Process and device for preparing carbidopa through continuous flow reaction

Abstract

The invention discloses a process and a device for preparing carbidopa through continuous flow reaction, and the process comprises the following steps: firstly mixing cyclohexanone and a solvent, then reacting with ammonia water and sodium hypochlorite to generate 1-oxa-2-azaspiro [2.5] octane, and carrying out gas-liquid-liquid phase separation to obtain an organic phase and 2-amino-3-(3, 3, 5, 6-tetramethyl-2-oxo-2-azaspiro [2.5] octane; the preparation method comprises the following steps: reacting 2-[(cyclohexyl) hydrazino]-3-(3, 4-dihydroxyphenyl)-2-methyl propionate (methyl dopa methyl ester) to generate 2-[(cyclohexyl) hydrazino]-3-(3, 4-dihydroxyphenyl)-2-methyl propionate, and finally hydrolyzing with hydrochloric acid to obtain carbidopa. According to the invention, the synthesis of high-purity and high-content carbidopa is realized through the full-flow continuous flow reactor. The yield reaches 90%, and the purity reaches 99% or above. The reaction system solves the problems that the reaction temperature is difficult to control, the production efficiency is low, an intermediate product is unstable and the like in an existing kettle type process, the yield and the purity of a target product are remarkably improved, material consumption is greatly reduced, and the reaction system has the advantages of being short in production period, high in selectivity, continuous in production and intrinsically safe.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of fine chemical technology, and particularly relates to a process and device for preparing carbidopa by continuous flow reaction. BACKGROUND

[0002] Carbidopa is a white or off-white crystalline powder at room temperature, which is easily oxidized to form quinone compounds. Carbidopa is a peripheral aromatic amino acid decarboxylase inhibitor, which is often combined with Levodopa to treat Parkinson's disease.

[0003] Yang Zhiyong et al. used methyl dopa as a starting material to synthesize carbidopa by N-acylation, methylation, Hofmann degradation reaction and ether bond hydrolysis reaction. Although this method is mature, a large amount of sodium cyanate is used, which brings many troubles to the post-treatment; and dimethyl sulfate is also toxic, which brings inconvenience to production; the reaction route is as follows:

[0004]

[0005] Patent 230865A1 uses methyl dopa methyl ester as a raw material, protects two hydroxyl groups with boric acid, then reacts with 3,3-pentamethylene oxaziridine, and finally hydrolyzes to obtain carbidopa. The method has a yield of only 40%, which is low; the reaction route is as follows:

[0006]

[0007] European patent (WO 2007 / 042848) uses S-2-amino-3-(3,4-dimethoxyphenyl)-2-methylpropionic acid methyl ester as a raw material, and reacts with 1-oxa-2-azaspiro[2.5]octane to obtain the corresponding hydrazine methyl propionate, and removes the methyl protecting group under the action of hydrobromic acid to obtain carbidopa. In this method, 1-oxa-2-azaspiro[2.5]octane is unstable and easy to decompose, which has a high risk coefficient and is not suitable for traditional kettle type mass production. The reaction route is as follows:

[0008]

[0009] Lu Yanmin uses acetone as a starting material to prepare oxaziridine, which reacts with methyl dopa ester to form methyl dopa imine ester, and then hydrolyzes to form carbidopa. Since acetone has high water solubility, the generated oxaziridine is also easily soluble in water, so that the content of oxaziridine in the organic phase is low, the utilization rate of acetone is low, and the raw material is wasted. The reaction route is as follows:

[0010]

[0011] In summary, at present, the preparation of carbidopa mainly relies on intermittent reaction process, but these processes have the following technical problems:

[0012] 1) The substrate is highly toxic: sodium cyanide or sodium cyanate is used in most routes. Due to the high toxicity of sodium cyanide and sodium cyanate, it brings trouble to safety production and management, and makes the production cost and investment too high.

[0013] 2) Low reaction efficiency and long production cycle: The traditional process usually adopts multi-step intermittent reaction, including the preparation of 1-oxa-2-azaspiro[2.5]octane, condensation, hydrolysis and other steps. After each reaction, intermediate separation and purification are required, resulting in long total production cycle and low production efficiency. Especially in the hydrolysis process, the traditional kettle type process takes a long time, resulting in low production efficiency.

