A synthesis process of metaraminol bitartrate

Abstract

The application provides a synthesis process of methysergide tartrate, wherein N-benzyloxy carbonyl-L-alanine and 3-benzyloxy bromobenzene are simultaneously used as starting materials, the cost is low and the materials are easy to obtain, the reaction steps can be reduced, the risk of increasing impurities caused by synthesis of a mother nucleus can be avoided, a conventional and accurate method can be used for quality control, the process has good reproducibility, and is suitable for commercial production. The total yield of methysergide tartrate obtained by the synthesis method is high, reaches 80% at most, the purity is high, reaches 99.993% at most, the total impurity content is low, the non-specific single impurity is low, impurities A and B are not detected, and diastereoisomers are not detected. The synthesis method does not use enzyme catalysts and expensive catalysts, has low requirements on equipment, is easy to implement, is easy to control, is mild, safe and reliable, the required reagents are environmentally friendly, and can lay a foundation for later industrial scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular to a synthesis process of metaraminol bitartrate. BACKGROUND

[0002] Metaraminol bitartrate is a tartrate salt of metaraminol, which is an alpha adrenergic receptor agonist developed by Fresenius Kabi in 1972. It mainly acts on alpha receptors and has weak effects on beta1 receptors. Some of its effects are achieved by promoting the release of norepinephrine from sympathetic nerve endings. It is suitable for the treatment of early shock and the prevention and treatment of acute hypotension caused by intraspinal block anesthesia. It can also be used for the auxiliary symptomatic treatment of hypotension caused by bleeding, drug allergy, surgical complications, and brain trauma or brain tumor combined with shock, and for the treatment of hypotension caused by cardiogenic shock or sepsis.

[0003] At present, the common synthesis routes of metaraminol bitartrate are as follows:

[0004] (1) Patent CN103739504 reports a synthesis method of metaraminol bitartrate using m-hydroxybenzaldehyde as the raw material, asymmetric Henry reaction with nitroethane in an isoquinoline and copper acetate system, followed by hydrogen reduction with palladium-carbon, and finally salt formation with heavy tartaric acid to obtain the target product.

[0005]

[0006] This method uses 3-hydroxybenzaldehyde as the raw material, and uses a metal catalyst or other chiral catalyst to perform asymmetric Henry reaction to obtain the corresponding chiral nitro compound, and then reduces the nitro group to obtain the target product, which increases the risk of isomer and impurities.

[0007] (2) Patent CN114315614A reports a synthesis method of metaraminol bitartrate using N-(tert-butoxycarbonyl)-L-alanine-N'-methoxy-N'-formamide as the raw material to form the corresponding Grignard reagent with isopropylmagnesium bromide, and then reacting with the Grignard reagent of 3-benzyl bromobenzene to obtain the key intermediate, followed by reduction, palladium-carbon hydrogen gas deprotection, and salt formation with heavy tartaric acid to obtain the target product.

[0008]

[0009] This method uses N-(tert-butoxycarbonyl)-L-alanine-N'-methoxy-N'-formamide as the raw material, and after two-step Grignard reaction and carbonyl reduction, palladium-carbon hydrogen gas deprotection is used. The stability of Grignard reaction is poor, the process controllability is not high, the route is long, and the chiral selectivity is high when using isopropyl aluminum catalyst for reduction.

[0010] (3) taking 3-hydroxybenzaldehyde as a starting material, obtaining R-1-hydroxy-1-(3-acetoxyphenyl)propanone through enzyme catalysis, and obtaining the target product through palladium-carbon hydrogen reduction and deprotection in the presence of ammonia.

[0011]

[0012] The method takes 3-hydroxybenzaldehyde as a raw material, performs enzyme catalysis, and then performs reductive amination, and the source, activity and catalytic ability of the enzyme are uncertain, and the technical difficulty is great.

