] The results in Table 8 show that as the amount of organic solvent increases from 10 v / v to 20 v / v, the yield of meta-hydroxylamine bitartrate also increases significantly, and the purity does not change. However, when the amount of solvent is further increased from 20 v / v to 40 v / v, the yield of meta-hydroxylamine bitartrate also increases, but its purity decreases and the content of specific impurities increases. Therefore, 20 v / v is selected as the amount of organic solvent for removing specific impurities in meta-hydroxylamine bitartrate after comprehensive consideration.

[0097] Example 5: Preparation of compound of formula A

[0098] To a 250 mL round-bottom flask, 10.0 g of benzyloxycarbonyl-L-alanine (1.0 eq), 5.24 g of dimethylhydroxylamine hydrochloride (1.2 eq), and 7.26 g of HOBT (1.2 eq) were added, followed by 50 mL of THF. The mixture was placed at 0-30°C, and 8.7 g of DIEA (1.5 eq) was slowly added dropwise. 10.3 g of EDCI (1.2 eq) was then added portionwise. After the addition was complete, the mixture was returned to room temperature and stirred for 1 hour. TLC analysis confirmed the completion of the condensation reaction between benzyloxycarbonyl-L-alanine and dimethylhydroxylamine hydrochloride, with the formation of new spots. 100 mL of water was added to the reaction mixture, and extraction was performed with ethyl acetate (50 mL x 2). The ethyl acetate layers were combined and washed once with 100 mL of dilute hydrochloric acid (1 M), 5% sodium bicarbonate solution, and 20% brine. The ethyl acetate layer was collected and concentrated under reduced pressure to yield the crude compound. The crude compound was dissolved in 10 mL of ethyl acetate, and after the solution was clear, 50 mL of n-heptane was added for crystallization. The temperature was lowered to 0-10°C and stirred for 1 h. The mixture was filtered, and the filter cake was rinsed with 20 mL of n-heptane. The filter cake was air-dried at 50-60°C for 2 h to obtain 11.02 g of compound A (purity determined by HPLC area normalization method was 99.3%), with a yield of 92.4%, as a white solid.

[0099] Example 6: Screening of condensation reaction conditions

[0100] Referring to the experimental operation process of Example 5, the condensation reaction conditions were screened by detecting the purity of the compound of formula A in the reaction mixture. The results are shown below.

[0101] (1) Screening of dimethylhydroxylamine hydrochloride dosage

[0102] According to the method in Example 5, the amount of dimethylhydroxylamine hydrochloride was changed. The reaction conditions and results are listed in Table 9 below.

[0103] Table 9

[0104] (2) EDCI dosage screening

[0105] According to the method in Example 5, the amount of EDCI was changed. The reaction conditions and results are listed in Table 10 below.

[0106] Table 10

[0107] (3) HOBT dosage screening

[0108] According to the method in Example 5, the amount of HOBT was changed. The reaction conditions and results are listed in Table 11 below.

[0109] Table 11

[0110] (4) DIEA dosage screening

[0111] According to the method in Example 5, the amount of DIEA was changed. The reaction conditions and results are listed in Table 12 below.

[0112] Table 12

[0113] (5) Screening of reaction temperature

[0114] According to the method in Example 5, the reaction temperature was changed. The reaction conditions and results are listed in Table 13 below.

[0115] Table 13

[0116] (6) Screening of reaction time

[0117] According to the method in Example 5, the reaction time was changed. The reaction conditions and results are listed in Table 14 below.

[0118] Table 14

[0119] Example 7: Preparation of the compound of formula I

[0120] To a 250 mL three-necked flask, add 2.38 g of magnesium (1.3 eq), 60 mL of dry THF, and 0.40 g of iodine. Stir at 60-70°C. Then, dissolve 23.72 g of 3-benzyloxybromobenzene (1.2 eq) in 100 mL of dry THF. Slowly add 5%-15% of the solution dropwise to initiate the reaction. Then, add the remaining solution dropwise, maintaining a slight boil. After the addition is complete, continue stirring at 60-70°C for 1 hour until the solution turns yellow-green and is set aside. Then, weigh 20.0 g of compound A (1 eq) into a 1000 mL round-bottom flask and dissolve it in 100 mL of THF. At 0°C, slowly add 48 mL of isopropylmagnesium chloride (2 M, 1.3 eq) dropwise, followed by the Grignard reagent prepared above. After the addition is complete, return the temperature to 30°C and stir for 1-2 hours.