[0014] 3) High safety risk: The reaction of sodium hypochlorite oxidation to prepare 1-oxa-2-azaspiro[2.5]octane is a strong exothermic process and will produce a large amount of gas. When intermittent kettle operation is used, the temperature may rise rapidly due to the delay in heat dissipation, and there is a risk of explosion. A large amount of gas is released during the decomposition of 1-oxa-2-azaspiro[2.5]octane, and the traditional kettle type reaction has high safety risk.

[0015] 4) Poor economic benefit: The prepared 1-oxa-2-azaspiro[2.5]octane is easy to decompose, and the heat removal capacity of the traditional kettle type reaction is limited, so the reaction time is very long, which causes the continuous decomposition of 1-oxa-2-azaspiro[2.5]octane and the gradual increase of its dosage, resulting in the increase of cost. SUMMARY

[0016] In view of the above technical problems existing in the prior art, the present application provides a process and device for continuously synthesizing carbidopa from cyclohexanone and methyl dopa methyl ester, which realizes the continuous operation of low-temperature 1-oxa-2-azaspiro[2.5]octane preparation, condensation and hydrolysis reaction, improves the yield and purity, and reduces the safety risk.

[0017] The present application provides a method for preparing carbidopa by continuous flow synthesis process, and the synthesis route is as follows:

[0018] A process for preparing carbidopa by continuous flow reaction, comprising the following steps:

[0019] 1) The raw material cyclohexanone is dissolved in an organic solvent to obtain solution 1, and the solution 1 and the ammonia solution are respectively transported to the tubular reactor R1 for reaction, and the reaction liquid from the tubular reactor R1 is transported to the tubular reactor R2 for reaction with sodium hypochlorite solution;

[0020] 2) The reaction solution generated in step 1) is continuously separated by a gas-liquid-liquid separator to obtain an organic phase containing 1-oxa-2-azaspiro[2.5]octane, which is transported to a storage tank B for storage;

[0021] 3) The methyl dopa methyl ester is dissolved in an organic solvent to obtain a methyl dopa methyl ester solution, and the organic phase stored in step 2) and the methyl dopa methyl ester solution are respectively transported to a tubular reactor R3 for reaction. The reaction solution generated in the reaction is subjected to distillation to recover the solvent, thereby obtaining a methyl 2-[(cyclohexylidene)hydrazino]-3-(3,4-dihydroxyphenyl)-2-methylpropanoate solution;

[0022] 4) The solution obtained in step 3) and a concentrated hydrochloric acid solution are respectively transported to a tubular reactor R4 for reaction, thereby obtaining a carbidopa reaction solution, which is received in a reaction kettle C;

[0023] 5) A lye is transported to the reaction kettle C to adjust the pH value of the carbidopa reaction solution, thereby obtaining a carbidopa precipitate. Finally, the carbidopa precipitate is filtered, washed, and dried to obtain a carbidopa pure product.

[0024] Further, the organic solvent in step 1) is one or more of benzene, toluene, xylene, and dichloromethane, and toluene is preferred.

[0025] Further, in step 1), the mass fraction of cyclohexanone is 10% to 40%, the concentration of ammonia water is 10% to 25%, and the effective chlorine content of sodium hypochlorite is 6% to 13%; the molar flow ratio of cyclohexanone, ammonia water, and sodium hypochlorite is 1:0.1 to 5:0.1 to 5, and preferably 1:1 to 2:1 to 2.

[0026] Further, in step 1), the residence time of the material in the tubular reactor R1 is 1 to 15 minutes, and preferably 5 to 15 minutes; and the residence time of the material in the tubular reactor R2 is 1 to 120 seconds, and preferably 10 to 60 seconds.

[0027] Further, the reaction temperature in the tubular reactor R1 and the tubular reactor R2 is -10 to 10°C, and preferably -5 to 5°C.

[0028] Further, the inner diameter of the tubular reactor R1 and the tubular reactor R2 is 1 to 10 mm.

[0029] Further, the tubular reactor R1 and the tubular reactor R2 are both filled with spherical media, the inner diameter of the tubular reactor R1 and the tubular reactor R2 is greater than the diameter of the spherical media, and the diameter of the spherical media is 0.5 to 5 mm.

