Production method of lobeline hydrochloride

Abstract

The invention mainly relates to the technical field of heterocyclic compounds. According to the production process of lobeline hydrochloride, LBL00 and a glutaraldehyde aqueous solution are used as starting materials, LBL00 is hydrolyzed to obtain LBL01, LBL01 and glutaraldehyde react to construct a key intermediate LBL02, LBL02 is reduced to obtain LBL03, the intermediate LBL03 is subjected to catalytic acylation through a chiral ligand to obtain an intermediate LBL04, the intermediate LBL04 is oxidized to obtain an intermediate LBL05, the intermediate LBL05 is hydrolyzed to obtain an intermediate LBL06, and the intermediate LBL06 is subjected to hydrolysis to obtain the lobeline hydrochloride. And decolorizing the intermediate LBL06, recrystallizing, drying and sub-packaging to obtain LBL, namely lobeline hydrochloride. Compared with the prior art, the materials LBL00 and glutaraldehyde are the main chemical structure fragments of LBL, the reaction steps can be reduced by selecting the materials as the starting materials, and the risk of impurity increase in the synthesis process can be avoided.

Description

Technical Field

[0001] The present invention relates to the technical field of heterocyclic compounds, and in particular to a production method of lobeline hydrochloride. Background Art

[0002] Lobeline hydrochloride, also known as lobeline theophylline, is an alkaloid extracted from lobelia. Lobeline hydrochloride can stimulate the carotid sinus and aortic body chemoreceptors (both N1 receptors), reflexively excite the respiratory center and accelerate respiration, but has no direct excitatory effect on the respiratory center. It also has a reflex excitatory effect on the vagus nerve center and vasomotor center at the same time; it first excites and then blocks the autonomic ganglia. Clinically, it is applicable to neonatal asphyxia, inhalation anesthetics and other central inhibitors such as morphine or barbiturate poisoning, asphyxia caused by carbon monoxide, and respiratory failure caused by infectious diseases such as pneumonia and diphtheria. The original research patent of lobeline hydrochloride has not been found yet, and only some related patents and literature have been found. Calculated according to its time of approval for listing in the United States, the original research patent of this compound has expired. Our company combined the synthetic routes of lobeline hydrochloride reported in relevant domestic and foreign patent documents, and finally determined our synthetic process through exploration.

[0003] In the prior art, the synthesis is usually carried out through the following process. Li Wensen, Zhang Wenqi, etc. invented a method for lobeline hydrochloride, using 3,4-dihydro-2H-pyran as the starting material, and obtaining the target product through ring-opening reaction, oxidation reaction, dehydration reaction, addition reaction, reduction reaction, protection reaction, substitution reaction, hydrolysis reaction, coupling reaction and hydrolysis ring-closure reaction; this route uses the introduction of chiral auxiliaries to determine the configuration preferentially, but the synthesis route is long, the introduction of ethanethiol and boron trifluoride will make the post-treatment cumbersome, and the total yield is relatively low, which is not suitable for industrial production. The synthesis route reported by Francois-Xavier Felpin et al. studied four chiral centers and carried out individual syntheses; this route focused on the four chiral centers and constructed them one by one, failed to utilize the structural advantages of desymmetrization, and had a long route and low yield, which was not suitable for industrial production. Franz-Dietrich et al. designed a method for a key intermediate of lobeline hydrochloride, using benzoylacetic acid as the starting material, and preparing the key intermediate through asymmetric reduction synthesis using metal rhodium complex and bidentate phosphine ligand, and further synthesizing the target product; this route uses metal rhodium complex and bidentate phosphine ligand to prepare the key intermediate through asymmetric reduction synthesis, and the target product can be synthesized in one step. The synthesis of this catalyst is difficult and expensive, and this step requires a high-pressure condition of 1520 bar, with low preparation purification and yield, and it is difficult to be used in industrial production. Wu Xuan, Zou Zejin, Hu Zhenyu, etc. designed a method for enzymatic catalytic chiral reduction synthesis of lobeline hydrochloride, using benzoylacetic acid as the raw material, and obtaining the target product through condensation reaction and enzymatic catalytic chiral reduction reaction; this route selects the enzymatic catalytic reaction of selective reduction, the process route is relatively short, and the raw materials are easy to obtain, but the yield of the enzymatic reaction is small, the cost is high, the enzyme stability is poor, and it is not easy to preserve, which is not suitable for industrial production. Li Wensen et al. designed a method for chiral synthesis of lobeline hydrochloride, using benzoylacetic acid as the raw material, and obtaining the target product through condensation reaction and selective reduction reaction; the synthesis of the chiral catalyst in this route requires acylation and two-step substitution reactions, and the obtained chiral catalyst has low chiral purity and low yield, and it is difficult to be used in industrial production. Xuan Yining, Chu Shilin, etc. proposed a method for the preparation of optically pure lobeline hydrochloride and its enantiomer, using benzoylacetic acid, methylamine hydrochloride and glutaraldehyde as raw materials, and the target product can be prepared after condensation reaction, reduction reaction, acylation reaction, resolution, oxidation reaction and hydrolysis reaction in sequence; this route uses benzoylacetic acid as the starting material, the route is long, uses chiral auxiliaries for resolution, the product yield is low, and the final product needs to be prepared and purified, which is not conducive to industrial production.

[0004] CN112920107A discloses a synthesis method of lobeline hydrochloride, that is, using ethyl acetoacetate and benzoyl chloride as raw materials in NaOH, NH 4In the presence of Cl etc., an acylation reaction is carried out to obtain ethyl benzoylacetate. The ethyl benzoylacetate is hydrolyzed in water in the presence of potassium hydroxide to obtain benzoylacetic acid. Then, a condensation reaction is carried out with glutaraldehyde and methylamine hydrochloride in a citric acid buffer solution. Lobeline dione hydrochloride obtained from the condensation reaction is subjected to a reduction reaction in a mixed solution composed of potassium borohydride, activated carbon, sodium hydroxide and methanol. The obtained reaction solution is quenched with sulfuric acid to inactivate the reducing agent, and then filtered, extracted, concentrated, and cooled and crystallized to obtain racemic lobeline. Then, L-DBTA is added, and after resolution, liberation, and hydrochlorination in sequence, lobeline hydrochloride is obtained. The synthesis method of this invention uses ethyl acetoacetate and benzoyl chloride as raw materials, and synthesizes lobeline hydrochloride through four steps of reactions in sequence. Among them, the steps include resolving the lobeline dione hydrochloride intermediate to obtain racemic lobeline hydrochloride. Although the synthesis steps are few, the yield is also low, the utilization rate of drug raw materials is low, and the production cost is high.

[0005] CN105198795A discloses a preparation process of lobeline hydrochloride, which includes the following steps: Under stirring, at room temperature, add levo-lobeline, absolute ethanol and methyl tert-butyl ether into a reactor in sequence, and mix evenly to obtain a mixture a; add a hydrogen chloride-ethanol solution with a mass percentage concentration of 10% - 25% to the mixture a, then start to slowly heat up, with a heating rate of 2 - 4 °C / min. When reflux appears, stop heating up, keep the temperature for reaction for 0.5 - 2 h, and stop stirring; then cool down to 0 - 5 °C, crystallize for 4 - 6 h, and filter to obtain a filter cake; wash the filter cake with methyl tert-butyl ether and absolute ethanol once each, and collect the product; dry it by blowing air at a temperature of 45 - 60 °C to obtain a white crystalline powder, which is the product. This invention synthesizes lobeline hydrochloride with levo-lobeline as the raw material, and improves the yield and reduces the cost by reducing the resolution step of the racemate. Summary of the Invention

[0006] In view of the above-mentioned defects of the prior art, the technical problem to be solved by this invention is to provide a production method of synthesizing lobeline hydrochloride with ethyl benzoylacetate as the initial raw material. This method does not need to carry out a racemization step, and the yield can reach 70 - 90%.

[0007] To achieve the above purpose, this invention provides a production method of lobeline hydrochloride.

[0008] The process flow chart of the production method of the said lobeline hydrochloride is as Figure 1 shown, and is briefly described as follows: LBL00 → LBL01 → LBL02 → LBL03 → LBL04 → LBL05 → LBL06 → LBL, where LBL00 refers to ethyl benzoylacetate, LBL refers to lobeline hydrochloride, and LBL01, LBL02, LBL03, LBL04, LBL05, LBL06 respectively refer to the intermediates in the synthesis of lobeline hydrochloride from ethyl benzoylacetate.

[0009] The production method of lobeline hydrochloride includes the following steps, in parts by weight:

[0010] (1) Synthesis of LBL01 from LBL00:

[0011] ① Charging: Add 90 - 110 parts of water, 4.48 - 4.68 parts of sodium hydroxide to the reactor and start stirring; add 19.9 - 20.1 parts of ethyl benzoylacetate and continue stirring. Determine the reaction end point by HPLC inspection.

