Synthesis process of metaraminol bitartrate

Abstract

The invention provides a synthesis process of metaraminol bitartrate, which adopts N-benzyloxycarbonyl-L-alanine and 3-benzyloxybromobenzene as initial raw materials at the same time, is low in cost and easy to obtain, not only can reduce reaction steps, but also can avoid the risk of impurity increase caused by parent nucleus synthesis, can adopt a conventional accurate method to perform quality control, and is suitable for industrial production. And the method is good in process reproducibility and suitable for commercial production. The metaraminol bitartrate obtained by the synthesis method disclosed by the invention has the advantages of high total yield (up to 80%), high purity (up to 99.993%), low total impurity content, low non-specific single impurity content, no impurity A or impurity B detected, and no diastereoisomer detected. According to the synthesis method, an enzyme catalyst and an expensive catalyst are not used, the requirement for equipment is low, implementation is easy, reaction operation is easy to control, mildness, safety and reliability are achieved, needed reagents are environmentally friendly, and a foundation can be laid for later industrial enlarged production.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, and in particular to a synthesis process of metaryl tartrate. Background Art

[0002] Metaraminol Bitartrate is the bitartrate salt of metaraminol. It is an α-adrenaline receptor agonist developed by Fresenius Kabi in the United States in 1972. It mainly acts on α receptors and has a weaker effect on β1 receptors. Part of its effect is to promote the release of norepinephrine from sympathetic nerve endings. It is suitable for the early treatment of shock and the prevention and treatment of acute hypotension during spinal block anesthesia. It is used for the auxiliary symptomatic treatment of hypotension caused by bleeding, drug allergy, surgical complications, brain trauma or brain tumor combined with shock. It can also be used to treat hypotension caused by cardiogenic shock or sepsis.

[0003] At present, the common synthetic routes for the synthesis of meta-hydroxylamine bitartrate are as follows:

[0004] (1) Patent CN103739504 reported that m-hydroxybenzaldehyde was used as a raw material, and an asymmetric Henry reaction was carried out with nitroethane in an isoquinoline and copper acetate system, followed by palladium-carbon hydrogen reduction, and finally salt formation with heavy tartaric acid to obtain the target product.

[0005]

[0006] This method uses 3-hydroxybenzaldehyde as a raw material, uses a metal catalyst or other chiral catalyst to carry out an asymmetric Henry reaction to obtain the corresponding chiral nitro compound, and then obtains the target product through nitro reduction, which increases the risk of isomers and radical-toxic impurities.

[0007] (2) Patent CN114315614A reports a method for synthesizing meta-hydroxylamine bitartrate, using N-(tert-butoxycarbonyl)-L-alanine-N′-methoxy-N′-formamide as a raw material and isopropylmagnesium bromide to form a corresponding Grignard reagent, which is then reacted with the Grignard reagent of 3-benzylbromobenzene to obtain a key intermediate, which is then reduced, deprotected with palladium-carbon hydrogen, and salified with bitartrate to obtain the target product.

[0008]

[0009] This method uses N-(tert-butoxycarbonyl)-L-alanine-N′-methoxy-N′-formamide as a raw material, undergoes a two-step Grignard reaction, reduces the carbonyl group, and then uses palladium carbon hydrogen for deprotection. The Grignard reaction has poor stability, low process controllability, and a long route. When aluminum isopropoxide is used for catalytic reduction, the chiral selectivity is higher.

[0010] (3) Using 3-hydroxybenzaldehyde as the starting material, R-1-hydroxy-1-(3-acetoxyphenyl)acetone is obtained through enzyme catalysis, and palladium-carbon hydrogen reduction and deprotection are carried out in the presence of ammonia to obtain the target product.

[0011]

[0012] This method uses 3-hydroxybenzaldehyde as raw material, carries out enzyme-catalyzed reaction, and then undergoes reductive amination. The source, activity, catalytic ability, etc. of the enzyme are all uncertain, and the technology is difficult.

[0013] Therefore, it is necessary to develop a method for synthesizing metaryl tartrate with low cost, mild reaction conditions, environmental friendliness, process operation friendliness, safety and reliability. Summary of the invention

[0014] In view of this, the present invention proposes a synthesis process of meta-hydroxylamine bitartrate, which has mild conditions, low requirements on equipment and environment, simple operation, high purity and high yield of the obtained meta-hydroxylamine bitartrate product, environmentally friendly reagents, low cost, and is suitable for industrial production.