[0030] Further, in step 2), the gas-liquid-liquid phase separator is a cross four-way pipe structure with one inlet and three outlets, one side of which is a horizontal inlet receiving the reaction liquid flowing out of the tubular reactor R2, the opposite side of which is a horizontal outlet discharging the separated organic phase, the upper vertical outlet discharging the gas, and the lower vertical outlet discharging the aqueous phase.

[0031] Further, the phase separation time in the gas-liquid-liquid phase separator is 1-20 s. The inner diameter of the one inlet and the three outlets of the cross four-way pipe is 1-50 mm, preferably 10-20 mm.

[0032] Further, the storage temperature in the storage tank B in step 2) is -10-10°C, preferably -1-1°C.

[0033] Further, the organic solvent for dissolving methyl dopa methyl ester in step 3) is one or both of methanol and ethanol.

[0034] Further, the concentration of the methyl dopa methyl ester solution in step 3) is 0.1-5 mol / L; and the molar flow ratio of methyl dopa methyl ester to 1-oxa-2-azaspiro[2.5]octane is 1:1-5, preferably 1:1-2.

[0035] Further, in step 3), the reaction temperature in the tubular reactor R3 is 20-90°C, preferably 40-58°C; the residence time of the material in the tubular reactor R3 is 0.5-15 min, preferably 1-3 min; and the inner diameter of the tube of the tubular reactor R3 is 1.7-12 mm.

[0036] Further, in step 4), the concentration of the concentrated hydrochloric acid is 20%-37%, preferably 30%-37%; and the molar flow ratio of the concentrated hydrochloric acid to methyl dopa methyl ester is 1-2:1, preferably 1-1.5:1.

[0037] Further, in step 4), the reaction temperature in the tubular reactor R4 is 80-180°C, preferably 120-160°C; and the residence time of the material in the tubular reactor R4 is 0.5-10 h, preferably 0.5-2 h.

[0038] Further, the inner diameter of the tube of the tubular reactor R4 is 1.7-21 mm, and the material is selected from 316L, Hastelloy, tantalum, silicon carbide, and other corrosion-resistant materials with good heat conduction performance.

[0039] Further, in order to increase the hydrolysis temperature and accelerate the hydrolysis speed, the reaction pressure in the tubular reactor R4 is 0.3-2 MPa.

[0040] Further, in step 5), the alkali liquor is selected from one or more of sodium hydroxide, ammonia water and potassium hydroxide as a pH regulator, preferably ammonia water; the concentration of ammonia water is 10% to 25%; in step 5), the pH value is adjusted to 1 to 5, preferably the pH value is adjusted to 3 to 4, and after cooling and crystallization, filtration, washing and drying, the pure carbidopa is obtained.

[0041] The reaction device of the present application comprises a tubular reactor R1, a tubular reactor R2, a gas-liquid-liquid separator, a storage tank B, a tubular reactor R3, a distillation device, a tubular reactor R4 and a reaction kettle C connected in sequence.

[0042] Compared with the prior art, the present application has the following beneficial effects by using the above method:

[0043] 1) The substrate is green and environmentally friendly. The process route avoids the use of highly toxic raw materials such as sodium cyanide or sodium cyanate, avoiding the trouble of safety production and management.

[0044] 2) High production efficiency and short reaction period. The present application first realizes the continuous preparation of carbidopa in the whole process of 1-oxa-2-azaspiro[2.5]octane preparation, condensation, hydrolysis and neutralization. The reaction process is continuous, pipelined and closed, which significantly improves the automation level of the process. Compared with the previously reported tank reaction process, the quality is improved while the reaction time is greatly shortened, and the material consumption is greatly reduced. In the hydrolysis process, the hydrolysis temperature is increased by pressurization, which greatly shortens the reaction time and greatly improves the production efficiency.

[0045] 3) Reduce production risk. The process route avoids the problem of safety hidden trouble caused by a large amount of gas generated by product decomposition during the preparation, storage and use of 1-oxa-2-azaspiro[2.5]octane, significantly enhances the intrinsic safety of the process, and greatly reduces the production risk.

