Preparation method of metaraminol bitartrate

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of metaraminol bitartrate. The preparation method comprises the following steps: reacting benzyloxycarbonyl-L-alanine serving as a raw material with dimethylhydroxylamine hydrochloride, then reacting with 3-benzyloxybromobenzene, then carrying out one-step hydrogenation reaction to obtain m-hydroxylamine, and finally salifying to obtain the metaraminol bitartrate. The method adopts a one-step hydrogenation method to simultaneously realize dual effects of reduction and deprotection, reduces operation steps and material consumption, saves material cost, and reduces generation of reaction wastes; in the preparation process, reaction conditions are mild, safety and reliability are achieved, operation is easy, and the obtained target product is high in yield, good in selectivity and suitable for large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing an improved meta-hydroxylamine bitartrate. Background Art

[0002] Metaraminol Bitartrate (CAS: 33402-03-8) is the bitartrate salt of metaraminol. 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] Since meta-hydroxylamine has two chiral carbon atoms, 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] At present, the 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 the use of 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. At present, it is only used in the laboratory small-scale research stage and cannot reach large-scale commercial production. In addition, the route uses nitroethane, which is a flammable and explosive chemical. The safety is difficult to guarantee during the production process and is not suitable for scaled-up production.

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

[0008] CN 107311875 A discloses a method of using benzyloxycarbonyl-L-alanine as a raw material, carrying out a cyclization reaction, and reacting with a Grignard reagent to obtain an intermediate, the intermediate undergoing a hydrolysis ring-opening reaction to generate a ketone, and the ketone is then reacted with sodium borohydride (NaBH 4) is reduced to obtain alcohol, followed by hydrogenation and deprotection to obtain meta-hydroxylamine, and finally salting to obtain meta-hydroxylamine bitartrate. This route requires six steps of reaction, with many operation steps, and the yield of the target product is only 31%. There is no chiral selectivity, the cost of chiral separation is very high, and NaBH 4 It is an explosive and dangerous chemical. When added, it produces a large amount of hydrogen, which poses a certain risk. The preparation process also contains a large amount of hazardous substances such as polyformaldehyde and toluene, which is not conducive to industrial production.

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

[0010]

[0011] In the reaction route, benzyloxycarbonyl-L-alanine is used as a raw material, and a multi-step reaction is performed to generate meta-hydroxylamine bitartrate. When preparing meta-hydroxylamine, a reducing agent must be used to reduce the ketocarbonyl group first, and then the amino group and the phenolic hydroxyl group are deprotected. Finally, meta-hydroxylamine reacts with L-tartaric acid to generate the target product. This route has the following defects: 1) The reaction process includes two necessary steps of ketocarbonyl reduction and amino group and phenolic hydroxyl group deprotection. The reaction steps are lengthy, resulting in a low overall yield (the total yield of meta-hydroxylamine bitartrate obtained by five steps of condensation, Grignard reaction, reduction, deprotection, and salt formation of benzyloxycarbonyl-L-alanine is 71%×74%×85%×88%=39.3%); 2) The key intermediate needs to be prepared by column chromatography purification, and the preparation process contains hazardous substances such as toluene, which is not conducive to production scale-up. Summary of the invention

[0012] Problem that the invention aims to solve

[0013] The purpose of the present invention is to provide an improved method for preparing meta-hydroxylamine bitartrate, so as to solve the technical problems existing in the prior art of low reaction yield, inconvenient operation and unsuitability for large-scale production.

[0014] Solutions for solving problems

[0015] According to the first aspect of the present invention, the present invention provides a method for preparing meta-hydroxylamine bitartrate, the method comprising the following steps: using the compound of formula I as a raw material, reacting in an anhydrous solvent under the action of hydrogen and palladium carbon to generate meta-hydroxylamine, and then salifying with L-tartaric acid to obtain the target product, the reaction equation is as follows:

[0016]

[0017] Preferably, the solvent is an alcohol, preferably methanol, ethanol or isopropanol, more preferably methanol.