[0012] ② Post - treatment: Continuously add 122.5 - 142.5 parts of dichloromethane to the reactor and start stirring. Let it stand and separate the liquid phases, retaining the aqueous phase; add dilute hydrochloric acid dropwise to adjust the pH to 1 - 2, crystallize for 0.5 - 1.5 h, centrifuge until dry. Wash the filter cake with 19 - 21 parts of water for 2 - 4 times, centrifuge until dry to obtain the undried wet product, that is, the intermediate LBL01.

[0013] (2) Synthesis of LBL02 from LBL01:

[0014] ① Charging: Add 95.5 - 105.5 parts of water, 0.36 - 0.42 parts of acetic acid, 0.26 - 0.32 parts of sodium acetate, 2.91 - 3.01 parts of methylamine hydrochloride and 36.7 - 42.7 parts of methyl tert - butyl ether to the reactor and start stirring. Add the intermediate LBL01, 6.6 - 6.8 parts of glutaraldehyde aqueous solution, and stir at 15 - 25 °C for 14 - 16 h to reach the reaction end point.

[0015] ② Post - treatment: Control the temperature in the kettle to 5 - 15 °C, add dilute hydrochloric acid dropwise to adjust the pH to 1 - 2, keep warm and crystallize for 0.5 - 1.5 h, centrifuge until dry. Wash the filter cake with 9.1 - 11.1 parts of methyl tert - butyl ether for 2 - 4 times, and continue to centrifuge until dry to obtain the undried wet product LBL01.

[0016] ③ Purification: Transfer the undried wet product LBL01 to the reactor, add 14.8 - 16.8 parts of absolute ethanol, 27.7 - 31.7 parts of methyl tert - butyl ether, beat for 1 - 2 h, centrifuge. Wash the filter cake with 4.6 - 5.6 parts of methyl tert - butyl ether for 2 - 4 times, centrifuge until dry, and dry for 10 - 14 h. Take a sample for inspection to obtain the intermediate LBL02.

[0017] (3) Synthesis of LBL03 from LBL02:

[0018] ① Charging: Add 58.2 - 68.2 parts of absolute ethanol and the intermediate LBL02 to the reactor and start stirring. Add 2.42 - 2.46 parts of sodium borohydride in 3 - 5 batches, keep warm and react at - 5 - 5 °C for 1 - 2 h, then raise the temperature to 15 - 25 °C and keep warm and react for 1 - 2 h. Determine the reaction end point by HPLC inspection.

[0019] ② Post-treatment: Cool down to -5 to 15 °C, add dilute hydrochloric acid dropwise to adjust the pH to 1 to 2, keep warm and stir for 1.5 to 2.5 h, centrifuge until dry, wash the filter cake with 7.5 to 8.5 parts of drinking water for 2 to 4 times, centrifuge until dry, then the crude product of LBL03 is obtained and the stirring is started;

[0020] ③ Purification:

[0021] Pump sodium hydroxide aqueous solution and 101.0 to 111.0 parts of dichloromethane into the reactor, add the crude product of LBL03, stir for 0.5 to 1 h, separate the liquid and retain the organic phase; pump the organic phase into the reactor, pump in 75.0 to 85.0 parts of water, stir for 10 to 15 min, separate the liquid and retain the organic phase; pump the organic phase into the reactor, pump in sodium chloride aqueous solution and stir for 10 to 15 min, separate the liquid and retain the organic phase; transfer the organic phase to the reactor for concentration until no obvious distillate flows out, add 3.2 to 4.2 parts of absolute ethanol, continue to concentrate under reduced pressure for 1 to 2 h, pump in 17.9 to 19.9 parts of absolute ethanol, stir at 65 to 75 °C until dissolved clearly, crystallize at 5 to 15 °C for 0.5 to 1 h, pump in 22.0 to 26.0 parts of water, keep warm and crystallize for 1 to 2 h, centrifuge until dry, wash the filter cake with ethanol aqueous solution for 2 to 4 times, centrifuge until dry; dry for 10 to 14 h, take a sample for inspection, then the intermediate LBL03 is obtained;

[0022] (4) Synthesis of LBL04 from LBL03:

[0023] ① Feeding: Add 54.2 to 60.2 parts of dichloromethane, intermediate LBL03, 1.73 to 1.93 parts of N,N - diisopropylethylamine, 1.91 to 2.11 parts of anhydrous sodium sulfate and 0.62 to 0.82 parts of catalyst into the reactor, add propionic anhydride solution dropwise, keep warm and react for 12 h, determine the reaction end point by HPLC inspection;

[0024] ② Post-treatment: Pump 43.0 to 53.0 parts of water into the reactor and stir for 10 to 15 min, separate the liquid and retain the organic phase; pump the organic phase into the reactor, pump in 43.0 to 53.0 parts of water, stir for 10 to 15 min, separate the liquid and retain the organic phase; pump the organic phase into the reactor, pump in sodium chloride aqueous solution, stir for 10 to 15 min, separate the liquid and retain the organic phase, then the dichloromethane solution containing intermediate LBL04 is obtained;

[0025] (5) Synthesis of LBL05 from LBL04:

[0026] ① Feeding: Add the dichloromethane solution containing intermediate LBL04 into the reactor, add Jones reagent dropwise, keep warm and react at 15 to 25 °C for 1 to 2 h, determine the reaction end point by HPLC inspection;

[0027] ②Post-treatment: Draw in 2N dilute hydrochloric acid, stir for 10 - 15 min, separate the liquid and retain the organic phase; Draw the organic phase into the reactor, draw in 2N dilute hydrochloric acid, stir for 10 - 15 min, separate the liquid and retain the organic phase;

[0028] ③Purification: Draw the organic phase into the reactor, draw in an aqueous sodium chloride solution, stir for 10 - 15 min, separate the liquid and retain the organic phase; Transfer the organic phase to the reactor, concentrate at 35 - 45 °C until no obvious distillate flows out, continue to concentrate under reduced pressure at 55 - 65 °C for 1 - 2 h to obtain the intermediate LBL05;

[0029] (6) Synthesis of LBL06 from LBL05:

[0030] ①Charging: Draw 14.7 - 15.7 parts of absolute ethanol, 2.7 - 3.1 parts of concentrated hydrochloric acid and 2.7 - 3.1 parts of water into the reactor, stir at a speed of 200 - 300 rpm, control the temperature in the kettle at 70 - 80 °C, react for 20 - 22 h, and determine the reaction end point by HPLC inspection;

[0031] ②Post-treatment: Control the temperature in the kettle at 65 - 75 °C, draw in 37.0 - 39.0 parts of methyl tert-butyl ether, stir at a speed of 200 - 300 rpm, keep the temperature in the kettle at 35 - 45 °C for heat preservation and crystallization for 0.5 - 1.5 h, and keep the temperature at 15 - 25 °C for heat preservation and crystallization for 0.5 - 1.5 h; Put it into a centrifuge for centrifugation, wash the filter cake with an absolute ethanol-methyl tert-butyl ether mixed solution for 2 - 4 times, and centrifuge until dry to obtain the crude product of LBL06;

[0032] ③Purification: Add 14.7 - 15.7 parts of absolute ethanol, 0.5 - 0.7 parts of concentrated hydrochloric acid and the crude product of LBL06 to the reactor, stir and dissolve until clear at 65 - 75 °C, add 28.4 - 32.4 parts of methyl tert-butyl ether, and crystallize at 15 - 25 °C for 1.5 - 2.5 h; Put it into a centrifuge for centrifugation, wash the filter cake with an absolute ethanol-methyl tert-butyl ether mixed solution for 2 - 4 times, and centrifuge until dry, then put it into a vacuum drying oven and dry for 10 - 14 h, take a sample for inspection to obtain the intermediate LBL06;

[0033] (7) Synthesis of LBL from LBL06:

[0034] ①Dissolution and decolorization: Add the intermediate LBL06, 7.6 - 8.6 parts of absolute ethanol, 1.12 - 1.52 parts of concentrated hydrochloric acid, 0.95 - 1.35 parts of water and 0.18 - 0.28 parts of activated carbon to the reactor, keep stirring at 55 - 65 °C for 0.5 - 1.5 h, transfer to a stainless steel pressure filter tank and filter through a micron filter, wash with 0.78 - 0.98 parts of absolute ethanol and filter under pressure;

[0035] ② Crystallization and filtration: Transfer the filtrate to a reactor, control the temperature in the kettle at 55 - 65 °C, pump in 19.4 - 21.4 parts of methyl tert-butyl ether. After adding, keep stirring for 0.5 - 1 h while maintaining the temperature, then cool down to 10 - 20 °C for crystallization for 1 - 2 h; centrifuge until dry, wash the filter cake with 1.53 - 1.93 parts of methyl tert-butyl ether for 2 - 4 times, and centrifuge until dry to obtain the wet product of lobeline hydrochloride;

[0036] ③ Drying, crushing, mixing and packaging: Put the wet product of lobeline hydrochloride into a vacuum drying oven and dry at 20 - 30 °C for 1.5 - 2.5 h, pass through a 15 - 25 mesh sieve, continue drying for 14 - 16 h, take samples for inspection, and then carry out packaging and sealing to obtain the said lobeline hydrochloride.