[0013] Therefore, it is necessary to research a method for synthesizing m-hydroxyamine tartrate which is low in cost, mild in reaction condition, friendly to environment, friendly to process operation, safe and reliable. SUMMARY

[0014] In view of this, the present application provides a synthesis process of m-hydroxyamine tartrate, which is mild in method condition, low in requirement for equipment and environment, simple in operation, high in purity and yield of the obtained m-hydroxyamine tartrate product, friendly to environment in required reagent, low in cost, and suitable for industrial production.

[0015] The technical scheme of the present application is as follows:

[0016] A synthesis process of m-hydroxyamine tartrate, and the specific steps include:

[0017] S1, preparation process of intermediate JQA01

[0018] (1) N-benzyloxy carbonyl-L-alanine, para-toluenesulfonic acid and toluene are added to toluene to react, cooled, washed, and the organic phase is reserved;

[0019] (2) the organic phase is added to petroleum ether to cool and crystallize to obtain the intermediate JQA01;

[0020] The intermediate JQA01 has the following structural formula:

[0021] S2, preparation process of intermediate JQAB01

[0022] The formula amount of 8-12% 3-benzyloxy bromobenzene is weighed, and the 3-benzyloxy bromobenzene is added to 2-methyl tetrahydrofuran to react with magnesium chips and iodine, and the remaining 3-benzyloxy bromobenzene is added to continue the reaction to obtain the intermediate JQAB01;

[0023] The intermediate JQAB01 has the following structural formula:

[0024] S3, preparation process of intermediate JQA03

[0025] (1) JQA01 is added into 2-methyltetrahydrofuran for cooling, and JQAB01 is added for reaction to obtain JQA02;

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

[0027] (3) Hydrochloric acid b is added into the organic phase, the system is allowed to react under heating, and the system is allowed to stand to separate into organic phase and aqueous phase, the organic phase is reserved, and the organic phase is concentrated under reduced pressure, recrystallized to obtain intermediate JQA03;

[0028] The structural formula of JQA02 is as follows: The structural formula of JQA03 is as follows:

[0029]

[0030] S4, preparation process of intermediate JQA05

[0031] (1) JQA03 and palladium-carbon are added into anhydrous ethanol, and anhydrous formic acid is added for reaction, and filtration is performed to obtain JQA04 reaction solution;

[0032] (2) The JQA04 reaction solution is warmed, and L-tartaric acid is added, and the system is allowed to stand to crystallize to obtain intermediate JQA05;

[0033] The structural formula of JQA04 is as follows: The structural formula of JQA05 is as follows:

[0034]

[0035] S5, preparation process of JQA

[0036] (1) JQA05 is added into purified water for warming, anhydrous ethanol is added, the system is allowed to stand to stir, the system is allowed to stand to crystallize, and filtration is performed to obtain filter cake;

[0037] (2) The filter cake is added into isopropyl alcohol for warming and beating, and the system is allowed to stand to crystallize to obtain JQA, that is, metaraminol bitartrate.

[0038] Further, the preparation process of the intermediate JQA01 comprises:

[0039] (1) N-benzyloxy carbonyl-L-alanine, paraformaldehyde and p-toluenesulfonic acid are added into toluene, and the system is allowed to stir at 40-60℃ for 4-5h, the system is allowed to stand to cool to 25-35℃, and the system is washed with sodium bicarbonate aqueous solution for 2-3 times, and the organic phase is reserved;

[0040] (2) The organic phase is added into petroleum ether, and the system is allowed to stand to crystallize, centrifuged and dried to a water content of less than 0.2%, and the product is discharged to obtain the intermediate JQA01.

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

[0042] In step (2), the solid-liquid ratio of the N-carbobenzyloxy-L-alanine and the petroleum ether is 1:4-6 g / mL; the temperature is reduced to -10-10 ℃ for crystallization for 1-3 h.

[0043] Further, the preparation process of the intermediate JQA B01 comprises: weighing 8-12% of the formula amount of 3-benzyloxybromobenzene, mixing and stirring with magnesium turnings and iodine monomer in 2-methyltetrahydrofuran, replacing with nitrogen, increasing the temperature to 30-50 ℃, and reacting for 1-2 h; adding the remaining 3-benzyloxybromobenzene, increasing the temperature to 50-70 ℃, and reacting for 0.5-1.5 h.