[0018] Preferably, the ratio of the solvent to the compound of formula I is 10-30 mL: 1 g, more preferably 20 mL: 1 g.

[0019] 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.

[0020] Preferably, the reaction pressure is 0.02-0.14 MPa, more preferably 0.10-0.14 MPa.

[0021] Preferably, the reaction temperature is 28-48°C, more preferably 33-38°C.

[0022] Preferably, the reaction time is 4-6 h, more preferably 4 h.

[0023] Preferably, the method further comprises the following purification step: 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.

[0024] Preferably, the organic solvent is C 2 -C 4 Nitrile, C 1 -C 4 Alkyl alcohol or C 3 -C 5 Alkyl ketone; preferably, the C 2 -C 4 The nitrile is acetonitrile, the C 1 -C 4 The alkyl alcohol is methanol, ethanol or isopropanol, and the C 3 -C 5 The alkyl ketone is acetone.

[0025] More preferably, the organic solvent is acetone.

[0026] More preferably, the volume ratio of the organic solvent to water is 10:1-40:1, preferably 20:1.

[0027] Furthermore, the preparation method of the compound of formula I comprises the following steps:

[0028] 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;

[0029] 2) The compound of formula A reacts with 3-benzyloxybromobenzene in the presence of an initiator, metal magnesium and a Grignard reagent to obtain a compound of formula I. The reaction equation is as follows:

[0030]

[0031] Preferably, the base in step 1) is an organic base, preferably an amine, more preferably DIEA.

[0032] Preferably, the condensing agent in step 1) is EDCI and HOBT.

[0033] Preferably, the solvent for the condensation reaction in step 1) is an ether, preferably a cyclic ether, more preferably tetrahydrofuran.

[0034] Preferably, in step 1), the molar ratio of benzyloxycarbonyl-L-alanine to dimethylhydroxylamine hydrochloride is 1:1-1:1.3, preferably 1:1.1-1:1.3, more preferably 1:1.2.

[0035] 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.

[0036] Preferably, in step 1), the molar ratio of benzyloxycarbonyl-L-alanine to HOBT is 1:0-1:1.3, preferably 1:1.1-1:1.3, more preferably 1:1.2.

[0037] 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.

[0038] Preferably, the temperature of the condensation reaction in step 1) is 15-45°C, more preferably 25-35°C.

[0039] Preferably, the condensation reaction time in step 1) is 1-3 h, more preferably 1 h.

[0040] Preferably, the initiator in step 2) is 1,2-dibromoethane or iodine, more preferably iodine.

[0041] 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.

[0042] Preferably, the solvent for the Grignard reaction in step 2) is an ether, preferably a cyclic ether, more preferably tetrahydrofuran.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] Preferably, the temperature of the Grignard reaction in step 2) is 25-65°C, more preferably 25-35°C.

[0048] Preferably, the time of the Grignard reaction in step 2) is 1-4 h, more preferably 2 h.

[0049] Effects of the Invention

[0050] Compared with the prior art, the synthesis method of meta-hydroxylamine bitartrate of the present invention has the following advantages:

[0051] 1) The present invention avoids the use of expensive chiral catalysts, greatly reducing costs;

[0052] 2) The present invention adopts a one-step hydrogenation method to achieve the dual effects of reduction and deprotection at the same time, and changes 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 operation steps and material consumption, saving material costs, and reducing the generation of reaction waste;

[0053] 3) The method of the present invention has readily available raw materials, fewer synthesis steps, mild reaction conditions, easy controllable operation, safety and reliability, and achieves a significant increase in the yield of the target product (the yield of the product of the two-step reaction of hydrogenation and salt formation is 85%), with a total yield of 67.8% (i.e., 92.4%×86.3%×85%), which can lay a foundation for later industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 is the HPLC spectrogram of the hydrogenated liquid in Example 1;

[0055] Figure 2 HPLC spectrum of meta-hydroxylamine bitartrate (crude product) in Example 1;

[0056] Figure 3 This is the HPLC spectrum of meta-hydroxylamine bitartrate (after purification) in Example 3. DETAILED DESCRIPTION

[0057] purity

[0058] The "purity" in the present invention refers to the HPLC purity measured by the peak area normalization method.