[0121] HPLC analysis indicated that the residual amount of compound A was ≤5%. 240 mL of 1 M hydrochloric acid solution was slowly added dropwise to the reaction solution, the mixture was separated, and the mixture was extracted with 200 mL of ethyl acetate. The organic phases were combined. The mixture was washed sequentially with 200 mL of purified water and 20% brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oil. 200 mL of isopropanol was added and stirred at 50°C to dissolve the oil. The mixture was cooled to -10-0°C and stirred for 1-2 hours. The mixture was filtered, washed with pre-cooled isopropanol, and dried under vacuum at 50-60°C for 2 hours to obtain 25.24 g of compound I (86.3% yield) as a white to yellow solid.

[0122] Example 8: Screening of Grignard Reaction Conditions

[0123] Referring to the experimental operation process of Example 7, the Grignard reaction conditions were screened by detecting the purity of the compound of formula I in the reaction solution. The results are shown below.

[0124] (1) Screening of initiator (iodine) dosage

[0125] According to the method in Example 7, the amount of initiator was changed, and the reaction conditions and results are listed in Table 15 below.

[0126] Table 15

[0127] (2) Screening of 3-benzyloxybromobenzene dosage

[0128] According to the method in Example 7, the amount of 3-benzyloxybromobenzene was changed. The reaction conditions and results are listed in Table 16 below.

[0129] Table 16

[0130] (3) Screening of magnesium metal dosage

[0131] According to the method in Example 7, the amount of metallic magnesium was changed. The reaction conditions and results are listed in Table 17 below.

[0132] Table 17

[0133] (4) Screening of dosage of isopropyl magnesium chloride

[0134] According to the method in Example 7, the amount of isopropylmagnesium chloride was changed. The reaction conditions and results are listed in Table 18 below.

[0135] Table 18

[0136] (5) Screening of reaction temperature

[0137] According to the method in Example 7, the reaction temperature was changed. The reaction conditions and results are listed in Table 19 below.

[0138] Table 19

[0139] (6) Screening of reaction time

[0140] According to the method in Example 7, the reaction time was changed. The reaction conditions and results are listed in Table 20 below.

[0141] Table 20

[0142] Comparative Example 1:

[0143] (1) Reduction reaction

[0144] To a 100mL flask, add 5.0g of compound I (1eq), then add 30mL of anhydrous methanol, stir to dissolve, and place at 0°C. Slowly add 0.73g of sodium borohydride (1.5eq) in portions while stirring. After the addition is complete, return the mixture to room temperature at 30°C and stir for 2 hours, resulting in the precipitation of a large amount of solid. TLC confirms the complete reaction of the starting materials. The reaction solution is slowly poured into ice water, then adjusted to a pH of approximately 7 with 0.5M dilute hydrochloric acid. Extract with dichloromethane (50mL x 2), wash with saturated brine, dry, and concentrate under reduced pressure to obtain the crude compound. The crude compound is recrystallized from 15mL of ethanol to obtain 3.85g of compound B (76.6% yield) as a white solid.

[0145] Table 21. Screening of reduction reaction conditions

[0146] The results in Table 21 show that when aluminum isopropoxide (Al(Oi-Pr)3) is used as a reducing agent, the yield of the compound of formula B is higher than that of the other two reducing agents, and the yield can be as high as more than 90%. However, during the reduction of the compound of formula I to obtain the intermediate compound of formula B, the system becomes viscous during quenching due to the presence of aluminum salt, stirring is difficult, and the reaction materials are difficult to react completely; when sodium borohydride (NaBH4) is used as a reducing agent, a large amount of hydrogen will be generated during the quenching process, which is dangerous; when lithium aluminum hydride (LiAlH4) is used as a reducing agent, the system becomes viscous during the quenching process, resulting in a large amount of adhesion and agglomeration of the reaction materials, and the release of a large amount of hydrogen; all three reducing agents require the use of a large amount of water during the quenching process, generating a large amount of wastewater, which is not suitable for industrial production.