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

[0045] Further, the magnesium turnings are used as raw materials after treatment, and the specific treatment operation is as follows: according to the molar ratio of 1:8.2-9.4, the magnesium turnings are added into a hydrochloric acid solution with a concentration of 8-12 wt%, stirring is performed during the process, the mixture is uniformly mixed, then filtration is performed, the filter cake is soaked with acetone, the molar ratio of the acetone and the magnesium turnings is 4.5-5.5:1, and the wet magnesium turnings are dried at 30-40 ℃ under vacuum to obtain the treated magnesium turnings.

[0046] Further, the preparation process of the intermediate JQA B01 comprises:

[0047] (1) The intermediate JQA01 is added into 2-methyltetrahydrofuran, stirring is performed, the temperature is reduced to -20--10 ℃ under a nitrogen atmosphere, the intermediate JQA B01 is added, temperature control reaction is performed, and JQA02 is obtained.

[0048] (2) The JQA02 is added into a saturated aqueous ammonium chloride solution, hydrochloric acid a is added dropwise into the system, standing and layering are performed, and the organic phase, i.e., the 2-methyltetrahydrofuran solution of JQA02, is obtained.

[0049] (3) Hydrochloric acid b is added into the 2-methyltetrahydrofuran solution of JQA02, temperature control reaction is performed, standing and layering are performed, and the organic phase is reserved.

[0050] (4) The organic phase in (3) is washed with saturated sodium bicarbonate solution for 2-3 times, washed with 2-4 wt% sodium chloride solution, the organic phase is obtained by standing, concentrated under reduced pressure, recrystallized, centrifuged and dried to a moisture content of less than 0.4%, and discharged to obtain JQA03.

[0051] Further, in step (1), the feed 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 -20-0℃ for 1-3 h;

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

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

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

[0055] Further, the preparation process of the intermediate JQA05 comprises:

[0056] (1) JQA03 and palladium-carbon are added to anhydrous ethanol, anhydrous formic acid is added, air is replaced with nitrogen for 2-4 times, nitrogen is replaced with hydrogen for 2-4 times, hydrogen is pressurized to 0.45-0.55 MPa, temperature-controlled reaction is carried out, and palladium-carbon is removed by filtration to obtain a JQA04 reaction liquid;

[0057] (2) The JQA04 reaction liquid is warmed to 75-85℃, L-tartaric acid is added, the temperature is first lowered to 45-55℃ for crystallization for 0.5-1.5 h, then the temperature is lowered to 0-20℃ for crystallization for 0.5-1.5 h, suction filtration is carried out, ethanol aqueous solution is added for beating, the temperature is lowered for crystallization, centrifugation is carried out to dryness to a moisture content of less than 15%, and the product is discharged to obtain the intermediate JQA05.

[0058] Further, in step (1), the mass ratio of JQA03 to palladium-carbon is 1:0.05-0.07; the feed 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 DEG C for 6-10 h.

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

[0060] Further, the preparation process of the JQA comprises:

[0061] (1) according to the feed liquid ratio of 1:0.8-1.0 g / mL, intermediate JQA05 is added into purified water, under the nitrogen atmosphere, the temperature is raised to 75-85 DEG C, anhydrous ethanol is added, the feed liquid ratio of JQA05 to ethanol is 1:6-10 g / mL, and the temperature is kept for 0.5-1.5 h, first, the temperature is reduced to 45-55 DEG C for crystallization for 0.5-1.5 h, then the temperature is reduced to 0-15 DEG C for crystallization for 0.5-1.5 h, and the filter cake is obtained by filtration;

[0062] (2) the filter cake is added into isopropyl alcohol, the feed liquid ratio of JQA05 to isopropyl alcohol is 1:6-10 g / mL, the temperature is raised to 45-55 DEG C for beating for 0.5-1.5 h, the temperature is reduced to 0-10 DEG C for crystallization for 0.5-1.5 h, and JQA, i.e., metaraminol bitartrate, is obtained by vacuum drying.