[0059] The abbreviations in this invention have the following meanings:

[0060] abbreviation meaning EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBT N-Hydroxybenzotriazole DIEA N,N-Diisopropylethylamine THF Tetrahydrofuran HPLC High performance liquid chromatography TLC Thin layer chromatography

[0061] Example

[0062] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0063] Example 1: Preparation of meta-hydroxylamine bitartrate

[0064]

[0065] Add 5.0g of Formula I compound, 0.2g of palladium carbon and 100mL of anhydrous methanol to a 400mL hydrogenation bottle and stir to dissolve. Replace with nitrogen three times, evacuate, introduce hydrogen, the hydrogen pressure is 0.10-0.14MPa, stir at 33-38℃ for 4h, close the hydrogen valve, the system pressure remains unchanged for 15min, that is, the reaction is complete. Take out the reaction solution, filter it, take a sample and send it to HPLC to detect the purity and impurity content of the intermediate hydroxylamine in the hydrogenation reaction mixture (see Figure 1 The filtrate was concentrated to obtain an oily substance, 25 mL of anhydrous ethanol was added and stirred to dissolve, then a solution of L-tartaric acid (1.92 g) in anhydrous ethanol (25 mL) was added dropwise and stirred for 2 h. Filtered, the filter cake was washed with a small amount of ethanol, and dried at 50-60 ° C for 2 h to obtain 3.48 g of meta-hydroxylamine bitartrate (see Figure 2 ), yield 85%, yellow to white solid.

[0066] Table 1. Screening of hydrogenation reaction solvents

[0067] Solvents Metahydroxylamine purity / % Total impurities / % Maximum single impurity / % Selectivity / % Methanol 92.17 7.83 2.45 94 Ethanol 92.03 7.97 1.87 92 Isopropyl alcohol 67.41 32.59 9.90 93

[0068] 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 (up to more than 90%), but considering the selectivity of meta-hydroxylamine, methanol is preferably used as the hydrogenation reaction solvent.

[0069] Example 2: Screening of hydrogenation reaction conditions

[0070] 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.

[0071] (1) Screening of the amount of solvent used for hydrogenation reaction:

[0072] 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.

[0073] Table 2. Screening of the amount of solvent used in the hydrogenation reaction

[0074] Solvent dosage (v / w) Metahydroxylamine purity / % Total impurities / % Maximum single impurity / % Selectivity / % 10 85.22 14.78 2.99 93 20 92.17 7.83 2.45 94 30 92.98 7.02 2.41 93

[0075] 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 in an amount of 20 v / w is preferably used as the reaction solvent in the hydrogenation reaction.

[0076] (2) Screening of the amount of palladium on carbon used in hydrogenation reaction:

[0077] 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.

[0078] Table 3. Screening of palladium carbon dosage for hydrogenation reaction

[0079] Palladium on carbon / % (relative to the compound of formula I) Metahydroxylamine purity / % Total impurities / % Maximum single impurity / % Selectivity 2 88.03 11.97 2.60 93 4 92.17 7.83 2.45 94 8 92.64 7.36 2.50 95 12 91.97 8.03 2.37 94 20 91.64 8.36 2.40 95

[0080] The results in Table 3 show that as the amount of palladium carbon increases from 2% to 8%, the purity of meta-hydroxylamine gradually increases, and the impurity content also decreases. However, when the amount of palladium carbon further increases from 8% to 20%, the purity of meta-hydroxylamine decreases. In the range of 4%-8% of palladium carbon, the purity of meta-hydroxylamine can reach more than 92%, which is a relatively ideal result. Therefore, from the perspective of saving materials, the amount of palladium carbon in the hydrogenation reaction is preferably 4%.