[0015] The technical solution of the present invention is achieved in this way:

[0016] A synthesis process of meta-hydroxylamine bitartrate, the specific steps comprising:

[0017] S1. Preparation process of intermediate JQA01

[0018] (1) adding N-benzyloxycarbonyl-L-alanine, paraformaldehyde and p-toluenesulfonic acid to toluene for reaction, cooling, washing and retaining the organic phase;

[0019] (2) adding the organic phase to petroleum ether, cooling and crystallizing to obtain the intermediate JQA01;

[0020] The structural formula of the intermediate JQA01 is:

[0021] S2. Preparation process of intermediate JQAB01

[0022] Weigh 8-12% of the formula amount of 3-benzyloxybromobenzene, add it to 2-methyltetrahydrofuran for reaction with magnesium chips and iodine, and add the remaining amount of 3-benzyloxybromobenzene to continue the reaction to obtain the intermediate JQAB01;

[0023] The structural formula of the intermediate JQAB01 is:

[0024] S3. Preparation process of intermediate JQA03

[0025] (1) Add JQA01 to 2-methyltetrahydrofuran and cool it down, then add JQAB01 to react to obtain JQA02;

[0026] (2) JQA02 is added to a saturated aqueous ammonium chloride solution, hydrochloric acid a is added dropwise to the system, and the system is allowed to stand for stratification to obtain an organic phase;

[0027] (3) Add hydrochloric acid b to the organic phase, heat the reaction, stand the mixture for separation, retain the organic phase, concentrate under reduced pressure, and recrystallize to obtain the intermediate JQA03;

[0028] The structural formula of the JQA02 is: The structural formula of the JQA03 is:

[0029]

[0030] S4. Preparation process of intermediate JQA05

[0031] (1) Add JQA03 and palladium carbon to anhydrous ethanol, add anhydrous formic acid to react, filter, and obtain a JQA04 reaction solution;

[0032] (2) heating the JQA04 reaction solution, adding L-tartaric acid, cooling and crystallizing to obtain the intermediate JQA05;

[0033] The structural formula of the JQA04 is: The structural formula of the JQA05 is:

[0034]

[0035] Preparation process of S5 and JQA

[0036] (1) Add JQA05 to purified water and heat it, add anhydrous ethanol, keep the temperature and stir, cool it down for crystallization, and filter it with suction to obtain a filter cake;

[0037] (2) The filter cake is added to isopropanol and the mixture is heated and slurried, and the mixture is cooled and crystallized to obtain JQA, i.e., meta-hydroxylamine bitartrate.

[0038] Furthermore, the preparation process of the intermediate JQA01 includes:

[0039] (1) Add N-benzyloxycarbonyl-L-alanine, paraformaldehyde and p-toluenesulfonic acid to toluene, stir at 40-60° C. for 4-5 hours, cool to 25-35° C., add sodium bicarbonate aqueous solution for washing 2-3 times, and retain the organic phase;

[0040] (2) The organic phase was added to petroleum ether, cooled and crystallized, and centrifuged and dried until the moisture content was less than 0.2%, and the intermediate JQA01 was obtained.

[0041] Furthermore, in step (1), the molar ratio of the N-benzyloxycarbonyl-L-alanine, paraformaldehyde and p-toluenesulfonic acid is 1:1.1-1.3:0.06-0.14; the solid-liquid ratio of the N-benzyloxycarbonyl-L-alanine to toluene is 1:4-6 g / mL; the concentration of the sodium bicarbonate aqueous solution is 4-6 wt%; the solid-liquid ratio of the N-benzyloxycarbonyl-L-alanine to the sodium bicarbonate aqueous solution is 1:4-6 g / mL;

[0042] In step (2), the solid-liquid ratio of N-benzyloxycarbonyl-L-alanine to petroleum ether is 1:4-6 g / mL; and the cooling crystallization is to reduce the temperature to -10 to 10° C. and keep the temperature for crystallization for 1 to 3 hours.

[0043] Furthermore, the preparation process of the intermediate JQAB01 comprises: weighing 8-12% of the formula amount of 3-benzyloxybromobenzene, adding magnesium chips and iodine element into 2-methyltetrahydrofuran, mixing and stirring, replacing with nitrogen, raising the temperature to 30-50° C., reacting for 1-2 hours, adding the remaining amount of 3-benzyloxybromobenzene, raising the temperature to 50-70° C., and reacting for 0.5-1.5 hours;

[0044] The molar ratio of the 3-benzyloxybromobenzene to magnesium chips and iodine is 1:1.1-1.3:0.01-0.03; the solid-liquid ratio of the 3-benzyloxybromobenzene to 2-methyltetrahydrofuran is 1:1-1.5 g / mL.

[0045] Furthermore, the magnesium chips are used as raw materials after being processed, and the specific processing operation is: according to the molar ratio of 1:8.2-9.4, the magnesium chips are added to the hydrochloric acid solution with a concentration of 8-12wt%, and stirred during the process. After mixing evenly, the filter is filtered, and the filter cake is soaked with acetone, and the molar ratio of acetone to magnesium chips is 4.5-5.5:1. The wet magnesium chips are vacuum dried at 30-40°C to obtain processed magnesium chips.