[0037] Specifically, the production method of the said lobeline hydrochloride includes the following steps, in parts by weight:

[0038] (1) Synthesis of LBL01 from LBL00:

[0039] ① Charging: Add 90 - 110 parts of water, 4.48 - 4.68 parts of sodium hydroxide to a reactor and start stirring, with the stirring speed at 35 - 45 HZ, control the temperature in the kettle at 15 - 25 °C; add 19.9 - 20.1 parts of ethyl benzoylacetate (LBL00), continue stirring at 15 - 25 °C for 20 - 22 h, and determine the reaction end point by HPLC inspection;

[0040] ② Post-treatment: Continue to add 122.5 - 142.5 parts of dichloromethane to the reactor and start stirring, with the stirring speed at 35 - 45 HZ, stir for 10 - 15 min, let stand for 10 - 15 min, separate the liquid, discard the organic phase, and retain the aqueous phase; control the temperature in the kettle at 5 - 15 °C, dropwise add dilute hydrochloric acid (preparation of dilute hydrochloric acid: stir 11.3 - 12.3 parts of concentrated hydrochloric acid and 9.5 - 10.5 parts of water for 0.5 - 1 h) to adjust the pH to 1 - 2, control the stirring speed at 35 - 45 HZ, keep the temperature for crystallization for 0.5 - 1.5 h, put it into a centrifuge and centrifuge until dry, wash the filter cake with 19 - 21 parts of water for 2 - 4 times, and centrifuge until dry to obtain the undried wet product, that is, the intermediate LBL01;

[0041] (2) Synthesis of LBL02 from LBL01:

[0042] ① Charging: Add 95.5 - 105.5 parts of water, 0.36 - 0.42 parts of acetic acid, 0.26 - 0.32 parts of sodium acetate, 2.91 - 3.01 parts of methylamine hydrochloride and 36.7 - 42.7 parts of methyl tert-butyl ether to a reactor and start stirring, with the stirring speed at 30 - 40 HZ, control the temperature in the kettle at 15 - 25 °C, add the intermediate LBL01, 6.6 - 6.8 parts of glutaraldehyde aqueous solution, and keep stirring at 15 - 25 °C for 14 - 16 h to reach the reaction end point;

[0043] ② Post-treatment: Control the temperature in the reactor at 5 - 15°C, the stirring speed at 30 - 40 HZ, add dilute hydrochloric acid dropwise (preparation of dilute hydrochloric acid: stir 3.8 - 4.2 parts of concentrated hydrochloric acid and 3.15 - 3.55 parts of water for 0.5 - 1 h) to adjust the pH to 1 - 2, keep warm and crystallize for 0.5 - 1.5 h, put it into a centrifuge and centrifuge until dry, wash the filter cake with 9.1 - 11.1 parts of methyl tert-butyl ether for 2 - 4 times, continue to centrifuge until dry, and the undried wet product LBL01 is obtained;

[0044] ③ Purification: Transfer the undried wet product LBL01 to a reactor, add 14.8 - 16.8 parts of absolute ethanol and 27.7 - 31.7 parts of methyl tert-butyl ether, slurry at 15 - 25°C and a stirring speed of 300 - 400 rpm for 1 - 2 h, put it into a centrifuge and centrifuge, wash the filter cake with 4.6 - 5.6 parts of methyl tert-butyl ether for 2 - 4 times, centrifuge until dry, put it into a vacuum drying oven, control the temperature of the water tank at 45 - 55°C, dry at a vacuum ≥ -0.080 MPa for 10 - 14 h, take a sample for inspection, and the intermediate LBL02 is obtained;

[0045] (3) Synthesis of LBL03 from LBL02:

[0046] ① Charging: Add 58.2 - 68.2 parts of absolute ethanol and the intermediate LBL02 to the reactor and start stirring, the stirring speed is 30 - 40 HZ, displace with nitrogen for 2 - 4 times, control the temperature in the reactor at -15 - -5°C, add 2.42 - 2.46 parts of sodium borohydride in 3 - 5 equal batches under the condition of controlling the temperature in the reactor at -5 - 0°C, after adding, raise the temperature to -5 - 5°C and keep warm for reaction for 1 - 2 h, then raise the temperature to 15 - 25°C and keep warm for reaction for 1 - 2 h, and determine the end point of the reaction by HPLC inspection;

[0047] ② Post-treatment: Lower the temperature to 5 - 15°C, the stirring speed is 30 - 40 HZ, add dilute hydrochloric acid dropwise (preparation of dilute hydrochloric acid: stir 8.0 - 8.6 parts of concentrated hydrochloric acid and 68.0 - 78.0 parts of water for 0.5 - 1 h) to adjust the pH to 1 - 2, keep warm and stir for 1.5 - 2.5 h, put it into a centrifuge and centrifuge until dry, wash the filter cake with 7.5 - 8.5 parts of water for 2 - 4 times, centrifuge until dry, and the crude product of LBL03 is obtained and start stirring;

[0048] ③ Purification:

[0049] Pump aqueous sodium hydroxide solution (preparation method of aqueous sodium hydroxide solution: add 6.2 - 6.6 parts of sodium hydroxide to 75.0 - 85.0 parts of water and stir for 0.5 - 1 h), 101.0 - 111.0 parts of dichloromethane into the reactor. Add the crude product of LBL03, control the stirring speed at 30 - 40 HZ, control the temperature in the kettle at 20 - 30 °C and keep stirring for 0.5 - 1 h. Let it stand for liquid separation, discard the aqueous phase, and retain the organic phase; Pump the organic phase into the reactor, pump in 75.0 - 85.0 parts of water, stir for 10 - 15 min, let it stand for liquid separation, discard the aqueous phase, and retain the organic phase; Pump the organic phase into the reactor, pump in aqueous sodium chloride solution (preparation of aqueous sodium chloride solution: add 28.3 - 29.3 parts of sodium chloride and 75.0 - 85.0 parts of water and stir for 0.5 - 1 h), stir for 10 - 15 min, let it stand for liquid separation, discard the aqueous phase, and retain the organic phase; Transfer the organic phase to the reactor for concentration, with the stirring speed of 200 - 400 rpm, control the jacket temperature at 55 - 65 °C, the vacuum degree ≥ -0.080 Mpa. Concentrate until no obvious distillate flows out, add 3.2 - 4.2 parts of absolute ethanol. When the jacket temperature rises to 75 - 85 °C and the internal temperature rises to 40 - 85 °C, continue to concentrate under reduced pressure for 1 - 2 h. Pump 17.9 - 19.9 parts of absolute ethanol into it, with the stirring speed of 200 - 400 rpm, heat up to 65 - 75 °C and stir until it becomes clear. Cool down to 5 - 15 °C for crystallization for 0.5 - 1 h. Pump in 22.0 - 26.0 parts of water, keep the temperature for crystallization for 1 - 2 h. Put it into a centrifuge and centrifuge until it is dry. Wash the filter cake with ethanol aqueous solution (preparation of ethanol aqueous solution: add 3.0 - 3.4 parts of absolute ethanol to 3.5 - 4.5 parts of water and stir for 0.5 - 1 h) for 2 - 4 times and centrifuge until it is dry; Put it into a vacuum drying oven, control the water tank temperature at 55 - 65 °C, the vacuum ≥ -0.080 Mpa, dry for 10 - 14 h, take a sample for inspection, and the intermediate LBL03 is obtained;

[0050] (4) Synthesis of LBL04 from LBL03:

[0051] ① Charging: Add 54.2 - 60.2 parts of dichloromethane, intermediate LBL03, 1.73 - 1.93 parts of N,N - diisopropylethylamine, 1.91 - 2.11 parts of anhydrous sodium sulfate and 0.62 - 0.82 parts of catalyst into the reactor. The stirring speed is 200 - 400 rpm. Replace with nitrogen for 2 - 4 times. Control the temperature in the kettle at 15 - 25 °C. Dropwise add propionic anhydride solution (preparation of propionic anhydride solution: add 2.20 - 2.40 parts of propionic anhydride to 5.4 - 7.4 parts of dichloromethane and stir for 0.5 - 1 h). During the dropwise addition, control the internal temperature at 10 - 20 °C. After adding, keep the temperature at 15 - 25 °C for reaction for 10 - 14 h. Determine the reaction end point by HPLC inspection;