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

[0064] 1、 the present application uses N-benzyloxy carbonyl-L-alanine and 3-benzyloxy bromobenzene as starting materials at the same time, which are low in cost and easy to obtain, can reduce the reaction steps, avoid the risk of increasing impurities caused by the synthesis of the mother nucleus, can be controlled by a conventional and accurate method, has good process reproducibility, and is suitable for commercial production.

[0065] 2、 the metaraminol bitartrate obtained by the synthesis method of the present application has high yield, up to 80%, high purity, up to 99.993%, low total impurity content, low non-specific single impurity, no impurities A and B are detected, and no diastereoisomer is detected.

[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 examples are provided below to further illustrate the present invention.

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

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

[0070] Abbreviations Material Name JQA00 N-benzyloxycarbonyl-L-alanine JQAB00 3-benzyloxybromobenzene

[0071] The JQA00 of the present invention is sourced from Changzhou Huaren Chemical Co., Ltd.; 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 and benzyl chloroformate, followed by post-treatment.

[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 produced 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), para-toluenesulfonic acid (308.56 mg, 0.1 eq) and paraformaldehyde (699.44 mg, 1.3 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% aqueous sodium bicarbonate 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 crystallized for 2 h, centrifuged and dried to a moisture content of less than 0.2%, and the product was discharged to obtain intermediate JQA01.

[0085] Test results of intermediate JQA01

[0086]

[0087] S2, Preparation process of intermediate JQAB01

[0088] JQAB00 (5.0 g, 1.0 eq) was weighed out, 10% of JQAB00 (0.5 g, 10%) was removed and mixed with magnesium turnings (600.39 mg, 1.3 eq) and iodine (48.23 mg, 0.01 eq) in 2-methyltetrahydrofuran (5 mL, 1 mL / g) and stirred, the temperature was raised to 40°C, and the reaction was carried out for 2 h, the remaining 3-benzyloxybromobenzene (4.5 g, 90%) was added, the temperature was raised to 60°C, and the reaction was carried out for 1 h to obtain intermediate JQAB01.

[0089] The magnesium turnings were treated as follows: magnesium turnings were added to a 10 wt% hydrochloric acid solution in a molar ratio of 1:8.8, stirring was carried out during the addition, the mixture was filtered under suction after being well mixed, the filter cake was soaked in acetone, the molar ratio of acetone to magnesium turnings was 5:1, and the wet magnesium turnings were dried under vacuum at 35°C to obtain treated magnesium turnings.

[0090] S3, Preparation process of intermediate JQA03

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

[0092] (2) Add JQA02 into saturated ammonium chloride aqueous solution (40 mL, 1 mL / g), drop hydrochloric acid a (120 mL, 3 mL / g) into the system, stand to separate layers, and obtain the organic phase, i.e. 2-methyltetrahydrofuran solution of JQA02;

[0093] (3) Add hydrochloric acid b (320 mL, 8 mL / g) into the 2-methyltetrahydrofuran solution of JQA02, and react at 50℃ for 8 h, stand to separate layers, and reserve the organic phase;

[0094] (4) Wash the organic phase in (3) twice with saturated sodium bicarbonate (200 mL, 5 mL / g), wash with 3 wt% sodium chloride solution (200 mL, 5 mL / g), stand to take the organic phase, concentrate under reduced pressure, add methanol (24 mL, 3 mL / g) for recrystallization, stand at 0℃ for 1 h for crystallization, centrifuge and dry until the moisture content is less than 0.4%, and discharge to obtain JQA03.