[0046] Furthermore, the preparation process of the intermediate JQA03 includes:

[0047] (1) The intermediate JQA01 was added to 2-methyltetrahydrofuran and stirred. Under a nitrogen atmosphere, the temperature was lowered to -20 to -10°C, and the intermediate JQAB01 was added to carry out a temperature-controlled reaction to obtain JQA02;

[0048] (2) Add JQA02 to a saturated aqueous solution of ammonium chloride, add hydrochloric acid a dropwise to the system, allow to stand and separate, and obtain an organic phase, i.e., a 2-methyltetrahydrofuran solution of JQA02;

[0049] (3) Add hydrochloric acid b to the 2-methyltetrahydrofuran solution of JQA02, raise the temperature to react, stand for separation, and retain the organic phase;

[0050] (4) Add saturated sodium bicarbonate to the organic phase in (3) for washing 2-3 times, add 2-4 wt% sodium chloride solution for washing, let stand, take the organic phase, concentrate under reduced pressure, recrystallize, and centrifuge to dry until the moisture content is less than 0.4%, and obtain JQA03.

[0051] Furthermore, in step (1), the liquid-to-solid ratio of the intermediate JQA01 to 2-methyltetrahydrofuran is 1:2-4 g / mL; the molar ratio of the intermediate JQA01 to the intermediate JQAB01 is 1:1.1-1.3; and the temperature-controlled reaction is carried out at -20 to 0°C for 1 to 3 hours;

[0052] In step (2), the material-liquid ratio of JQA01 to saturated aqueous ammonium chloride solution is 1:0.8-1.2 g / mL; the material-liquid ratio of JQA01 to hydrochloric acid a is 1:2-4 g / mL, and the concentration of hydrochloric acid a is 2-4 mol / L;

[0053] In step (3), the liquid ratio of JQA01 to hydrochloric acid b is 1:6-10 g / mL, and the concentration of hydrochloric acid b is 4-6 mol / L; the temperature rise reaction is carried out at 50-60° C. for 6-10 h;

[0054] In step (4), the liquid ratio of JQA01 to saturated sodium bicarbonate is 1:4-6 g / mL; the liquid ratio of JQA01 to sodium chloride solution is 1:4-6 g / mL; the recrystallization solvent is methanol, wherein the liquid ratio of JQA01 to methanol is 1:3-5 g / mL, the crystallization temperature is -15 to 5°C, and the crystallization time is 1-2 h.

[0055] Furthermore, the preparation process of the intermediate JQA05 includes:

[0056] (1) Add JQA03 and palladium carbon to anhydrous ethanol, add anhydrous formic acid, replace air with nitrogen 2-4 times, replace nitrogen with hydrogen 2-4 times, pressurize the hydrogen to 0.45-0.55 MPa, control the temperature for reaction, filter and remove palladium carbon to obtain JQA04 reaction solution;

[0057] (2) The JQA04 reaction solution was heated to 75-85°C, L-tartaric acid was added, and the temperature was first lowered to 45-55°C for crystallization for 0.5-1.5h, and then lowered to 0-20°C for crystallization for 0.5-1.5h, filtered, added to ethanol aqueous solution for pulping, cooled and crystallized, and centrifuged and dried until the water content was less than 15%, and the intermediate JQA05 was obtained.

[0058] Furthermore, in step (1), the mass ratio of JQA03 to palladium carbon is 1:0.05-0.07; the material-liquid ratio of JQA03 to anhydrous ethanol is 1:6-10 g / mL; the molar ratio of JQA03 to anhydrous formic acid is 1:5-7; and the temperature-controlled reaction is carried out at 30-40°C for 6-10 hours;

[0059] In step (2), the molar ratio of JQA03 to L-tartaric acid is 1:1-1.4; the solid-liquid ratio of JQA03 to ethanol in the ethanol aqueous solution is 1:8-10 g / mL, and the solid-liquid ratio of JQA03 to water in the ethanol aqueous solution is 1:0.5-0.7 g / mL; the pulping temperature is 40-70°C, and the time is 20-40 min; the crystallization temperature is 10-20°C, and the time is 0.5-1.5 h.

[0060] Furthermore, the preparation process of JQA includes:

[0061] (1) According to the solid-liquid ratio of 1:0.8-1.0 g / mL, the intermediate JQA05 is added to purified water, and under a nitrogen atmosphere, the temperature is raised to 75-85° C., anhydrous ethanol is added, and the solid-liquid ratio of JQA05 to ethanol is 1:6-10 g / mL, and the mixture is stirred at this temperature for 0.5-1.5 h, first cooled to 45-55° C. for crystallization for 0.5-1.5 h, and then cooled to 0-15° C. for crystallization for 0.5-1.5 h, and filtered to obtain a filter cake;

[0062] (2) The filter cake is added to isopropanol, with the solid-liquid ratio of JQA05 to isopropanol being 1:6-10 g / mL, and the mixture is heated to 45-55° C. for slurrying for 0.5-1.5 h, cooled to 0-10° C. for crystallization for 0.5-1.5 h, and vacuum dried to obtain JQA, i.e., meta-hydroxylamine bitartrate.