[0052] ②Post-treatment: Pump 43.0 - 53.0 parts of water into the reactor, stir at a speed of 400 - 600 rpm for 10 - 15 min, let it stand for layer separation, separate out the aqueous phase and discard it, and retain the organic phase; Pump the organic phase into the reactor, pump in 43.0 - 53.0 parts of water, stir for 10 - 15 min, let it stand for layer separation, separate out the aqueous phase and discard it, and retain the organic phase; Pump the organic phase into the reactor, pump in an aqueous sodium chloride solution (preparation of the aqueous sodium chloride solution: add 15.3 - 19.3 parts of sodium chloride to 43.0 - 53.0 parts of water and stir for 0.5 - 1 h), stir for 10 - 15 min, let it stand for layer separation, separate out the aqueous phase and discard it, and retain the organic phase, thus obtaining a dichloromethane solution containing intermediate LBL04;

[0053] (5) Synthesis of LBL05 from LBL04:

[0054] ①Charging: Add the dichloromethane solution containing intermediate LBL04 to the reactor, stir at a speed of 200 - 300 rpm, control the temperature in the kettle at -5 - 5 °C, dropwise add Jones reagent (preparation of Jones reagent: add 2.0 - 2.2 parts of chromium trioxide and 5.7 - 6.7 parts of water to the reactor, stir at a speed of 100 - 200 rpm, control the temperature in the kettle at -5 - 5 °C, dropwise add 3.7 - 4.1 parts of concentrated sulfuric acid, control the internal temperature during dropping at 0 - 10 °C, and stir for 0.5 - 1 h after dropping), control the internal temperature at 0 - 10 °C, after adding, raise the temperature to 15 - 25 °C and keep the reaction for 1 - 2 h, and determine the end point of the reaction by HPLC inspection;

[0055] ②Post-treatment: Pump in 2N dilute hydrochloric acid (preparation of 2N dilute hydrochloric acid: add 9.4 - 10.4 parts of concentrated hydrochloric acid to 36.7 - 46.7 parts of water and stir for 0.5 - 1 h), stir at a speed of 300 - 400 rpm for 10 - 15 min, let it stand for layer separation, separate out the aqueous phase and discard it, and retain the organic phase; Pump the organic phase into the reactor, pump in 2N dilute hydrochloric acid (preparation of 2N dilute hydrochloric acid: add 9.4 - 10.4 parts of concentrated hydrochloric acid to 36.7 - 46.7 parts of water and stir for 0.5 - 1 h), stir for 10 - 15 min, let it stand for layer separation, separate out the aqueous phase and discard it, and retain the organic phase;

[0056] ③Purification: Pump the organic phase into the reactor, pump in an aqueous sodium chloride solution (preparation of the aqueous sodium chloride solution: add 4.3 - 5.3 parts of sodium chloride to 43.0 - 53.0 parts of water and stir for 0.5 - 1 h), stir for 10 - 15 min, let it stand for layer separation, separate out the aqueous phase and discard it, and retain the organic phase; Transfer the organic phase to the reactor, stir at a speed of 300 - 400 rpm, control the jacket temperature at 35 - 45 °C, the vacuum degree ≥ -0.080 Mpa, concentrate until no obvious distillate flows out, raise the jacket temperature to 55 - 65 °C and continue to concentrate under reduced pressure for 1 - 2 h, thus obtaining intermediate LBL05;

[0057] (6) Synthesis of LBL06 from LBL05:

[0058] ① Charging: Pump 14.7 - 15.7 parts of absolute ethanol, 2.7 - 3.1 parts of concentrated hydrochloric acid, and 2.7 - 3.1 parts of water into the reactor. Stir at a speed of 200 - 300 rpm, control the temperature in the kettle at 70 - 80 °C, react for 20 - 22 h, and determine the reaction end point by HPLC inspection.

[0059] ② Post-treatment: Control the temperature in the kettle at 65 - 75 °C, pump in 37.0 - 39.0 parts of methyl tert-butyl ether, stir at a speed of 200 - 300 rpm, keep the temperature in the kettle at 35 - 45 °C for heat preservation and crystallization for 0.5 - 1.5 h, and then keep the temperature in the kettle at 15 - 25 °C for heat preservation and crystallization for 0.5 - 1.5 h; put it into a centrifuge for centrifugation, and wash the filter cake 2 - 4 times with an absolute ethanol-methyl tert-butyl ether mixed solution (preparation of the absolute ethanol-methyl tert-butyl ether mixed solution: add 1.7 - 2.1 parts of absolute ethanol to 4.8 - 5.8 parts of methyl tert-butyl ether and stir for 0.5 - 1 h), centrifuge until dry to obtain the crude product of LBL06.

[0060] ③ Purification: Add 14.7 - 15.7 parts of absolute ethanol, 0.5 - 0.7 parts of concentrated hydrochloric acid, and the crude product of LBL06 to the reactor. Stir at a speed of 200 - 300 rpm, control the temperature in the kettle at 65 - 75 °C and stir until dissolved and clear, add 28.4 - 32.4 parts of methyl tert-butyl ether, control the temperature in the kettle at 15 - 25 °C for crystallization for 1.5 - 2.5 h; put it into a centrifuge for centrifugation, wash the filter cake 2 - 4 times with an absolute ethanol-methyl tert-butyl ether mixed solution (preparation of the absolute ethanol-methyl tert-butyl ether mixed solution: add 1.7 - 2.1 parts of absolute ethanol to 4.8 - 5.8 parts of methyl tert-butyl ether and stir for 0.5 - 1 h), centrifuge until dry, put it into a vacuum drying oven, control the temperature of the water tank at 45 - 55 °C, and dry under a vacuum of ≥ -0.080 Mpa for 10 - 14 h, take a sample for inspection, and then obtain the intermediate LBL06.

[0061] (7) Synthesis of LBL from LBL06:

[0062] ① Dissolution and decolorization: Add the intermediate LBL06, 7.6 - 8.6 parts of absolute ethanol, 1.12 - 1.52 parts of concentrated hydrochloric acid, 0.95 - 1.35 parts of water, and 0.18 - 0.28 parts of activated carbon to the reactor. Stir at a speed of 200 - 300 rpm, under nitrogen protection (keep the nitrogen flow rate at 0.2 - 0.5 L / min), heat up to 55 - 65 °C and keep stirring for 0.5 - 1.5 h, transfer it to a 50 L stainless steel pressure filtration tank and filter it through a micron filter, control the pressure ≤ 0.2 Mpa and filter and press it into the reactor, wash it with 0.78 - 0.98 parts of absolute ethanol and filter and press.

[0063] ② Crystallization and filtration: Transfer the filtrate to a reactor, with a stirring speed of 200 - 300 rpm, control the temperature in the kettle at 55 - 65 °C, pump in 19.4 - 21.4 parts of methyl tert-butyl ether. After adding, keep stirring for 0.5 - 1 h, then cool down to 10 - 20 °C for crystallization for 1 - 2 h; Centrifuge the liquid material until dry, wash the filter cake with 1.53 - 1.93 parts of methyl tert-butyl ether for 2 - 4 times, and centrifuge until dry to obtain the wet product of lobeline hydrochloride;

[0064] ③ Drying, crushing, mixing and packaging: Put the wet product of lobeline hydrochloride into a vacuum drying oven, with a vacuum degree ≥ -0.080 Mpa, control the temperature at 20 - 30 °C, dry for 1.5 - 2.5 h, pass through a 15 - 25 mesh sieve, continue to dry for 14 - 16 h to obtain LBL and take samples for inspection, then carry out packaging and sealing to obtain the said lobeline hydrochloride.

[0065] The reaction end point in the said step (1) is that the peak area ratio of the raw material LBL00 during HPLC inspection ≤ 5.0%.

[0066] The aqueous glutaraldehyde solution in the said step (2) is a 50 wt% aqueous glutaraldehyde solution.

[0067] The reaction end point in the said step (3) is that the peak area ratio of the raw material LBL02 during HPLC inspection ≤ 0.2%.

[0068] The reaction end point in the said step (4) is that the peak area ratio of the raw material LBL03 during HPLC inspection ≤ 1.0%.

[0069] The catalyst in the said step (4) is one of (-)-benzoimidazole, 4-dimethylaminopyridine, 2-mercaptobenzothiazole, 2-chlorobenzothiazole; preferably (-)-benzoimidazole. Further preferably, the catalyst is a composition of (-)-benzoimidazole and 4-dimethylaminopyridine, and the mass ratio of the two is 1:(0.2 - 5).

[0070] The reaction end point in the said step (5) is that the peak area ratio of the raw material LBL04 during HPLC inspection ≤ 0.2%.

[0071] The reaction end point in the said step (6) is that the peak area ratio of the raw material LBL05 during HPLC inspection ≤ 5.0%.