[0095] Test results of intermediate JQA03

[0096]

[0097] S4, preparation process of intermediate JQA05

[0098] (1) Add JQA03 (1.0 g, 1.0 eq) and palladium-carbon (50 mg, 5%) into anhydrous ethanol (8 mL, 8 mL / g), add anhydrous formic acid (0.59 g, 5.0 eq), replace air with nitrogen for 3 times, replace nitrogen with hydrogen for 3 times, pressurize hydrogen to 0.5 MPa, control the temperature at 30℃, stand to stir for 8 h, remove the palladium-carbon by filtration, and obtain JQA04 reaction liquid;

[0099] (2) Warm the JQA04 reaction liquid to 80℃, add L-tartaric acid (3.85 g, 1.0 eq), first cool to 50℃ for 1 h for crystallization, then cool to 10℃ for 1 h for crystallization, suction filter, add into ethanol aqueous solution (16 mL+1 mL, 8 mL / g+0.5 mL / g), warm to 50℃ for 0.5 h for beating, cool to 15℃ for 1 h for crystallization, centrifuge and dry until the moisture content is less than 15%, and discharge to obtain intermediate JQA05.

[0100] Test results of intermediate JQA05

[0101]

[0102] S5, preparation process of JQA

[0103] (1) The intermediate JQA05 (2.0 g, 1.0 eq) was added to purified water (2 mL, 1 mL / g) under a nitrogen atmosphere, and heated to 80°C. Anhydrous ethanol (16 mL, 8 mL / g) was added, and after stirring at constant temperature for 1 h, the temperature was lowered to 50°C, and the mixture was crystallized for 1 h. After the temperature was lowered to 10°C and the mixture was crystallized for 1 h, the mixture was filtered to obtain a filter cake;

[0104] (2) The filter cake was added to isopropyl alcohol (12 mL, 6 mL / g), and the mixture was slurried at 50°C for 1 h. The temperature was lowered to 10°C, and the mixture was crystallized for 1 h. The solid was dried under vacuum at 50°C to obtain JQA, i.e., m-hydroxy amine bitartrate.

[0105] Test results of m-hydroxy amine bitartrate

[0106]

[0107] In other embodiments,

[0108] In the preparation process of intermediate JQA01, in step (1) of S1, the molar ratio of N-benzyloxy carbonyl-L-alanine, polyformaldehyde and p-toluenesulfonic acid was 1:1.1-1.3:0.06-0.14, the solid-liquid ratio of N-benzyloxy carbonyl-L-alanine to toluene was 1:4-6 g / mL, the reaction was stirred at 40-60°C for 4-5 h, the temperature was lowered to 25-35°C, the concentration of sodium bicarbonate aqueous solution was 4-6 wt%, the solid-liquid ratio of N-benzyloxy carbonyl-L-alanine to sodium bicarbonate aqueous solution was 1:4-6 g / mL, and the washing was performed 2-3 times; in step (2) of S1, the solid-liquid ratio of N-benzyloxy carbonyl-L-alanine to petroleum ether was 1:4-6 g / mL, and the temperature was lowered to -10-10°C for 1-3 h for crystallization;

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

[0110] In the preparation process of S3, 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 1:6-10 g / mL, the concentration of hydrochloric acid b is 4-6 mol / L, and the temperature reaction is carried out at 50-60°C for 6-10 h; in step (4), the material-liquid ratio of JQA01 to saturated sodium bicarbonate is 1:4-6 g / mL, the material-liquid ratio of JQA01 to sodium chloride solution is 1:4-6 g / mL, the recrystallization solvent is methanol, wherein the material-liquid ratio of JQA01 to methanol is 1:3-5 g / mL, the crystallization temperature is -155°C, and the crystallization time is 1-2 h;

[0111] S4, in the preparation process of the 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-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 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 hours;

[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 cooling crystallization is first performed by cooling to 45-55°C for crystallization for 0.5-1.5 h, and then cooling to 0-15°C for crystallization for 0.5-1.5 h; in step (2), the solid-liquid ratio of JQA05 to isopropanol is 1:6-10 g / mL, heating beating is beating at 45-55°C for 0.5-1.5 h, and cooling crystallization is cooling to 0-10°C for crystallization 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 the toluene in the preparation process of intermediate JQA01 is replaced by acetonitrile, methanol, ethyl acetate, tetrahydrofuran, ethanol or 2-methyltetrahydrofuran, respectively, and the others are consistent with Example 1.