[0081] (3) Screening of hydrogenation reaction pressure:

[0082] Referring to the experimental operation process of Example 1, 20 v / w of methanol was used as the reaction solvent, and the amount of palladium carbon was 4%. The hydrogenation reaction pressure was screened. The results are shown in Table 4.

[0083] Table 4. Screening of hydrogenation reaction pressure

[0084] Pressure / MPa Metahydroxylamine purity / % Total impurities / % Maximum single impurity / % Selectivity / % 0.02-0.06 91.97 8.03 2.3 92 0.06-0.10 91.51 8.49 2.13 93 0.10-0.14 92.17 7.83 2.45 94

[0085] 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.

[0086] (4) Screening of hydrogenation reaction temperature:

[0087] 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.

[0088] Table 5. Screening of hydrogenation reaction temperature

[0089] Temperature / ℃ Metahydroxylamine purity / % Total impurities / % Maximum single impurity / % Selectivity / % 28-33 89.71 10.29 1.95 92 33-38 92.17 7.83 2.45 94 38-43 88.3 11.7 2.39 94 43-48 84.37 15.63 2.67 92

[0090] The results in Table 5 show that as the reaction temperature increases, the purity of meta-hydroxylamine increases and the impurity content decreases, but when the reaction temperature further increases, the purity of meta-hydroxylamine gradually decreases and the impurity content gradually increases: in the temperature range of 33-38° C., the purity of meta-hydroxylamine can reach more than 90%, which is a relatively ideal result. Therefore, the reaction temperature in the hydrogenation reaction is preferably 33-38° C.

[0091] (5) Screening of hydrogenation reaction time:

[0092] 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.

[0093] Table 6. Screening of hydrogenation reaction time

[0094] Time / h Metahydroxylamine purity / % Total impurities / % Maximum single impurity / % Selectivity / % 4 92.17 7.83 2.45 94 5 90.93 9.07 1.98 93 6 90.72 9.28 2.05 93

[0095] 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.

[0096] Example 3: Removal of specific impurities in meta-hydroxylamine bitartrate

[0097] 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 for crystallization for 2 h. 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 purified meta-hydroxylamine bitartrate (see Figure 3 ), yield 95.2%, white solid.

[0098] Example 4: Screening of specific impurity removal conditions

[0099] During the experiment, the inventors found that there was a specific impurity peak at about 13 minutes in the liquid chromatogram, 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-tartaric acid hydroxylamine, and the results are shown below.

[0100] (1) Screening of organic solvents:

[0101] Referring to the experimental operation process of Example 3, the volume ratio of the organic solvent to purified water was controlled to be 10:1, and the organic solvent was screened. The results are shown in Table 7.

[0102] Table 7. Screening of organic solvents

[0103] Organic solvents Meta-hydroxylamine bitartrate purity / % Yield / % Total impurities / % Specific impurities / % Methanol 99.92 75.5 0.08 0.05 Ethanol 99.91 92.2 0.09 0.09 Isopropyl alcohol 99.90 94.9 0.10 0.08 acetone 99.96 75.1 0.04 0 Acetonitrile 99.89 86.5 0.11 0.02

[0104] 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 still around 0.05%-0.10%, and the solvent system of acetonitrile / water is too viscous, resulting in great difficulty in stirring; when acetone is used as an organic solvent, although the yield of meta-hydroxylamine bitartrate after refining 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 amplification production and avoid the problem of unqualified products, 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.

[0105] (2) Screening of organic solvent volume:

[0106] Referring to the experimental operation process of Example 3, acetone was used as the organic solvent, and the volume of the organic solvent was screened. The results are shown in Table 8.