[0072] The micro filter in the said step (7) consists of a 1.0 μm titanium rod filter and a 0.22 μm polyethersulfone filter cartridge filter.

[0073] The inspection items, acceptable standards and inspection methods for sampling and inspection of each intermediate in the said steps (2), (3), (6) are summarized in Table 1 as follows.

[0074] In step (7), the test items, acceptable criteria, test results, and conclusions of LBL sampling and submission for inspection are summarized as shown in Table 2.

[0075] Table 1 Intermediate Quality Control and Its Standards

[0076]

[0077]

[0078] Table 2 LBL Quality Control and Its Standards

[0079]

[0080]

[0081] The production process of lobeline hydrochloride in the present invention selects LBL00 and glutaraldehyde as starting materials. LBL00 is obtained by reacting benzoyl chloride and ethyl acetoacetate, followed by post-treatment and vacuum distillation (the synthesis diagram of LBL000 is as Figure 2 shown); 50% aqueous glutaraldehyde solution is obtained by reacting acetylene with methanol to form vinyl methyl ether, which then undergoes a Diels-Alder reaction with acrolein to produce 2-methoxy-3,4-dihydropyran, followed by hydrolysis (the synthesis diagram of 50% aqueous glutaraldehyde solution is as Figure 3 shown). The production process of lobeline hydrochloride in the present invention selects LBL00 and glutaraldehyde as starting materials based on the following reasons:

[0082] ① The materials LBL00 and glutaraldehyde are the main chemical structure fragments of LBL. Selecting them as starting materials can not only reduce the reaction steps but also avoid the risk of increased impurities during the synthesis process;

[0083] ② The relevant impurity profiles in the synthesis route can be controlled by conventional and accurate methods, avoiding the problem of difficult quality control;

[0084] ③ Both the materials LBL00 and glutaraldehyde are separated chemically pure products. There are multiple chemical reactions and crude product refining processes from the starting materials to the finished product, and there are corresponding purification and separation steps. The intermediates obtained in each step have corresponding quality control requirements and can only enter the next reaction after meeting the standards;

[0085] ④ The inventors have conducted detailed research on the elimination and derivatization pathways of the possible impurities in the materials LBL00 and glutaraldehyde, and confirmed that under the control of the proposed starting material quality standards, it is possible to ensure the production of bulk drugs that meet the declaration standards;

[0086] ⑤ The raw materials LBL00 and glutaraldehyde are stable, easily available, inexpensive, and their quality meets the internal control standards, meeting the production requirements.

[0087] Advantages of the present invention:

[0088] 1. Compared with the prior art, the production process of lobeline hydrochloride in the present invention uses LBL00 and 50% glutaraldehyde aqueous solution as starting materials. First, the starting material LBL00 is hydrolyzed to obtain LBL01, LBL01 reacts with the starting material glutaraldehyde to construct the key intermediate LBL02, LBL02 is reduced to obtain LBL03, the intermediate LBL03 is acylated by chiral ligand catalysis to obtain the intermediate LBL04, the intermediate LBL04 is oxidized to obtain the intermediate LBL05, the intermediate LBL05 is hydrolyzed to obtain the intermediate LBL06, and the intermediate LBL06 is decolorized, recrystallized, dried, and packaged to obtain LBL, that is, lobeline hydrochloride.

[0089] 2. Compared with the prior art, the production process of lobeline hydrochloride in the present invention selects LBL00 and glutaraldehyde as starting materials, based on the following:

[0090] ① The materials LBL00 and glutaraldehyde are the main chemical structure fragments of LBL. Selecting them as starting materials can not only reduce the reaction steps, but also avoid the risk of increased impurities in the synthesis process;

[0091] ② The relevant impurity spectra in the synthesis route can be controlled by conventional and accurate methods, avoiding the problem of difficult quality control;

[0092] ③ The materials LBL00 and glutaraldehyde are both separated chemical pure products. There are multiple chemical reactions and crude product refining processes from the starting materials to the finished product, and there are corresponding purification and separation steps. The intermediates obtained in each step have corresponding quality control requirements and can only enter the next reaction after meeting the standards;

[0093] ④ The inventors have conducted detailed studies on the elimination and derivation pathways of the possible impurities in the materials LBL00 and glutaraldehyde, and confirmed that under the control of the proposed starting material quality standards, it is possible to ensure the production of active pharmaceutical ingredients that meet the declaration standards;

[0094] ⑤ The materials LBL00 and glutaraldehyde are stable, easily available, inexpensive, and their quality meets the internal control standards, meeting the production requirements. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Figure 1 is the process flow chart of lobeline hydrochloride.

[0096] Figure 2 is the synthesis diagram of LBL000.

[0097] Figure 3 is the synthesis diagram of 50% glutaraldehyde aqueous solution.

[0098] Figure 4.1 、 4.2, 4.3 is the in-house control standard for materials such as sodium hydroxide, dichloromethane, hydrochloric acid, methylamine hydrochloride, acetic acid, sodium acetate, methyl tert-butyl ether, absolute ethanol, sodium borohydride, sodium chloride, propionic anhydride, N,N-diisopropylethylamine, anhydrous sodium sulfate, (-)-benzoimidazole, chromium trioxide, sulfuric acid, and medicinal charcoal (activated carbon).

[0099] Figure 5 is the structure of (-)-benzoimidazole. Detailed implementation methods

[0100] The sources of the starting materials and other materials used in the examples are shown in Table 3:

[0101] Table 3 Sources of starting materials and other materials

[0102]

[0103]

[0104] Example 1

[0105] A production method of lobeline hydrochloride includes the following steps:

[0106] (1) Synthesis of LBL01 from LBL00:

[0107] ① Charging: Add 100.0 g of water and 4.58 g of sodium hydroxide to the reactor, start stirring at a speed of 40 HZ, and control the temperature in the kettle to 20 °C; add 20.0 g of ethyl benzoylacetate (LBL00), continue stirring at 20 °C for 21 h, and send it for inspection by HPLC. The peak area ratio of the raw material LBL00 is 2.41%, reaching the end point of the reaction;

[0108] ② Post-treatment: Continue to add 132.5 g of dichloromethane to the reactor, start stirring at a speed of 40 HZ, stir for 10 min, let it stand for 10 min, separate the liquid, discard the organic phase, and retain the aqueous phase; control the temperature in the kettle to 10 °C, dropwise add dilute hydrochloric acid (preparation of dilute hydrochloric acid: stir 11.8 g of 37 wt% concentrated hydrochloric acid and 10.0 g of water for 0.5 h) to adjust the pH to 1.5, control the stirring speed to 40 HZ, keep warm and crystallize for 1 h, put it into a centrifuge and centrifuge until dry, wash the filter cake with 20.0 g of water 3 times, and centrifuge until dry to obtain the undried wet product, that is, the intermediate LBL01;

[0109] (2) Synthesis of LBL02 from LBL01:

[0110] ① Charging: Add 100.5 g of water, 0.39 g of acetic acid, 0.29 g of sodium acetate, 2.96 g of methylamine hydrochloride, and 39.7 g of methyl tert-butyl ether to the reactor and start stirring at a stirring speed of 35 HZ. Control the temperature in the kettle to 20 °C, add intermediate LBL01 and 6.7 g of 50 wt% glutaraldehyde aqueous solution, and keep stirring at 20 °C for 15 h to reach the reaction end point.

[0111] ② Post-treatment: Control the temperature in the kettle to 10 °C, stir at a speed of 35 HZ, and add dilute hydrochloric acid dropwise (preparation of dilute hydrochloric acid: stir 4.0 g of 37 wt% concentrated hydrochloric acid and 3.35 g of water for 0.5 h) to adjust the pH to 1.5. Keep the temperature for crystallization for 1 h, put it into a centrifuge and centrifuge until dry. The filter cake is rinsed 3 times with 10.1 g of methyl tert-butyl ether and then centrifuged until dry to obtain the undried wet product LBL01.

[0112] ③ Purification: Transfer the undried wet product LBL01 to the reactor, add 15.8 g of absolute ethanol and 29.7 g of methyl tert-butyl ether, and slurry at 20 °C and a stirring speed of 350 rpm for 1.5 h. Then put it into a centrifuge and centrifuge. The filter cake is rinsed 3 times with 5.1 g of methyl tert-butyl ether and centrifuged until dry. Put it into a vacuum drying oven, control the temperature of the water tank to 50 °C, and dry it for 12 h under a vacuum of ≥ -0.080 MPa. Take a sample for inspection, and then obtain intermediate LBL02, which meets the next charging standard after quality control testing.