[0147] (2) Deprotection and salt formation reaction

[0148] 5g of compound B, 0.25g of palladium on carbon and 100mL of anhydrous methanol were added to a 250mL three-necked flask and stirred to dissolve. The nitrogen was replaced three times, vacuumed, and hydrogen (hydrogen balloon) was introduced. The mixture was stirred at 30-35°C for 4h until the hydrogen balloon showed no change, indicating that the reaction was complete. The reaction solution was taken out, filtered, and a sample was taken and sent to HPLC to detect the purity and impurity content of the hydroxylamine in the hydrogenation reaction mixture. The filtrate was concentrated to obtain an oily substance. 25mL of anhydrous ethanol was added and stirred to dissolve the oily substance. Then, a solution of L-tartaric acid (1.92g) in anhydrous ethanol (25mL) was added dropwise and stirred for 2h. The filter cake was washed with a small amount of ethanol and dried at 50-60°C for 2h to obtain 3.65g of meta-hydroxylamine bitartrate, with a yield of 90.1%, as a yellow to white solid.

[0149] Table 22. Screening of deprotection reaction conditions

[0150] The optimal yield of the product obtained by the two-step reduction-deprotection reaction and the salt formation reaction is 82% (90.1% × 91%), which is lower than the yield of the one-step hydrogenation reaction. In addition, the system is viscous during the reduction of the compound of formula I to the intermediate compound of formula B, resulting in a large amount of adhesion and agglomeration of the reaction materials, making stirring difficult and the reaction materials difficult to react completely. Therefore, this method is not suitable for industrial production.

[0151] While various embodiments of the present disclosure have been described above, the foregoing description is intended to be illustrative, non-exhaustive, and not limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is selected to best explain the principles of the embodiments, their practical applications, or technological improvements in the marketplace, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A method for preparing meta-hydroxylamine bitartrate, comprising the following steps: using a compound of formula I as a raw material, reacting in an anhydrous solvent under the action of hydrogen and palladium on carbon to generate meta-hydroxylamine, and then salifying with L-tartaric acid to obtain a target product; 2. The method according to claim 1, characterized in that The solvent is an alcohol; and / or, The ratio of the solvent to the compound of formula I is 10-30 mL: 1 g; and / or, The mass ratio of the palladium carbon to the compound of formula I is 0.02:1-0.20:1; and / or, The reaction pressure is 0.02-0.14 MPa; and / or, The reaction temperature is 28-48°C; and / or, The reaction time is 4-6h.

3. The method according to claim 1, characterized in that: The solvent is methanol, ethanol or isopropanol; and / or, The ratio of the solvent to the compound of formula I is 20 mL: 1 g; and / or, The mass ratio of the palladium carbon to the compound of formula I is 0.04:1; and / or, The reaction pressure is 0.10-0.14 MPa; and / or, The reaction temperature is 33-38°C; and / or, The reaction time is 4 hours.

4. The method according to claim 1, characterized in that The solvent is methanol.

5. The method according to claim 1, characterized in that The method also includes a post-salting refining step, and the refining method includes the following steps: adding water and an organic solvent to the target product, heating to dissolve, cooling to crystallize, filtering, washing, and drying to obtain the target product.

6. The method according to claim 5, characterized in that The organic solvent is C2-C4 nitrile, C1-C4 alkyl alcohol or C3-C5 alkyl ketone.

7. The method according to claim 6, characterized in that The C2-C4 nitrile is acetonitrile, the C1-C4 alkyl alcohol is methanol, ethanol or isopropanol, and the C3-C5 alkyl ketone is acetone.

8. The method according to claim 6, characterized in that The organic solvent is acetone; The volume ratio of the organic solvent to water is 10:1-40:

1.

9. The method according to claim 8, characterized in that The volume ratio of the organic solvent to water is 20:

1.