[0107] Table 8. Screening of organic solvent volumes

[0108] Volume ratio of acetone to purified water (v / v) Meta-hydroxylamine bitartrate purity / % Yield / % Impurities / % Specific impurities / % 10:1 99.96 75.1 0.04 0 20:1 99.96 95.2 0.04 0 30:1 99.92 95.8 0.08 0.03 40:1 99.90 96.1 0.10 0.07

[0109] 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.

[0110] Example 5: Preparation of Compound A

[0111]

[0112] Add 10.0g benzyloxycarbonyl-L-alanine (1.0eq), 5.24g dimethylhydroxylamine hydrochloride (1.2eq), 7.26g HOBT (1.2eq) to a 250mL round-bottom flask, then add 50mL THF, place at 0-30℃, slowly drop 8.7g DIEA (1.5eq), add 10.3g EDCI (1.2eq) in batches, after the addition is complete, return to room temperature and stir for 1h. TLC detection shows that the condensation reaction of benzyloxycarbonyl-L-alanine and dimethylhydroxylamine hydrochloride is complete, and new spots are generated. Add 100mL water to the reaction solution, add ethyl acetate to extract (50mL×2), combine and collect the ethyl acetate layer, then use 100mL dilute hydrochloric acid (1M), 5% sodium bicarbonate solution, 20% brine to wash once, collect the ethyl acetate layer, and concentrate under reduced pressure to obtain a crude compound. The crude compound was dissolved in 10 mL of ethyl acetate, and after the solution became clear, 50 mL of n-heptane was added for crystallization. The mixture was cooled 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 dried at 50-60°C for 2 h to obtain 11.02 g of compound A (the purity was 99.3% as determined by HPLC area normalization method), with a yield of 92.4%, as a white solid.

[0113] Example 6: Screening of condensation reaction conditions

[0114] 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.

[0115] (1) Screening of dosage of dimethylhydroxylamine hydrochloride

[0116] According to the method in Example 5, the amount of dimethylhydroxylamine hydrochloride was changed, and the reaction conditions and results are listed in the following Table 9.

[0117] Table 9

[0118]

[0119] (2) EDCI dosage screening

[0120] According to the method in Example 5, the amount of EDCI was changed, and the reaction conditions and results are listed in Table 10 below.

[0121] Table 10

[0122]

[0123] (3) HOBT dosage screening

[0124] According to the method in Example 5, the amount of HOBT was changed, and the reaction conditions and results are listed in the following Table 11.

[0125] Table 11

[0126]

[0127] (4) DIEA dosage screening

[0128] According to the method in Example 5, the amount of DIEA was changed, and the reaction conditions and results are listed in the following Table 12.

[0129] Table 12

[0130]

[0131] (5) Screening of reaction temperature

[0132] According to the method in Example 5, the reaction temperature was changed. The reaction conditions and results are listed in Table 13 below.

[0133] Table 13

[0134]

[0135] (6) Screening of reaction time

[0136] According to the method in Example 5, the reaction time was changed. The reaction conditions and results are listed in Table 14 below.

[0137] Table 14

[0138]

[0139] Example 7: Preparation of Compounds of Formula I

[0140]

[0141] Add 2.38g of magnesium metal (1.3eq) to a 250mL three-necked flask, add 60mL of dry THF, then add 0.40g of iodine, and stir at 60-70°C; then dissolve 23.72g of 3-benzyloxybromobenzene (1.2eq) in 100mL of dry THF, slowly drop 5%-15% into the reaction solution to initiate the reaction, then drop the remaining amount, maintain a slightly boiling state throughout the process, continue to stir at 60-70°C for 1h after the dropwise addition is completed, the solution turns yellow-green, and is set aside. Then weigh 20.0g of Formula A compound (1eq) into a 1000mL round-bottom flask, add 100mL of THF to dissolve, place at 0°C, first slowly drop 48mL of isopropylmagnesium chloride (2M, 1.3eq), and then slowly drop the above-prepared Grignard reagent into the reaction system, return to 30°C after the dropwise addition is completed, and stir for 1-2h.