[0116]

[0117] From the above table, it can be seen that the reaction effect of toluene in Example 1 as a reaction solvent is good, and the reaction effect of other solvents in Comparative Example 1 is poor. The raw material residue and the content of intermediate JQA01 in the reaction solvent system of Example 1 are better than those in Comparative Example 1. The other solvents in Comparative Example 1 are not conducive to the purity and yield of the subsequent product.

[0118] Comparative Example 2

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

[0120]

[0121]

[0122] From the above table, it can be seen that the 2-methyltetrahydrofuran in Example 1 can successfully initiate the reaction. The toluene, acetonitrile and methyl tert-butyl ether in Comparative Example 2 as reaction solvents do not initiate the reaction. Although the tetrahydrofuran in Comparative Example 2 can also initiate, but the post-treatment is more complex, and additional extraction operation is needed, 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 intermediate JQA03 is replaced by ethanol or isopropanol, and the others are consistent with Example 1.

[0125]

[0126] From the above table, it can be seen that when the recrystallization solvent in Example 1 is methanol, the purity and yield are better than those 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 others are consistent with Example 1.

[0129]

[0130]

[0131] As seen from the above table, the tetrahydrofuran of Comparative Example 4 has a very low pulping yield and impurities are produced by condensation with primary amines during the acetone refining, so that isopropyl alcohol of Example 1 is the best choice.

[0132] The above description is merely the preferred embodiment of this application, and is not used to limit the scope of the application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the application shall fall within the scope of the protection of the application.

Claims

1. A process for the synthesis of metaraminol bitartrate, characterized in that, The specific steps include: S1, preparation process of intermediate JQA01 (1) N-benzyloxy carbonyl-L-alanine, para-toluene sulfonic acid and polyformaldehyde are added into toluene to react, cooled, washed, and the organic phase is reserved; (2) The organic phase is added into petroleum ether to cool and crystallize to obtain the intermediate JQA01; The structural formula of the intermediate JQA01 is: S2, preparation process of intermediate JQAB01 The formula amount of 8-12% of 3-benzyloxy bromobenzene is weighed, and the magnesium chips and iodine are added into 2-methyl tetrahydrofuran to react, and the rest of the 3-benzyloxy bromobenzene is added to continue the reaction to obtain the intermediate JQAB01; The structural formula of the intermediate JQAB01 is: S3, preparation process of intermediate JQA03 (a) JQA01 is added into 2-methyl tetrahydrofuran to cool, and JQAB01 is added to react to obtain JQA02; (b) JQA02 is added into saturated ammonium chloride aqueous solution, and hydrochloric acid a is added dropwise into the system, and the system is allowed to stand to separate into two layers to obtain the organic phase; (c) Hydrochloric acid b is added into the organic phase to react at a high temperature, and the system is allowed to stand to separate into two layers, and the organic phase is reserved, and concentrated under reduced pressure, and recrystallized 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 (A) JQA03 and palladium-carbon are added into anhydrous ethanol, and anhydrous formic acid is added, and the air is replaced by nitrogen for 2-4 times, and the nitrogen is replaced by hydrogen for 2-4 times, and the hydrogen is pressurized to 0.45-0.55 MPa, and the reaction is controlled at a temperature, and the palladium-carbon is removed by filtration to obtain JQA04 reaction liquid; (B) The JQA04 reaction liquid is warmed, and L-tartaric acid is added to cool and crystallize to obtain the intermediate JQA05; The structural formula of the JQA04 is: The structural formula of the JQA05 is: S5, preparation process of JQA (I) JQA05 is added into purified water to warm, and anhydrous ethanol is added, and the system is stirred at a constant temperature, and cooled to crystallize, and filtered to obtain a filter cake; (II) The filter cake is added into isopropyl alcohol to warm and beat, and cooled to crystallize to obtain JQA, i.e. methylenediamine hydrochloride.