[0113] (3) Synthesis of LBL03 from LBL02:

[0114] ① Charging: Add 63.2 g of absolute ethanol and intermediate LBL02 to the reactor and start stirring at a stirring speed of 35 HZ. Replace the gas with nitrogen 3 times. Control the temperature in the kettle to -10 °C. Under the condition of controlling the temperature in the kettle to -5 to 0 °C, add 2.44 g of sodium borohydride in 4 equal batches. After adding, raise the temperature to 0 °C and keep the reaction for 1.5 h, then raise the temperature to 20 °C and keep the reaction for 1.5 h. Send it for inspection by HPLC. The peak area ratio of raw material LBL02 is 0.52%, and the reaction end point is reached.

[0115] ② Post-treatment: Lower the temperature to 10 °C, stir at a speed of 35 HZ, and add dilute hydrochloric acid dropwise (preparation of dilute hydrochloric acid: stir 8.3 g of 37 wt% concentrated hydrochloric acid and 73.0 g of water for 0.5 h) to adjust the pH to 1.5. Keep stirring for 2 h, put it into a centrifuge and centrifuge until dry. The filter cake is rinsed 3 times with 8.0 g of water and centrifuged until dry to obtain the crude product LBL03 and start stirring.

[0116] ③ Purification:

[0117] Pump aqueous sodium hydroxide solution (preparation method of aqueous sodium hydroxide solution: add 6.4 g of sodium hydroxide to 80.0 g of water and stir for 0.5 h), 106.0 g of dichloromethane into the reactor, add the crude product of LBL03, control the stirring speed at 35 HZ, control the temperature in the kettle at 25 °C and stir for 0.5 h while maintaining the temperature, let it stand for liquid separation, separate out the aqueous phase and discard it, retain the organic phase; pump the organic phase into the reactor, pump in 80.0 g of water, stir for 10 min, let it stand for liquid separation, separate out the aqueous phase and discard it, retain the organic phase; pump the organic phase into the reactor, pump in aqueous sodium chloride solution (preparation of aqueous sodium chloride solution: add 28.8 g of sodium chloride and 80.0 g of water and stir for 0.5 h), stir for 10 min, let it stand for liquid separation, separate out the aqueous phase and discard it, retain the organic phase; transfer the organic phase to the reactor for concentration, control the stirring speed at 300 rpm, control the jacket temperature at 60 °C, the vacuum degree ≥ -0.080 Mpa, concentrate until no obvious distillate flows out, add 3.7 g of absolute ethanol, continue to concentrate under reduced pressure for 1.5 h when the jacket temperature rises to 80 °C and the internal temperature rises to 70 °C, pump in 18.9 g of absolute ethanol, control the stirring speed at 300 rpm, raise the temperature to 70 °C and stir until it dissolves clearly, cool down to 10 °C and crystallize for 0.5 h, pump in 24.0 g of water, keep the temperature for crystallization for 1 h, put it into a centrifuge and centrifuge until dry, wash the filter cake 3 times with ethanol aqueous solution (preparation of ethanol aqueous solution: add 3.2 g of absolute ethanol to 4.0 g of water and stir for 0.5 h), centrifuge until dry; put it into a vacuum drying oven, control the water tank temperature at 60 °C, the vacuum ≥ -0.080 Mpa, dry for 12 h, take a sample for inspection, and then obtain the intermediate LBL03, which meets the next feeding standard after quality control detection;

[0118] (4) Synthesis of LBL04 from LBL03:

[0119] ① Charging: Add 57.2 g of dichloromethane, intermediate LBL03, 1.83 g of N,N - diisopropylethylamine, 2.01 g of anhydrous sodium sulfate and 0.72 g of (-)-benzoimidazole catalyst into the reactor, control the stirring speed at 300 rpm, displace with nitrogen for 3 times, control the temperature in the kettle at 20 °C, dropwise add propionic anhydride solution (preparation of propionic anhydride solution: add 2.30 g of propionic anhydride to 6.4 g of dichloromethane and stir for 0.5 h), control the internal temperature at 15 °C during the dropping, after adding, keep the temperature at 20 °C and react for 12 h, send it for inspection by HPLC, the peak area ratio of raw material LBL03 is 0.45%, reaching the end point of the reaction;

[0120] ②Post-treatment: 48.0 g of water was pumped into the reactor, the stirring speed was 500 rpm, and it was stirred for 10 min. Then it was allowed to stand for phase separation. The aqueous phase was separated and discarded, and the organic phase was retained; the organic phase was pumped into the reactor, 48.0 g of water was pumped in, and it was stirred for 10 min. Then it was allowed to stand for phase separation. The aqueous phase was separated and discarded, and the organic phase was retained; the organic phase was pumped into the reactor, and an aqueous sodium chloride solution (preparation of the aqueous sodium chloride solution: 17.3 g of sodium chloride was added to 48.0 g of water and stirred for 0.5 h) was pumped in, and it was stirred for 10 min. Then it was allowed to stand for phase separation. The aqueous phase was separated and discarded, and the organic phase was retained, thus obtaining a dichloromethane solution containing intermediate LBL04;

[0121] (5) Synthesis of LBL05 from LBL04:

[0122] ①Charging: The dichloromethane solution containing intermediate LBL04 was added to the reactor, the stirring speed was 250 rpm, the temperature inside the kettle was controlled at 0 °C, and Jones reagent was added dropwise (preparation of Jones reagent: 2.1 g of chromium trioxide and 6.2 g of water were added to the reactor, the stirring speed was 150 rpm, the temperature inside the kettle was controlled at 0 °C, 3.9 g of 98 wt% concentrated sulfuric acid was added dropwise, the internal temperature during dropping was controlled at 5 °C, and after dropping, it was stirred for 0.5 h). The internal temperature was controlled at 5 °C, and after addition, the temperature was raised to 20 °C and kept for reaction for 1 h. It was sent for inspection by HPLC, and the peak area ratio of raw material LBL04 was 0.08%, reaching the end point of the reaction;

[0123] ②Post-treatment: 2N dilute hydrochloric acid was pumped in (preparation of 2N dilute hydrochloric acid: 9.9 g of 37 wt% concentrated hydrochloric acid was added to 31.7 g of water and stirred for 0.5 h), the stirring speed was 350 rpm, and it was stirred for 10 min. Then it was allowed to stand for phase separation. The aqueous phase was separated and discarded, and the organic phase was retained; the organic phase was pumped into the reactor, and 2N dilute hydrochloric acid (preparation of 2N dilute hydrochloric acid: 9.9 g of 37 wt% concentrated hydrochloric acid was added to 31.7 g of water and stirred for 0.5 h) was pumped in, and it was stirred for 10 min. Then it was allowed to stand for phase separation. The aqueous phase was separated and discarded, and the organic phase was retained;

[0124] ③Purification: The organic phase was pumped into the reactor, and an aqueous sodium chloride solution (preparation of the aqueous sodium chloride solution: 4.8 g of sodium chloride was added to 48.0 g of water and stirred for 0.5 h) was pumped in, and it was stirred for 10 min. Then it was allowed to stand for phase separation. The aqueous phase was separated and discarded, and the organic phase was retained; the organic phase was transferred to the reactor, the stirring speed was 350 rpm, the jacket temperature was controlled at 40 °C, the vacuum degree was ≥ -0.080 Mpa, and it was concentrated until no obvious distillate flowed out. Then the jacket temperature was raised to 60 °C and continued to be concentrated under reduced pressure for 1.5 h, thus obtaining intermediate LBL05;

[0125] (6) Synthesis of LBL06 from LBL05:

[0126] ① Feeding: 15.2 g of absolute ethanol, 2.9 g of 37 wt% concentrated hydrochloric acid and 2.9 g of water were pumped into the reactor. The stirring speed was 250 rpm. The temperature inside the kettle was controlled at 75 °C and the reaction was carried out for 21 h. It was sent for inspection by HPLC. The peak area ratio of raw material LBL05 was 3.02%, reaching the reaction end point;

[0127] ② Post-treatment: The temperature inside the kettle was controlled at 70 °C, and 38.0 g of methyl tert-butyl ether was pumped in. The stirring speed was 250 rpm. The temperature inside the kettle was controlled at 40 °C for heat preservation and crystallization for 1 h, and the temperature inside the kettle was controlled at 20 °C for heat preservation and crystallization for 1 h; It was put into a centrifuge for centrifugation. The filter cake was rinsed 3 times with an absolute ethanol-methyl tert-butyl ether mixed solution (preparation of the absolute ethanol-methyl tert-butyl ether mixed solution: 1.9 g of absolute ethanol was added to 5.3 g of methyl tert-butyl ether and stirred for 0.5 h), and centrifuged until dry to obtain the crude product of LBL06;