[0063] Compared with the prior art, the present invention has the following beneficial effects:

[0064] 1. The present invention uses N-benzyloxycarbonyl-L-alanine and 3-benzyloxybromobenzene as starting materials at the same time, which are low-cost and easily available, can not only reduce the reaction steps, but also avoid the risk of increased impurities caused by the synthesis of the parent nucleus, can use conventional and accurate methods for quality control, has good process reproducibility, and is suitable for commercial production.

[0065] 2. The meta-hydroxylamine bitartrate obtained by the synthesis method of the present invention has a high yield, which can reach up to 80%, a high purity, which can reach up to 99.993%, a low total impurity content, a low non-specific single impurity content, no impurity A and impurity B, and no diastereoisomers.

[0066] 3. The synthesis method of the present invention does not use enzyme catalysts and expensive catalysts, has low equipment requirements, is easy to implement, and the reaction operation is easy to control, mild, safe and reliable. The required reagents are environmentally friendly and can lay the foundation for later industrial scale-up production. DETAILED DESCRIPTION

[0067] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0068] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0069] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0070] abbreviation Material Name JQA0 N-Benzyloxycarbonyl-L-alanine JQAB00 3-Benzyloxybromobenzene

[0071] The JQA00 of the present invention is sourced from Changzhou Huaren Chemical Co., Ltd.; and the JQAB00 of the present invention is sourced from Nantong Kaisheng Biotechnology Co., Ltd.

[0072] The preparation process of JQA00 is as follows: JQA00 is obtained by condensing L-alanine with benzyl chloroformate and post-processing.

[0073]

[0074] JQA00 is a white or off-white powder with a moisture content of no more than 0.2%, a non-specific impurity content of no more than 0.20%, a total impurity content of no more than 1.0%, and a purity of no less than 99.0%.

[0075] The preparation process of JQAB00 is as follows: JQAB00 is prepared from 3-nitrobromobenzene as a raw material, 3-methoxybromobenzene is produced, and then demethylated to obtain 3-bromophenol, which reacts with benzyl chloride, undergoes post-treatment, and then is recrystallized and dried to obtain the starting material JQAB00.

[0076]

[0077] JQAB00 is a white powder with a moisture content of no more than 0.2%, a non-specific impurity content of no more than 0.10%, a total impurity content of no more than 1.0%, and a purity of no less than 99.0%.

[0078]

[0079]

[0080] Example 1

[0081]

[0082] S1. Preparation process of intermediate JQA01

[0083] (1) JQA00 (4.0 g, 1.0 eq), paraformaldehyde (699.44 mg, 1.3 eq) and p-toluenesulfonic acid (308.56 mg, 0.1 eq) were added to toluene (20 mL, 5 mL / g), stirred at 50 ° C for 4 h, cooled to 30 ° C, washed twice with 5 wt% sodium bicarbonate aqueous solution (20 mL, 5 mL / g), and the organic phase was retained;

[0084] (2) The organic phase was added to petroleum ether (20 mL, 5 mL / g), cooled to 0°C and kept for crystallization for 2 h, and centrifuged and dried until the moisture content was less than 0.2%, and the intermediate JQA01 was obtained.

[0085] Intermediate JQA01 test results

[0086]

[0087] S2. Preparation process of intermediate JQAB01

[0088] Weigh JQAB00 (5.0 g, 1.0 eq), take out 10% of JQAB00 (0.5 g, 10%), add magnesium chips (600.39 mg, 1.3 eq) and iodine element (48.23 mg, 0.01 eq) into 2-methyltetrahydrofuran (5 mL, 1 mL / g), mix and stir, replace with nitrogen 3 times, raise the temperature to 40°C, react for 2 h, add the remaining amount of 3-benzyloxybromobenzene (4.5 g, 90%), raise the temperature to 60°C and react for 1 h to obtain the intermediate JQAB01;

[0089] The magnesium chips are treated as follows: the magnesium chips are added to a 10wt% hydrochloric acid solution at a molar ratio of 1:8.8, stirred during the process, and filtered after mixing evenly. The filter cake is soaked in acetone, and the molar ratio of acetone to magnesium chips is 5:1. The wet magnesium chips are vacuum dried at 35°C to obtain treated magnesium chips.

[0090] S3. Preparation process of intermediate JQA03

[0091] (1) The intermediate JQA01 (40.0 g, 1.0 eq) was added to 2-methyltetrahydrofuran (120 mL, 3 mL / g) and stirred. Under a nitrogen atmosphere, the temperature was lowered to -15°C, and the intermediate JQAB01 (71.33 g, 1.2 eq) was added. The temperature was controlled at -10°C for 1 h to obtain JQA02;

[0092] (2) JQA02 was added to a saturated aqueous ammonium chloride solution (40 mL, 1 mL / g), hydrochloric acid a (120 mL, 3 mL / g) was added dropwise to the system, and the system was allowed to stand for stratification to obtain an organic phase, i.e., a 2-methyltetrahydrofuran solution of JQA02;

[0093] (3) Add hydrochloric acid b (320 mL, 8 mL / g) to the 2-methyltetrahydrofuran solution of JQA02, heat to 50°C and react for 8 h, stand for separation, and retain the organic phase;

[0094] (4) Saturated sodium bicarbonate (200 mL, 5 mL / g) was added to the organic phase in (3) for washing twice, and 3 wt% sodium chloride solution (200 mL, 5 mL / g) was added for washing. The organic phase was allowed to stand for concentration under reduced pressure, and methanol (24 mL, 3 mL / g) was added for recrystallization. The mixture was kept at 0°C for 1 h for crystallization, and centrifuged and dried until the moisture content was less than 0.4%. JQA03 was obtained.