2. A process for the synthesis of metaraminol bitartrate according to claim 1, characterized in that, The preparation process of the intermediate JQA01 includes: (1) N-benzyloxy carbonyl-L-alanine, para-toluene sulfonic acid and polyformaldehyde are added into toluene, and stirred at 40-60℃ for 4-5h, and cooled to 25-35℃, and washed with sodium bicarbonate aqueous solution for 2-3 times, and the organic phase is reserved; (2) The organic phase is added into petroleum ether to cool and crystallize, and centrifuged and dried to less than 0.2% of water content, and discharged to obtain the intermediate JQA01.

3. The synthesis process of methylenediamine hydrochloride according to claim 2, wherein In step (1), the molar ratio of N-benzyloxy carbonyl-L-alanine, polyformaldehyde and para-toluene sulfonic acid is 1:1.1-1.3:0.06-0.14; the solid-liquid ratio of N-benzyloxy carbonyl-L-alanine and toluene is 1:4-6 g / mL; the concentration of sodium bicarbonate aqueous solution is 4-6 wt%; and the solid-liquid ratio of N-benzyloxy carbonyl-L-alanine and sodium bicarbonate aqueous solution is 1:4-6 g / mL; In step (2), the solid-liquid ratio of N-benzyloxy carbonyl-L-alanine and petroleum ether is 1:4-6 g / mL; and the temperature is cooled to -10-10℃ for 1-3h to cool and crystallize.

4. A process for the synthesis of metaraminol bitartrate as claimed in claim 1, wherein, The preparation process of the intermediate JQAB01 comprises: taking the formula amount of 8-12% of 3-benzyloxybromobenzene, mixing and stirring with magnesium turnings and iodine in 2-methyltetrahydrofuran, replacing with nitrogen, increasing the temperature to 30-50℃, and reacting for 1-2h; adding the remaining 3-benzyloxybromobenzene, increasing the temperature to 50-70℃, and reacting for 0.5-1.5h; The molar ratio of the 3-benzyloxybromobenzene, the magnesium turnings and the iodine is 1:1.1-1.3:0.01-0.03; and the solid-liquid ratio of the 3-benzyloxybromobenzene and the 2-methyltetrahydrofuran is 1:1-1.5g / mL.

5. A process for the synthesis of metaraminol bitartrate as claimed in claim 4 wherein, The magnesium turnings are used as raw materials after treatment, and the specific treatment operation is as follows: according to the molar ratio of 1:8.2-9.4, the magnesium turnings are added into a hydrochloric acid solution with a concentration of 8-12wt%, stirring is performed during the process, the mixture is uniformly mixed, then filtration is performed, the filter cake is soaked with acetone, the molar ratio of the acetone and the magnesium turnings is 4.5-5.5:1, and the wet magnesium turnings are dried under vacuum at 30-40℃ to obtain the treated magnesium turnings.

6. A process for the synthesis of metaraminol bitartrate as claimed in claim 1, wherein, The preparation process of the intermediate JQA03 comprises: (a) stirring the intermediate JQA01 in 2-methyltetrahydrofuran, reducing the temperature to-20 to-10℃ under a nitrogen atmosphere, adding the intermediate JQAB01 for temperature control reaction to obtain JQA02; (b) adding the JQA02 into a saturated ammonium chloride aqueous solution, adding hydrochloric acid a dropwise into the system, standing and separating the layers to obtain an organic phase, i.e., a 2-methyltetrahydrofuran solution of JQA02; (c) adding hydrochloric acid b into the 2-methyltetrahydrofuran solution of JQA02 for temperature increasing reaction, standing and separating the layers to retain the organic phase; (d) washing the organic phase in (c) with saturated sodium bicarbonate for 2-3 times, adding a 2-4wt% sodium chloride solution for washing, standing to take the organic phase for vacuum concentration, recrystallization, centrifugal drying until the moisture content is less than 0.4%, and discharging to obtain JQA03.