[0046] 4) Reduce production cost. The raw material cost is lower, the process selects relatively cheap and easily available solvents and substrates, the recovered toluene, cyclohexanone and methanol can be recycled, the amount of three wastes is small, and the post-treatment is simple. BRIEF DESCRIPTION OF DRAWINGS

[0047] Figure 1 The reaction flow chart for the continuous flow reaction preparation of carbidopa of the present application. DETAILED DESCRIPTION

[0048] The present application is further described in detail below in combination with examples.

[0049] The reaction flow chart for the continuous flow reaction preparation of carbidopa of the present application is shown in Figure 1The reaction device of the application comprises: a 1-oxa-2-azaspiro[2.5]octane preparation module S1, a gas-liquid-liquid three-phase separation module S2, a 2-[(cyclohexylidene)hydrazino]-3-(3,4-dihydroxyphenyl)-2-methylpropionic acid methyl ester preparation module S3, a continuous distillation device module S4, a 2-[(cyclohexylidene)hydrazino]-3-(3,4-dihydroxyphenyl)-2-methylpropionic acid methyl ester hydrolysis module S5, and an acid-base neutralization module S6.

[0050] In the device structure of the 1-oxa-2-azaspiro[2.5]octane preparation module S1, the inlet of the tubular reactor R1 is divided into two routes, one of which is connected by pipelines in sequence with the pre-cooling pipeline A1 and the metering pump P1, and the other of which is connected by pipelines in sequence with the pre-cooling pipeline A2 and the metering pump P2. The inlet of the tubular reactor R2 is divided into two routes, one of which is connected with the outlet of the tubular reactor R1, and the other of which is connected by pipelines in sequence with the pre-cooling pipeline A3 and the metering pump P3. The outlet of the tubular reactor R2 discharges the 1-oxa-2-azaspiro[2.5]octane reaction liquid into the gas-liquid-liquid three-phase separation module (S2).

[0051] The gas-liquid-liquid three-phase separation module S2 comprises a gas-liquid-liquid separator and a metering pump P4. The gas-liquid-liquid separator is a glass cross structure four-way, which comprises a reaction liquid inlet D1 and three outlets, namely an upper vertical gas outlet D2, a lower vertical water phase outlet D4, and a middle horizontal organic phase outlet D3. The reaction liquid inlet D1 is connected with the outlet of the tubular reactor R2, the 1-oxa-2-azaspiro[2.5]octane reaction liquid enters the glass cross structure four-way, by the action of gravity, the water phase is pumped out of the separation system by the metering pump P4 from the water phase outlet D4 at the lower end of the glass cross structure four-way, the gas is discharged from the gas outlet D2 at the upper end of the glass cross structure four-way, and the organic phase obtained by separation is discharged through the organic phase outlet D3 of the glass cross structure four-way and stored in the storage tank B.

[0052] The 2-[(cyclohexylidene)hydrazino]-3-(3,4-dihydroxyphenyl)-2-methylpropionic acid methyl ester preparation module S3 comprises a tubular reactor R3, a metering pump P5, a metering pump P6, a preheating tube A4, a preheating tube A5, and a storage tank B. The inlet of the tubular reactor R3 is divided into two routes, one of which is connected by pipelines in sequence with the preheating pipeline A4, the metering pump P5, and the storage tank B, and the other of which is connected by pipelines in sequence with the preheating pipeline A5 and the metering pump P6. The outlet of the tubular reactor R3 discharges the 2-[(cyclohexylidene)hydrazino]-3-(3,4-dihydroxyphenyl)-2-methylpropionic acid methyl ester reaction liquid into the continuous distillation device module S4.

[0053] The continuous distillation device module S4 is used to remove the solvents such as methanol existing in the reaction liquid system, and comprises a three-neck flask, the feed inlet E1 is connected with the outlet of the reactor R3, and the discharge outlet E2 is connected with the metering pump P7.

[0054] 2-[(cyclohexylidene)hydrazinyl]-3-(3,4-dihydroxyphenyl)-2-methylpropionic acid methyl ester hydrolysis module S5 includes a tubular reactor R4, a metering pump P7, a metering pump P8, a preheating tube A6, a preheating tube A7 and a back pressure valve BPR. The inlet of the tubular reactor R4 is divided into two routes, one of which is connected with the preheating tube A6 and the metering pump P7, and the other of which is connected with the preheating tube A7 and the metering pump P8. The outlet pipeline of the tubular reactor R4 is provided with the back pressure valve BPR, and the outlet of the tubular reactor R4 discharges the carbidopa reaction liquid into the reaction kettle C.