[0095] Intermediate JQA03 test results

[0096]

[0097] S4. Preparation process of intermediate JQA05

[0098] (1) JQA03 (1.0 g, 1.0 eq) and palladium carbon (50 mg, 5%) were added to anhydrous ethanol (8 mL, 8 mL / g), anhydrous formic acid (0.59 g, 5.0 eq) was added, the air was replaced by nitrogen 3 times, the nitrogen was replaced by hydrogen 3 times, the hydrogen was pressurized to 0.5 MPa, the temperature was controlled at 30°C, the mixture was stirred for 8 h, the palladium carbon was removed by filtration, and the JQA04 reaction solution was obtained;

[0099] (2) The JQA04 reaction solution was heated to 80°C, L-tartaric acid (3.85 g, 1.0 eq) was added, and the temperature was first lowered to 50°C for crystallization for 1 h, and then lowered to 10°C for crystallization for 1 h, filtered, added to an ethanol aqueous solution (16 mL + 1 mL, 8 mL / g + 0.5 mL / g), heated to 50°C for slurrying for 0.5 h, cooled to 15°C for crystallization for 1 h, and centrifuged and dried until the water content was less than 15%, and the intermediate JQA05 was obtained.

[0100] Intermediate JQA05 test results

[0101]

[0102] Preparation process of S5 and JQA

[0103] (1) The intermediate JQA05 (2.0 g, 1.0 eq) was added to purified water (2 mL, 1 mL / g), and the temperature was raised to 80°C under a nitrogen atmosphere. Anhydrous ethanol (16 mL, 8 mL / g) was added, and the mixture was stirred for 1 h. The temperature was then lowered to 50°C for crystallization for 1 h. The temperature was then lowered to 10°C for crystallization for 1 h, and then filtered to obtain a filter cake.

[0104] (2) The filter cake was added to isopropanol (12 mL, 6 mL / g), the temperature was raised to 50° C. for slurrying for 1 h, the temperature was lowered to 10° C. for crystallization for 1 h, and the solid was dried at 50° C. in vacuum to obtain JQA, i.e., meta-hydroxylamine bitartrate.

[0105] Test results of meta-hydroxylamine bitartrate

[0106]

[0107] In other embodiments,

[0108] S1. In the preparation process of intermediate JQA01, in step (1), the molar ratio of N-benzyloxycarbonyl-L-alanine, paraformaldehyde and p-toluenesulfonic acid is 1:1.1-1.3:0.06-0.14, the solid-liquid ratio of N-benzyloxycarbonyl-L-alanine to toluene is 1:4-6 g / mL, the reaction is stirred at 40-60°C for 4-5h, the temperature is cooled to 25-35°C, the concentration of sodium bicarbonate aqueous solution is 4-6wt%, the solid-liquid ratio of N-benzyloxycarbonyl-L-alanine to sodium bicarbonate aqueous solution is 1:4-6 g / mL, and washing is performed 2-3 times; in step (2), the solid-liquid ratio of N-benzyloxycarbonyl-L-alanine to petroleum ether is 1:4-6 g / mL, and the temperature is reduced to -1010°C for crystallization for 1-3h;

[0109] S2, in the preparation process of the intermediate JQAB01, 8-12% of JQAB00 is taken, the molar ratio of JQAB00 to magnesium chips and iodine is 1:1.1-1.3:0.01-0.03, the material-liquid ratio of JQAB00 to 2-methyltetrahydrofuran is 1:1-1.5 g / mL, the temperature is raised to 30-50°C for reaction for 1-2h, the remaining amount of 3-benzyloxybromobenzene is added, the temperature is raised to 50-70°C for reaction for 0.5-1.5h;

[0110] S3, in the preparation process of intermediate JQA03, in step (1), the material-liquid ratio of intermediate JQA01 to 2-methyltetrahydrofuran is 1:2-4 g / mL, the molar ratio of intermediate JQA01 to intermediate JQAB01 is 1:1.1-1.3, and the temperature-controlled reaction is carried out at -200°C for 1-3 hours; in step (2), the material-liquid ratio of JQA01 to saturated aqueous ammonium chloride solution is 1:0.8-1.2 g / mL, the material-liquid ratio of JQA01 to hydrochloric acid a is 1:2-4 g / mL, and the concentration of hydrochloric acid a is 2-4 mol / L; in step (3), the material-liquid ratio of JQA01 to hydrochloric acid b is 1:6-10g / mL, the concentration of hydrochloric acid b is 4-6mol / L, and the temperature reaction is carried out at 50-60°C for 6-10h; in step (4), the material-liquid ratio of JQA01 to saturated sodium bicarbonate is 1:4-6g / mL, the material-liquid ratio of JQA01 to sodium chloride solution is 1:4-6g / mL, the recrystallization solvent is methanol, wherein the material-liquid ratio of JQA01 to methanol is 1:3-5g / mL, the crystallization temperature is -155°C, and the crystallization time is 1-2h;