[0142] HPLC detection shows that the residual amount of the compound of formula A is ≤5%. 240 mL of hydrochloric acid solution (1 M) was slowly added dropwise to the reaction solution, separated, extracted with 200 mL of ethyl acetate, and the organic phases were combined. The mixture was washed with 200 mL of purified water and 20% brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily substance. 200 mL of isopropanol was added, stirred at 50°C to dissolve, cooled to -10-0°C and stirred for 1-2 hours, filtered, washed with pre-cooled isopropanol, and dried under vacuum at 50-60°C for 2 hours to obtain 25.24 g of the compound of formula I, with a yield of 86.3%, as a white to yellow solid.

[0143] Example 8: Screening of Grignard reaction conditions

[0144] 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.

[0145] (1) Screening of initiator (iodine) dosage

[0146] 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.

[0147] Table 15

[0148]

[0149] (2) Screening of dosage of 3-benzyloxybromobenzene

[0150] 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.

[0151] Table 16

[0152]

[0153] (3) Screening of magnesium dosage

[0154] According to the method in Example 7, the amount of metallic magnesium was changed, and the reaction conditions and results are listed in Table 17 below.

[0155] Table 17

[0156]

[0157] (4) Screening of dosage of isopropyl magnesium chloride

[0158] According to the method in Example 7, the amount of isopropyl magnesium chloride was changed, and the reaction conditions and results are listed in Table 18 below.

[0159] Table 18

[0160]

[0161] (5) Screening of reaction temperature

[0162] According to the method in Example 7, the reaction temperature was changed. The reaction conditions and results are listed in Table 19 below.

[0163] Table 19

[0164]

[0165] (6) Screening of reaction time

[0166] According to the method in Example 7, the reaction time was changed. The reaction conditions and results are listed in Table 20 below.

[0167] Table 20

[0168]

[0169] Comparative Example 1:

[0170]

[0171] (1) Reduction reaction

[0172] Add 5.0g of compound I (1eq) to a 100mL flask, then add 30mL of anhydrous methanol, stir to dissolve and place at 0℃, slowly add 0.73g of sodium borohydride (1.5eq) in batches while stirring. After the addition is complete, return to room temperature at 30℃ and stir for 2h, and a large amount of solid precipitates. TLC detects that the raw material reaction is complete, slowly pour the reaction solution into ice water, then adjust the pH to about 7 with 0.5M dilute hydrochloric acid, extract with dichloromethane (50mL×2), wash with saturated brine, dry, and concentrate under reduced pressure to obtain a crude compound. The crude compound is recrystallized with 15mL of ethanol to obtain 3.85g of compound B, with a yield of 76.6%, as a white solid.

[0173] Table 21. Screening of reduction reaction conditions

[0174]

[0175] The results in Table 21 show that when aluminum isopropoxide (Al(Oi-Pr) 3 ) 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 90% or more. However, in the process of reducing the compound of formula I to obtain the intermediate compound of formula B, the system becomes viscous and difficult to stir during quenching due to the presence of aluminum salt, and the reaction materials are difficult to react completely. When sodium borohydride (NaBH 4 ) as a reducing agent, a large amount of hydrogen will be produced during the quenching process, which is dangerous. 4 ) 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 a large amount of water during the quenching process, generating a large amount of wastewater, which is not suitable for industrial production.