10. The method according to any one of claims 1 to 9, characterized in that The preparation method of the compound of formula I comprises the following steps: 1) condensing benzyloxycarbonyl-L-alanine with dimethylhydroxylamine hydrochloride in the presence of a base and a condensing agent to obtain a compound of formula A; 2) the compound of formula A is subjected to a Grignard reaction with 3-benzyloxybromobenzene in the presence of an initiator, metal magnesium and a Grignard reagent to obtain a compound of formula I; 11. The method according to claim 10, characterized in that In step 1), The base is an organic base; and / or, The condensing agent is EDCI and HOBT; and / or, The solvent for the condensation reaction is ether.

12. The method according to claim 10, characterized in that In step 1), The base is an amine; and / or, The solvent for the condensation reaction is a cyclic ether.

13. The method according to claim 10, characterized in that The base is DIEA; and / or, The solvent for the condensation reaction is tetrahydrofuran.

14. The method according to claim 11, characterized in that In step 1), The molar ratio of benzyloxycarbonyl-L-alanine to dimethylhydroxylamine hydrochloride is 1:1-1:1.3; and / or, The molar ratio of benzyloxycarbonyl-L-alanine to EDCI is 1:1-1:1.3; and / or, The molar ratio of benzyloxycarbonyl-L-alanine to HOBT is 1:0-1:1.3; and / or, The molar ratio of the benzyloxycarbonyl-L-alanine to the base is 1:1-1:3; and / or, The condensation reaction temperature is 15-45°C; and / or, The condensation reaction time is 1-3h.

15. The method according to claim 11, characterized in that In step 1), The molar ratio of benzyloxycarbonyl-L-alanine to dimethylhydroxylamine hydrochloride is 1:1.1-1:1.3; and / or, The molar ratio of benzyloxycarbonyl-L-alanine to EDCI is 1:1.1-1:1.3; and / or, The molar ratio of benzyloxycarbonyl-L-alanine to HOBT is 1:1.1-1:1.3; and / or, The molar ratio of the benzyloxycarbonyl-L-alanine to the base is 1:1.5-1:2; and / or, The condensation reaction temperature is 25-35°C; and / or, The condensation reaction time is 1 h.

16. The method according to claim 11, characterized in that In step 1), The molar ratio of benzyloxycarbonyl-L-alanine to dimethylhydroxylamine hydrochloride is 1:1.2; and / or, The molar ratio of benzyloxycarbonyl-L-alanine to EDCI is 1:1.2; and / or, The molar ratio of benzyloxycarbonyl-L-alanine to HOBT is 1:1.2; and / or, The molar ratio of the benzyloxycarbonyl-L-alanine to the base is 1:1.

5.

17. The method according to claim 10, characterized in that In step 2), The initiator is 1,2-dibromoethane or iodine, The Grignard reagent is ethylmagnesium chloride, ethylmagnesium bromide, propylmagnesium chloride, propylmagnesium bromide, isopropylmagnesium bromide or isopropylmagnesium chloride; and / or, The solvent for the Grignard reaction is ether.

18. The method according to claim 10, characterized in that In step 2), The initiator is iodine; and / or, The Grignard reagent is isopropylmagnesium chloride; and / or, The solvent of the Grignard reaction is a cyclic ether.

19. The method according to claim 10, characterized in that In step 2), The solvent for the Grignard reaction is tetrahydrofuran.

20. The method according to claim 10, characterized in that In step 2), The mass ratio of the initiator to the compound of formula A is 0.01:1-0.1:1; and / or, The molar ratio of the 3-benzyloxybromobenzene to the compound of formula A is 1.1:1-1.4:1; and / or, The molar ratio of the magnesium metal to the compound of formula A is 1.1:1-1.4:1; and / or, The molar ratio of the Grignard reagent to the compound of formula A is 0.8:1-1.5:1; and / or, The temperature of the Grignard reaction is 25-65° C.; and / or, The time of the Grignard reaction is 1-4h.

21. The method according to claim 10, characterized in that In step 2), The mass ratio of the initiator to the compound of formula A is 0.02:1; and / or, The molar ratio of the 3-benzyloxybromobenzene to the compound of formula A is 1.2:1; and / or, The molar ratio of the magnesium metal to the compound of formula A is 1.3:1; and / or, The molar ratio of the Grignard reagent to the compound of formula A is 1.3:1; and / or, The temperature of the Grignard reaction is 25-35°C; and / or, The time of the Grignard reaction is 2 h.

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