[0111] S4, in the preparation process of intermediate JQA05, in step (1), the mass ratio of JQA03 to palladium carbon is 1:0.05-0.07, the solid-liquid ratio of JQA03 to anhydrous ethanol is 1:6-10 g / mL, the molar ratio of JQA03 to anhydrous formic acid is 1:5-7, and the temperature control reaction is carried out at 30-40°C for 6-10 hours; in step (2), the molar ratio of JQA03 to L-tartaric acid is 1:1-1.4, the solid-liquid ratio of JQA03 to ethanol in an ethanol aqueous solution is 1:8-10 g / mL, and the solid-liquid ratio of JQA03 to water in an ethanol aqueous solution is 1:0.5-0.7 g / mL, the beating temperature is 40-70°C, the time is 20-40 min, the crystallization temperature is 10-20°C, and the time is 0.5-1.5 h;

[0112] In the preparation process of S5 and JQA, in step (1), the solid-liquid ratio of JQA05 to purified water is 1:0.8-1.0 g / mL, the solid-liquid ratio of JQA05 to ethanol is 1:6-10 g / mL, and the crystallization by cooling is firstly to crystallize at 45-55°C for 0.5-1.5 h, and then to crystallize at 0-15°C for 0.5-1.5 h; in step (2), the solid-liquid ratio of JQA05 to isopropanol is 1:6-10 g / mL, the pulping by heating is to pulp at 45-55°C for 0.5-1.5 h, and the crystallization by cooling is to crystallize at 0-10°C for 0.5-1.5 h.

[0113] The purpose of the present invention can be achieved by adjusting the reaction raw materials, reagent dosage and process parameters within the above ranges.

[0114] Comparative Example 1

[0115] The difference from Example 1 is that in the preparation process of the intermediate JQA01, toluene is replaced by acetonitrile, methanol, ethyl acetate, tetrahydrofuran, ethanol or 2-methyltetrahydrofuran, and the rest is consistent with Example 1.

[0116]

[0117] As can be seen from the above table, the toluene in Example 1 has a better reaction effect as a reaction solvent, while the other solvents in Comparative Example 1 have a poor reaction effect. The residual raw materials and the intermediate JQA01 content of the reaction solvent system in Example 1 are better than those in Comparative Example 1, and the other solvents in Comparative Example 1 are not conducive to the purity and yield of the subsequent products.

[0118] Comparative Example 2

[0119] The difference from Example 1 is that 2-methyltetrahydrofuran in the preparation process of intermediate JQAB01 is replaced by toluene, acetonitrile, methyl tert-ether or tetrahydrofuran, and the rest is consistent with Example 1.

[0120]

[0121]

[0122] As can be seen from the above table, the 2-methyltetrahydrofuran in Example 1 can successfully initiate the reaction, while the toluene, acetonitrile and methyl tert-ether in Comparative Example 2, which are used as reaction solvents, cannot initiate the reaction. Although the tetrahydrofuran in Comparative Example 2 can also initiate the reaction, the post-processing is more complicated and requires additional extraction operations, which increases the cost.

[0123] Comparative Example 3

[0124] The difference from Example 1 is that the recrystallization solvent methanol in the preparation process of the intermediate JQA03 is replaced by ethanol or isopropanol, and the rest is consistent with Example 1.

[0125]

[0126] As can be seen from the above table, when the recrystallization solvent of Example 1 is methanol, the purity and yield are better than the solvent in Comparative Example 3.

[0127] Comparative Example 4

[0128] The difference from Example 1 is that the isopropanol in the preparation process of JQA is replaced by tetrahydrofuran or acetone, and the rest is consistent with Example 1.

[0129]

[0130]

[0131] As can be seen from the above table, the tetrahydrofuran pulping yield of Comparative Example 4 is very low, and acetone condenses with primary amines to produce impurities during refining. Therefore, isopropanol in Example 1 is the best choice.