[0128] ③ Purification: 15.2 g of absolute ethanol, 0.6 g of 37 wt% concentrated hydrochloric acid and the crude product of LBL06 were added to the reactor. The stirring speed was 250 rpm. The temperature inside the kettle was controlled at 70 °C and stirred until clear. 30.4 g of methyl tert-butyl ether was added. The temperature inside the kettle was controlled at 20 °C for crystallization for 2 h; It was put into a centrifuge for centrifugation. The filter cake was rinsed 3 times with an absolute ethanol-methyl tert-butyl ether mixed solution (preparation of the absolute ethanol-methyl tert-butyl ether mixed solution: 1.9 g of absolute ethanol was added to 5.3 g of methyl tert-butyl ether and stirred for 0.5 h), and centrifuged until dry. It was put into a vacuum drying oven. The temperature of the water tank was controlled at 50 °C and dried under vacuum ≥ -0.080 Mpa for 12 h. Sampling was sent for inspection, and the intermediate LBL06 was obtained. After quality control testing, it met the next feeding standard;

[0129] (7) Synthesis of LBL from LBL06:

[0130] ① Dissolution and decolorization: The intermediate LBL06, 8.1 g of absolute ethanol, 1.32 g of 37 wt% concentrated hydrochloric acid, 1.15 g of water and 0.32 g of activated carbon were added to the reactor. The stirring speed was 250 rpm. Under nitrogen protection (maintaining the nitrogen flow rate at 0.35 L / min), the temperature was raised to 60 °C and stirred for 1 h at constant temperature. It was transferred to a stainless steel pressure filter tank and filtered through a micron filter composed of a 1.0 μm titanium rod filter and a 0.22 μm polyethersulfone filter cartridge. The filtration pressure was controlled ≤ 0.2 Mpa and filtered into the reactor, and washed with 0.88 g of absolute ethanol and filtered under pressure;

[0131] ② Crystallization and filtration: The filtrate was transferred to the reactor. The stirring speed was 250 rpm. The temperature inside the kettle was controlled at 60 °C, and 20.4 g of methyl tert-butyl ether was pumped in. After adding, it was stirred for 0.5 h at constant temperature and cooled to 15 °C for crystallization for 1.5 h; The liquid material was centrifuged until dry by a centrifuge. The filter cake was rinsed 3 times with 1.68 g of methyl tert-butyl ether and centrifuged until dry to obtain the wet product of lobeline hydrochloride;

[0132] ③Drying, pulverizing, mixing and packaging: Put the wet Lobeline Hydrochloride into a vacuum drying oven with a vacuum degree ≥ -0.080 Mpa, control the temperature at 25°C, dry for 2 hours, pass through a 20-mesh sieve, continue drying for 15 hours to obtain LBL, take samples for inspection, and conduct packaging and sealing to obtain the said Lobeline Hydrochloride.

[0133] The appearance of the Lobeline Hydrochloride obtained in Example 1 was inspected by quality control and met the standards; the yield was 78.4%, the non-specific single impurity was 0.05%, and the total impurity was 0.09%.

[0134] Example 2

[0135] The difference between Example 2 and Example 1 lies only in the catalyst in the feeding step of synthesizing LBL04 from LBL03. In Example 2, the (-)-benzoimidazole catalyst was replaced with 0.72 g of 4-dimethylaminopyridine catalyst.

[0136] The appearance of the Lobeline Hydrochloride obtained in Example 2 was inspected by quality control and met the standards; the yield was 75.1%, the non-specific single impurity was 0.06%, and the total impurity was 0.10%.

[0137] Example 3

[0138] The difference between Example 3 and Example 1 lies only in the catalyst in the feeding step of synthesizing LBL04 from LBL03. In Example 3, the (-)-benzoimidazole catalyst was replaced with 0.72 g of 2-mercaptobenzothiazole catalyst.

[0139] The appearance of the Lobeline Hydrochloride obtained in Example 3 was inspected by quality control and met the standards; the yield was 72.5%, the non-specific single impurity was 0.07%, and the total impurity was 0.10%.

[0140] Example 4

[0141] The difference between Example 4 and Example 1 lies only in the catalyst in the feeding step of synthesizing LBL04 from LBL03. In Example 4, the (-)-benzoimidazole catalyst was replaced with 0.72 g of 2-chlorobenzothiazole catalyst.

[0142] The appearance of the Lobeline Hydrochloride obtained in Example 4 was inspected by quality control and met the standards; the yield was 70.8%, the non-specific single impurity was 0.08%, and the total impurity was 0.11%.

[0143] Example 5

[0144] The difference between Example 5 and Example 1 lies only in the catalyst in the feeding step of synthesizing LBL04 from LBL03. In Example 5, the (-)-benzoimidazole catalyst was replaced with a mixture of 0.36 g of (-)-benzoimidazole catalyst and 0.36 g of 2-mercaptobenzothiazole catalyst.

[0145] The appearance of lobeline hydrochloride obtained in Example 5 passed the quality control test and met the standards; the yield was 74.7%, the non-specific single impurity was 0.06%, and the total impurities were 0.10%.

[0146] Example 6

[0147] The difference between Example 6 and Example 1 lies only in the catalyst in the feeding step of synthesizing LBL04 from LBL03. In Example 6, the (-)-benzoimidazole catalyst was replaced with a mixture of 0.36 g of (-)-benzoimidazole catalyst and 0.36 g of 4-dimethylaminopyridine catalyst.

[0148] The appearance of lobeline hydrochloride obtained in Example 6 passed the quality control test and met the standards; the yield was 80.7%, the non-specific single impurity was 0.04%, and the total impurities were 0.08%.

[0149] The quality control test results of Example 6 are shown in Table 4.

[0150] Table 4 Quality control test results of lobeline hydrochloride in Example 6

[0151]

[0152]

[0153] In Example 1, (-)-benzoimidazole was used as a chiral catalyst. Through its steric effect and electronic effect, it precisely controlled the stereoselectivity of the acylation reaction, reduced the generation of by-products, and improved the reaction efficiency, thus obtaining a higher yield. In Example 2, 4-dimethylaminopyridine promoted the nucleophilic attack due to its strong basicity, accelerating the reaction rate, but had a lower catalytic selectivity and more by-products, affecting the yield. In Example 3, the 2-mercaptobenzothiazole catalyst had strong nucleophilicity but poor coordination with the reaction intermediate, resulting in frequent side reactions and reduced purity and yield. In Example 4, 2-chlorobenzothiazole had weak nucleophilicity, slow reaction rate, and many by-products, with a lower yield. In Example 5, (-)-benzoimidazole and 2-mercaptobenzothiazole were used as a composite catalyst, but the selectivity of this catalyst for the acylation reaction was poor, which might lead to an increase in by-products in the reaction, resulting in a lower purity of the product and thus reducing the final yield. Therefore, it shows that not any combination of catalysts can achieve a synergistic effect. In Example 6, (-)-benzoimidazole and 4-dimethylaminopyridine were used as a composite catalyst, synergistically enhancing the reaction rate and yield through chiral control and enhanced nucleophilicity. The effect was better than the single catalysts in Examples 1-4 and the (-)-benzoimidazole catalyst and 2-mercaptobenzothiazole composite catalyst in Example 5, showing a synergistic effect.

[0154] The preferred specific embodiments of the present invention have been described in detail above. It should be understood that those of ordinary skill in the art can make many modifications and variations based on the concept of the present invention without creative efforts. Therefore, all technical solutions that can be obtained by those skilled in the art in the technical field based on the concept of the present invention through logical analysis, reasoning or limited experiments on the basis of the prior art shall fall within the protection scope determined by the claims.