[0176] (2) Deprotection and salt formation reaction

[0177] Add 5g of compound B, 0.25g of palladium carbon and 100mL of anhydrous methanol to a 250mL three-necked flask and stir to dissolve. Replace with nitrogen three times, evacuate, introduce hydrogen (hydrogen balloon), stir at 30-35°C for 4h, until the hydrogen balloon does not change, that is, the reaction is complete. Take out the reaction solution, filter, and sample and send to HPLC to detect the purity and impurity content of the intermediate hydroxylamine in the hydrogenation reaction mixture. The filtrate is concentrated to obtain an oily substance, add 25mL of anhydrous ethanol and stir to dissolve, then add L-tartaric acid (1.92g) in anhydrous ethanol (25mL) solution and stir for 2h. Filter, wash the filter cake with a small amount of ethanol, dry at 50-60°C for 2h, and obtain 3.65g of heavy tartaric acid metahydroxylamine, with a yield of 90.1%, yellow to white solid.

[0178] Table 22. Screening of deprotection reaction conditions

[0179]

[0180] The optimal yield of the product obtained by the two-step reduction-deprotection reaction and the salt-forming 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 obtain 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.

[0181] The embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles of the embodiments, practical applications, or technical improvements in the market, or to enable other persons of ordinary skill 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 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, preferably methanol, ethanol or isopropanol, more preferably methanol; and / or, The ratio of the solvent to the compound of formula I is 10-30 mL: 1 g, preferably 20 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, preferably 0.04:1; and / or, The reaction pressure is 0.02-0.14 MPa, preferably 0.10-0.14 MPa; and / or, The reaction temperature is 28-48°C, preferably 33-38°C; and / or, The reaction time is 4-6 hours, preferably 4 hours.

3. The method according to claim 1 or 2, 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.

4. The method according to claim 3, characterized in that The organic solvent is C2-C4 nitrile, C1-C4 alkyl alcohol or 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.

5. The method according to claim 4, characterized in that The organic solvent is acetone; The volume ratio of the organic solvent to water is 10:1-40:1, preferably 20:

1.

6. The method according to any one of claims 1 to 5, 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; 7. The method according to claim 6, characterized in that In step 1), The base is an organic base, preferably an amine, more preferably DIEA; and / or, The condensing agent is EDCI and HOBT; and / or, The solvent for the condensation reaction is an ether, preferably a cyclic ether, more preferably tetrahydrofuran.

8. The method according to claim 7, characterized in that In step 1), The molar ratio of benzyloxycarbonyl-L-alanine to dimethylhydroxylamine hydrochloride is 1:1-1:1.3, preferably 1:1.1-1:1.3, more preferably 1:1.2; and / or, 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; and / or, The molar ratio of benzyloxycarbonyl-L-alanine to HOBT is 1:0-1:1.3, preferably 1:1.1-1:1.3, more preferably 1:1.2; and / or, 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; and / or, The condensation reaction temperature is 15-45°C, preferably 25-35°C; and / or, The condensation reaction time is 1-3 hours, preferably 1 hour.

9. The method according to any one of claims 6 to 8, characterized in that: In step 2), The initiator is 1,2-dibromoethane or iodine, preferably iodine; and / or, The Grignard reagent is ethylmagnesium chloride, ethylmagnesium bromide, propylmagnesium chloride, propylmagnesium bromide, isopropylmagnesium bromide or isopropylmagnesium chloride, preferably isopropylmagnesium chloride; and / or, The solvent for the Grignard reaction is an ether, preferably a cyclic ether, more preferably tetrahydrofuran.

10. The method according to any one of claims 6 to 9, 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, preferably 0.02:1; and / or, The molar ratio of the 3-benzyloxybromobenzene to the compound of formula A is 1.1:1-1.4:1, preferably 1.2:1; and / or, The molar ratio of the magnesium metal to the compound of formula A is 1.1:1-1.4:1, preferably 1.3:1; and / or, The molar ratio of the Grignard reagent to the compound of formula A is 0.8:1-1.5:1, preferably 1.3:1; and / or, The temperature of the Grignard reaction is 25-65°C, preferably 25-35°C; and / or, The time of the Grignard reaction is 1-4 h, preferably 2 h.

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