[0132] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A synthesis process of meta-hydroxylamine bitartrate, characterized in that: The specific steps include: S1. Preparation process of intermediate JQA01 (1) adding N-benzyloxycarbonyl-L-alanine, paraformaldehyde and p-toluenesulfonic acid to toluene for reaction, cooling, washing and retaining the organic phase; (2) adding the organic phase to petroleum ether, cooling and crystallizing to obtain the intermediate JQA01; The structural formula of the intermediate JQA01 is: S2. Preparation process of intermediate JQAB01 Weigh 8-12% of the formula amount of 3-benzyloxybromobenzene, add it to 2-methyltetrahydrofuran for reaction with magnesium chips and iodine, and add the remaining amount of 3-benzyloxybromobenzene to continue the reaction to obtain the intermediate JQAB01; The structural formula of the intermediate JQAB01 is: S3. Preparation process of intermediate JQA03 (1) Add JQA01 to 2-methyltetrahydrofuran and cool it down, then add JQAB01 to react to obtain JQA02; (2) JQA02 is added to a saturated aqueous ammonium chloride solution, hydrochloric acid a is added dropwise to the system, and the system is allowed to stand for stratification to obtain an organic phase; (3) Add hydrochloric acid b to the organic phase, heat the reaction, stand the mixture for separation, retain the organic phase, concentrate under reduced pressure, and recrystallize to obtain the intermediate JQA03; The structural formula of the JQA02 is: The structural formula of the JQA03 is: S4. Preparation process of intermediate JQA05 (1) Add JQA03 and palladium carbon to anhydrous ethanol, add anhydrous formic acid to react, filter, and obtain a JQA04 reaction solution; (2) heating the JQA04 reaction solution, adding L-tartaric acid, cooling and crystallizing to obtain the intermediate JQA05; The structural formula of the JQA04 is: The structural formula of the JQA05 is: Preparation process of S5 and JQA (1) Add JQA05 to purified water and heat it, add anhydrous ethanol, keep the temperature and stir, cool it down for crystallization, and filter it with suction to obtain a filter cake; (2) The filter cake is added to isopropanol and the mixture is heated and slurried, and the mixture is cooled and crystallized to obtain JQA, i.e., meta-hydroxylamine bitartrate.

2. A synthesis process of meta-hydroxylamine bitartrate according to claim 1, characterized in that: The preparation process of the intermediate JQA01 comprises: (1) Add N-benzyloxycarbonyl-L-alanine, paraformaldehyde and p-toluenesulfonic acid to toluene, stir at 40-60° C. for 4-5 hours, cool to 25-35° C., add sodium bicarbonate aqueous solution for washing 2-3 times, and retain the organic phase; (2) The organic phase was added to petroleum ether, cooled and crystallized, and centrifuged and dried until the moisture content was less than 0.2%, and the intermediate JQA01 was obtained.

3. A synthesis process of meta-hydroxylamine bitartrate as claimed in claim 2, characterized in that: In step (1), the molar ratio of N-benzyloxycarbonyl-L-alanine, paraformaldehyde and p-toluenesulfonic acid is 1:1.1-1.3:0.06-0.14; the solid-liquid ratio of N-benzyloxycarbonyl-L-alanine to toluene is 1:4-6 g / mL; the concentration of the sodium bicarbonate aqueous solution is 4-6 wt%; the solid-liquid ratio of N-benzyloxycarbonyl-L-alanine to the sodium bicarbonate aqueous solution is 1:4-6 g / mL; In step (2), the solid-liquid ratio of N-benzyloxycarbonyl-L-alanine to petroleum ether is 1:4-6 g / mL; and the cooling crystallization is to reduce the temperature to -10 to 10° C. and keep the temperature for crystallization for 1 to 3 hours.

4. A synthesis process of meta-hydroxylamine bitartrate according to claim 1, characterized in that: The preparation process of the intermediate JQAB01 comprises: weighing 8-12% of the formula amount of 3-benzyloxybromobenzene, adding magnesium chips and iodine element into 2-methyltetrahydrofuran, mixing and stirring, replacing with nitrogen, raising the temperature to 30-50° C., reacting for 1-2 hours, adding the remaining amount of 3-benzyloxybromobenzene, raising the temperature to 50-70° C., and reacting for 0.5-1.5 hours; The molar ratio of the 3-benzyloxybromobenzene to magnesium chips and iodine is 1:1.1-1.3:0.01-0.03; the solid-liquid ratio of the 3-benzyloxybromobenzene to 2-methyltetrahydrofuran is 1:1-1.5 g / mL.

5. A synthesis process of meta-hydroxylamine bitartrate as claimed in claim 4, characterized in that: The magnesium chips are used as raw materials after being processed. The specific processing operation is: according to the molar ratio of 1:8.2-9.4, the magnesium chips are added to the hydrochloric acid solution with a concentration of 8-12wt%, stirred during the process, and filtered after mixing evenly. The filter cake is soaked with acetone, and the molar ratio of acetone to magnesium chips is 4.5-5.5:

1. The wet magnesium chips are vacuum dried at 30-40°C to obtain processed magnesium chips.

6. A synthesis process of meta-hydroxylamine bitartrate according to claim 1, characterized in that: The preparation process of the intermediate JQA03 comprises: (1) The intermediate JQA01 was added to 2-methyltetrahydrofuran and stirred. Under a nitrogen atmosphere, the temperature was lowered to -20 to -10°C, and the intermediate JQAB01 was added to carry out a temperature-controlled reaction to obtain JQA02; (2) Add JQA02 to a saturated aqueous solution of ammonium chloride, add hydrochloric acid a dropwise to the system, allow to stand and separate, and obtain an organic phase, i.e., a 2-methyltetrahydrofuran solution of JQA02; (3) Add hydrochloric acid b to the 2-methyltetrahydrofuran solution of JQA02, raise the temperature to react, stand for separation, and retain the organic phase; (4) Add saturated sodium bicarbonate to the organic phase in (3) for washing 2-3 times, add 2-4 wt% sodium chloride solution for washing, let stand, take the organic phase, concentrate under reduced pressure, recrystallize, and centrifuge to dry until the moisture content is less than 0.4%, and obtain JQA03.