Claims

1. A method for producing lobeline hydrochloride, characterized in that: The method comprises the following steps, in parts by weight: (1) LBL00 synthesizes LBL01: ① Feeding: Add 90-110 parts of water and 4.48-4.68 parts of sodium hydroxide to the reactor and start stirring; add 19.9-20.1 parts of ethyl benzoyl acetate and continue stirring, and determine the reaction endpoint by HPLC; ② Post-treatment: Continue to add 122.5-142.5 parts of dichloromethane to the reactor and start stirring, let it stand, separate the liquids, and retain the aqueous phase; add dilute hydrochloric acid to adjust the pH to 1-2, crystallize for 0.5-1.5 hours, centrifuge to dryness, rinse the filter cake with 19-21 parts of water 2-4 times, centrifuge to dryness, and obtain an undried wet product, that is, the intermediate LBL01; (2) Synthesis of LBL01 to LBL02: ① Feeding: Add 95.5-105.5 parts of water, 0.36-0.42 parts of acetic acid, 0.26-0.32 parts of sodium acetate, 2.91-3.01 parts of methylamine hydrochloride and 36.7-42.7 parts of methyl tert-butyl ether into the reactor and start stirring, add the intermediate LBL01 and 6.6-6.8 parts of glutaraldehyde aqueous solution, keep warm at 15-25°C and stir for 14-16 hours, that is, reach the end point of the reaction; ② Post-treatment: Control the temperature in the autoclave to 5-15°C, add dilute hydrochloric acid to adjust the pH to 1-2, keep warm for 0.5-1.5h for crystallization, centrifuge to dryness, rinse the filter cake with 9.1-11.1 parts of methyl tert-butyl ether for 2-4 times, continue centrifugation to dryness, and obtain the undried wet product LBL01; ③ Purification: transfer the undried wet product LBL01 to a reactor, add 14.8-16.8 parts of anhydrous ethanol and 27.7-31.7 parts of methyl tert-butyl ether, beat for 1-2 hours, centrifuge, rinse the filter cake with 4.6-5.6 parts of methyl tert-butyl ether for 2-4 times, centrifuge to dryness, dry for 10-14 hours, take samples for inspection, and obtain the intermediate LBL02; (3) LBL02 synthesizes LBL03: ① Feeding: Add 58.2-68.2 parts of anhydrous ethanol and intermediate LBL02 to the reactor and start stirring, add 2.42-2.46 parts of sodium borohydride in 3-5 batches, keep the temperature at -5-5℃ for 1-2h, heat to 15-25℃ for 1-2h, and determine the reaction endpoint by HPLC. ② Post-treatment: cool to -5-15℃, add dilute hydrochloric acid to adjust pH to 1-2, keep warm and stir for 1.5-2.5h, centrifuge to dryness, rinse the filter cake with 7.5-8.5 parts of drinking water 2-4 times, centrifuge to dryness, and obtain crude LBL03 and start stirring; ③Purification: Sodium hydroxide aqueous solution and 101.0-111.0 parts of dichloromethane were pumped into the reactor, and crude LBL03 was added, stirred for 0.5-1h, and the organic phase was separated and retained; the organic phase was pumped into the reactor, 75.0-85.0 parts of water were pumped into the reactor, stirred for 10-15min, and the organic phase was separated and retained; the organic phase was pumped into the reactor, and sodium chloride aqueous solution was pumped into the reactor, stirred for 10-15min, and the organic phase was separated and retained; the organic phase was transferred to the reactor for concentration to If no obvious fraction flows out, add 3.2-4.2 parts of anhydrous ethanol, continue to concentrate under reduced pressure for 1-2 hours, pump 17.9-19.9 parts of anhydrous ethanol into it, stir at 65-75°C until dissolved, crystallize at 5-15°C for 0.5-1 hour, pump 22.0-26.0 parts of water, keep warm for crystallization for 1-2 hours, centrifuge to dryness, rinse the filter cake with ethanol-water solution 2-4 times, centrifuge to dryness; dry for 10-14 hours, take samples for inspection, and obtain the intermediate LBL03; (4) LBL03 synthesizes LBL04: ① Feeding: Add 54.2-60.2 parts of dichloromethane, intermediate LBL03, 1.73-1.93 parts of N,N-diisopropylethylamine, 1.91-2.11 parts of anhydrous sodium sulfate and 0.62-0.82 parts of catalyst into the reactor, dropwise add propionic anhydride solution, keep warm for 12 hours, and determine the reaction endpoint by HPLC; ② Post-treatment: 43.0-53.0 parts of water were pumped into the reactor and stirred for 10-15 minutes, and the organic phase was separated and retained; the organic phase was pumped into the reactor, 43.0-53.0 parts of water were pumped into the reactor, and stirred for 10-15 minutes, and the organic phase was separated and retained; the organic phase was pumped into the reactor, and sodium chloride aqueous solution was pumped into the reactor, and stirred for 10-15 minutes, and the organic phase was separated and retained to obtain a dichloromethane solution containing the intermediate LBL04; (5) LBL04 synthesizes LBL05: ① Feeding: Add the dichloromethane solution containing the intermediate LBL04 into the reactor, add Jones reagent dropwise, keep the reaction at 15-25℃ for 1-2h, and determine the reaction endpoint by HPLC; ② Post-treatment: pump in 2N dilute hydrochloric acid, stir for 10-15 minutes, separate and retain the organic phase; pump the organic phase into the reactor, pump in 2N dilute hydrochloric acid, stir for 10-15 minutes, separate and retain the organic phase; ③ Purification: The organic phase was pumped into the reactor, and sodium chloride aqueous solution was pumped into the reactor, stirred for 10-15 minutes, and the organic phase was retained after separation; the organic phase was transferred to the reactor, concentrated at 35-45°C until no obvious fraction flowed out, and then continued to concentrate under reduced pressure at 55-65°C for 1-2 hours to obtain the intermediate LBL05; (6) Synthesis of LBL05 and LBL06: ① Feeding: 14.7-15.7 parts of anhydrous ethanol, 2.7-3.1 parts of concentrated hydrochloric acid and 2.7-3.1 parts of water were pumped into the reactor, the stirring speed was 200-300 rpm, the temperature in the reactor was controlled at 70-80°C, the reaction was carried out for 20-22 hours, and the reaction endpoint was determined by HPLC; ② Post-treatment: control the temperature in the kettle to 65-75°C, draw in 37.0-39.0 parts of methyl tert-butyl ether, stir at 200-300 rpm, control the temperature in the kettle to 35-45°C for crystallization for 0.5-1.5 h, and then to 15-25°C for crystallization for 0.5-1.5 h; centrifuge, wash the filter cake with anhydrous ethanol-methyl tert-butyl ether mixed solution for 2-4 times, centrifuge to dryness, and obtain crude LBL06; ③ Purification: Add 14.7-15.7 parts of anhydrous ethanol, 0.5-0.7 parts of concentrated hydrochloric acid and crude LBL06 to the reactor, stir at 65-75°C to dissolve, add 28.4-32.4 parts of methyl tert-butyl ether, crystallize at 15-25°C for 1.5-2.5 hours; centrifuge, rinse the filter cake with anhydrous ethanol-methyl tert-butyl ether mixed solution 2-4 times, centrifuge to dryness, dry for 10-14 hours, take samples for inspection, and obtain the intermediate LBL06; (7) LBL06 synthesis of LBL: ① Dissolution and decolorization: add intermediate LBL06, 7.6-8.6 parts of anhydrous ethanol, 1.12-1.52 parts of concentrated hydrochloric acid, 0.95-1.35 parts of water and 0.18-0.28 parts of activated carbon into the reactor, keep warm at 55-65°C and stir for 0.5-1.5h, transfer to a stainless steel filter press tank, filter through a micron filter, wash with 0.78-0.98 parts of anhydrous ethanol and filter; ② Crystallization filtration: The filtrate is transferred to a reactor, the temperature in the reactor is controlled at 55-65°C, 19.4-21.4 parts of methyl tert-butyl ether are pumped in, and the mixture is stirred for 0.5-1h after addition, and the temperature is lowered to 10-20°C for crystallization for 1-2h; centrifuge to dryness, and the filter cake is rinsed 2-4 times with 1.53-1.93 parts of methyl tert-butyl ether, and centrifuged to dryness to obtain the wet product of lobeline hydrochloride; ③ Drying, crushing, mixing and packaging: Dry the wet lobeline hydrochloride product at 20-30° C. for 1.5-2.5 hours, pass through a 15-25 mesh sieve, continue drying for 14-16 hours, take samples for inspection, and package and seal to obtain the lobeline hydrochloride.

2. The method for producing lobeline hydrochloride according to claim 1, wherein: The reaction endpoint in the step (1) is when the peak area ratio of LBL00 of the raw material is ≤5.0% when tested by HPLC.

3. The method for producing lobeline hydrochloride according to claim 1, wherein: The glutaraldehyde aqueous solution in step (2) is a 50 wt % glutaraldehyde aqueous solution.

4. The method for producing lobeline hydrochloride according to claim 1, characterized in that: The reaction endpoint in the step (3) is when the peak area ratio of the raw material LBL02 is ≤0.2% when tested by HPLC.

5. The method for producing lobeline hydrochloride according to claim 1, characterized in that: The catalyst in step (4) is one of (-)-benzotetraimidazole, 4-dimethylaminopyridine, 2-mercaptobenzothiazole and 2-chlorobenzothiazole.

6. The method for producing lobeline hydrochloride according to claim 1 or 5, characterized in that: The catalyst in step (4) is (-)-benzotetraimidazole.

7. The method for producing lobeline hydrochloride according to claim 1 or 5, characterized in that: The catalyst in step (4) is a combination of (-)-benzotetraimidazole and 4-dimethylaminopyridine.

8. The method for producing lobeline hydrochloride according to claim 1, characterized in that: The reaction endpoint in the step (4) is when the peak area ratio of the raw material LBL03 is ≤1.0% when tested by HPLC.

9. The method for producing lobeline hydrochloride according to claim 1, characterized in that: The reaction endpoint in the step (5) is when the peak area ratio of the raw material LBL04 is ≤0.2% when tested by HPLC.

10. The method for producing lobeline hydrochloride according to claim 1, characterized in that: The reaction endpoint in the step (6) is when the peak area ratio of raw material LBL05 is ≤5.0% when tested by HPLC.

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