7. The synthesis process of m-hydroxyamphetamine heavy tartrate acid according to claim 6, characterized in that, In step (a), the solid-liquid ratio of the intermediate JQA01 and the 2-methyltetrahydrofuran is 1:2-4g / mL; and the molar ratio of the intermediate JQA01 and the intermediate JQAB01 is 1:1.1-1.3; and the temperature control reaction is performed at-20 to 0℃ for 1-3h; In step (b), the solid-liquid ratio of the JQA01 and the saturated ammonium chloride aqueous solution is 1:0.8-1.2g / mL; and the solid-liquid ratio of the JQA01 and the hydrochloric acid a is 1:2-4g / mL, and the concentration of the hydrochloric acid a is 2-4mol / L; In step (c), the solid-liquid ratio of the JQA01 and the hydrochloric acid b is 1:6-10g / mL, and the concentration of the hydrochloric acid b is 4-6mol / L; and the temperature increasing reaction is performed at 50-60℃ for 6-10h; In step (d), the ratio of JQA01 to saturated sodium bicarbonate solution is 1:4-6 g / mL; the ratio of JQA01 to sodium chloride solution is 1:4-6 g / mL; the solvent for recrystallization is methanol, wherein the ratio of JQA01 to methanol is 1:3-5 g / mL, the crystallization temperature is -15-5 ℃, and the crystallization time is 1-2 h.

8. A process for the synthesis of metaraminol bitartrate as claimed in claim 1, wherein, The preparation process of the intermediate JQA05 comprises: (A) adding JQA03 and palladium-carbon into anhydrous ethanol, adding anhydrous formic acid, replacing air with nitrogen for 2-4 times, replacing nitrogen with hydrogen for 2-4 times, pressurizing hydrogen to 0.45-0.55 MPa, controlling temperature for reaction, and removing palladium-carbon by filtration to obtain JQA04 reaction solution; (B) heating JQA04 reaction solution to 75-85 ℃, adding L-tartaric acid, first cooling to 45-55 ℃ for crystallization for 0.5-1.5 h, then cooling to 0-20 ℃ for crystallization for 0.5-1.5 h, suction filtration, adding ethanol aqueous solution for beating, cooling for crystallization, centrifugal drying until the water content is less than 15%, discharging, and obtaining the intermediate JQA05.

9. The synthesis process of mephentermine heavy tartrate according to claim 8, characterized in that, In step (A), the mass ratio of JQA03 to palladium-carbon is 1:0.05-0.07; the 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 ℃ for 6-10 h; In step (B), the molar ratio of JQA03 to L-tartaric acid is 1:1-1.4; the ratio of JQA03 to ethanol in the ethanol aqueous solution is 1:8-10 g / mL, and the ratio of JQA03 to water in the ethanol aqueous solution is 1:0.5-0.7 g / mL; the beating temperature is 40-70 ℃, and the beating time is 20-40 min; and the crystallization temperature is 10-20 ℃, and the crystallization time is 0.5-1.5 h.

10. A process for the synthesis of metaraminol bitartrate as claimed in claim 1 wherein, The preparation process of the JQA comprises: (I) adding the intermediate JQA05 into purified water according to a ratio of 1:0.8-1.0 g / mL, heating to 75-85 ℃ under a nitrogen atmosphere, adding anhydrous ethanol, the ratio of JQA05 to ethanol being 1:6-10 g / mL, and stirring for 0.5-1.5 h, first cooling to 45-55 ℃ for crystallization for 0.5-1.5 h, then cooling to 0-15 ℃ for crystallization for 0.5-1.5 h, and suction filtration to obtain a filter cake; (II) adding isopropyl alcohol into the filter cake, the ratio of JQA05 to isopropyl alcohol being 1:6-10 g / mL, heating to 45-55 ℃ for beating for 0.5-1.5 h, cooling to 0-10 ℃ for crystallization for 0.5-1.5 h, and vacuum drying to obtain JQA, i.e., mephentermine heavy tartrate.

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