7. A synthesis process of meta-hydroxylamine bitartrate as claimed in claim 6, characterized in that: In step (1), the liquid ratio of the intermediate JQA01 to 2-methyltetrahydrofuran is 1:2-4 g / mL; the molar ratio of the intermediate JQA01 to the intermediate JQAB01 is 1:1.1-1.3; the temperature-controlled reaction is carried out at -20 to 0°C for 1 to 3 hours; In step (2), the material-liquid ratio of JQA01 to saturated aqueous ammonium chloride solution is 1:0.8-1.2 g / mL; the material-liquid ratio of JQA01 to hydrochloric acid a is 1:2-4 g / mL, and the concentration of hydrochloric acid a is 2-4 mol / L; In step (3), the liquid ratio of JQA01 to hydrochloric acid b is 1:6-10 g / mL, and the concentration of hydrochloric acid b is 4-6 mol / L; the temperature rise reaction is carried out at 50-60° C. for 6-10 h; In step (4), the liquid ratio of JQA01 to saturated sodium bicarbonate is 1:4-6 g / mL; the liquid ratio of JQA01 to sodium chloride solution is 1:4-6 g / mL; the recrystallization solvent is methanol, wherein the liquid ratio of JQA01 to methanol is 1:3-5 g / mL, the crystallization temperature is -15 to 5°C, and the crystallization time is 1-2 h.

8. A synthesis process of meta-hydroxylamine bitartrate according to claim 1, characterized in that: The preparation process of the intermediate JQA05 comprises: (1) Add JQA03 and palladium carbon to anhydrous ethanol, add anhydrous formic acid, replace air with nitrogen 2-4 times, replace nitrogen with hydrogen 2-4 times, pressurize the hydrogen to 0.45-0.55 MPa, control the temperature for reaction, filter and remove palladium carbon to obtain JQA04 reaction solution; (2) The JQA04 reaction solution was heated to 75-85°C, L-tartaric acid was added, and the temperature was first lowered to 45-55°C for crystallization for 0.5-1.5h, and then lowered to 0-20°C for crystallization for 0.5-1.5h, filtered, added to ethanol aqueous solution for pulping, cooled and crystallized, and centrifuged and dried until the water content was less than 15%, and the intermediate JQA05 was obtained.

9. A synthesis process of meta-hydroxylamine bitartrate as claimed in claim 8, characterized in that: In step (1), the mass ratio of JQA03 to palladium carbon is 1:0.05-0.07; the material-liquid ratio of JQA03 to anhydrous ethanol is 1:6-10 g / mL; the molar ratio of JQA03 to anhydrous formic acid is 1:5-7; the temperature-controlled reaction is carried out at 30-40° C. for 6-10 hours; In step (2), the molar ratio of JQA03 to L-tartaric acid is 1:1-1.4; the solid-liquid ratio of JQA03 to ethanol in the ethanol aqueous solution is 1:8-10 g / mL, and the solid-liquid ratio of JQA03 to water in the ethanol aqueous solution is 1:0.5-0.7 g / mL; the pulping temperature is 40-70°C, and the time is 20-40 min; the crystallization temperature is 10-20°C, and the time is 0.5-1.5 h.

10. The synthesis process of meta-hydroxylamine bitartrate according to claim 1, characterized in that: The preparation process of JQA comprises: (1) According to the solid-liquid ratio of 1:0.8-1.0 g / mL, the intermediate JQA05 is added to purified water, and under a nitrogen atmosphere, the temperature is raised to 75-85° C., anhydrous ethanol is added, and the solid-liquid ratio of JQA05 to ethanol is 1:6-10 g / mL, and the mixture is stirred at this temperature for 0.5-1.5 h, first cooled to 45-55° C. for crystallization for 0.5-1.5 h, and then cooled to 0-15° C. for crystallization for 0.5-1.5 h, and filtered to obtain a filter cake; (2) The filter cake is added to isopropanol, with the solid-liquid ratio of JQA05 to isopropanol being 1:6-10 g / mL, and the mixture is heated to 45-55° C. for slurrying for 0.5-1.5 h, cooled to 0-10° C. for crystallization for 0.5-1.5 h, and vacuum dried to obtain JQA, i.e., meta-hydroxylamine bitartrate.

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