[0055] Acid-base neutralization module S6 includes a reaction kettle C, a metering pump P9 and a precooling tube A8. The inlet of the reaction kettle C is connected with the outlet of the tubular reactor R4 by a pipeline through the back pressure valve BPR. The inlet of the reaction kettle C is also connected with the precooling tube A8 and the metering pump P9 in sequence through a pipeline.

[0056] The experiments of the embodiments 1-6 of the present application adopt the reaction flow as shown in Figure 1 .

[0057] Embodiment 1

[0058] 1) Synthesis of 1-oxa-2-azaspiro[2.5]octane

[0059] Cyclohexanone 200.0 g was weighed, toluene 370.00 mL was added, and after stirring uniformly, a mixed solution 1 was obtained. 25% ammonia water was used as a solution 2, and sodium hypochlorite with an effective chlorine content of 13% was used as a solution 3.

[0060] The flow rates of the metering pumps P1 and P2 were set so that the molar ratio of cyclohexanone: ammonia water: sodium hypochlorite was 1:1:1. The metering pumps P1 and P2 were turned on, and the solution 1 and the solution 2 were delivered to the tubular reactor R1 (inner diameter 2.175 mm) containing fine glass beads (diameter 1 mm) by the metering pumps P1 and P2 respectively. The T1 temperature in the tubular reactor R1 was 0°C, and the residence time in the tubular reactor R1 was 10 min. After 10 min, the metering pump P3 was turned on, and the solution 3 was pumped into the tubular reactor R2 (inner diameter 2.175 mm) containing fine glass beads (diameter 1 mm) to react with the reaction liquid from the tubular reactor R1. The T2 temperature in the tubular reactor R2 was 0°C, and the residence time in the tubular reactor R2 was 30 s. The reaction liquid from the tubular reactor R2 was separated into phases by a gas-liquid-liquid phase separator, and the organic phase from the organic phase outlet D3 was collected. The organic phase was denoted as solution 4 and was temporarily stored in a low-temperature storage tank B, and the temperature in the storage tank B was 0°C. The continuously obtained organic phase was sampled and titrated, and the product yield was 23.66%.

[0061] 2) Synthesis reaction of 2-[(cyclohexylidene)hydrazinyl]-3-(3,4-dihydroxyphenyl)-2-methylpropionic acid methyl ester

[0062] Methyl dopa methyl ester 112.62 g was weighed, methanol 791.8 g was added, heated and dissolved to prepare solution 5. Solution 4 was delivered by metering pump P5 and solution 5 was delivered by metering pump P6. The flow rates of metering pumps P5 and P6 were set so that the flow molar ratio of methyl dopa methyl ester: 1-oxa-2-azaspiro[2.5]octane = 1:1. Metering pumps P5 and P6 were started to deliver solution 4 and solution 5 into tubular reactor R3 (inner diameter 2.175 mm). The reaction temperature T3 in tubular reactor R3 was 65°C and the reaction residence time was 2 min.

[0063] 3) Distillation of reaction liquid to remove methanol

[0064] The reaction liquid was delivered from tubular reactor R3 into distillation module S4. The distillation temperature was set to 70°C and the distillation was carried out under normal pressure. After methanol was distilled off, reaction liquid 7 was obtained. The distilled methanol was reused.

[0065] 4) Hydrolysis reaction

[0066] Metering pump P7 delivered reaction liquid 7 from which methanol was removed and metering pump P8 delivered solution 8 which was 20% hydrochloric acid solution. The flow rates of metering pumps P7 and P8 were set so that the flow molar ratio of methyl dopa methyl ester: HCl = 1:1.2. Metering pump P7 was started to pump reaction liquid 7 into tubular reactor R4 and metering pump P8 was started to pump 20% hydrochloric acid solution into tubular reactor R4 (inner diameter 2.175 mm). The pressure of back pressure valve was adjusted so that the internal pressure of tubular reactor R4 was 0.5 MPa. The reaction temperature T4 of tubular reactor R4 was 150°C and the reaction residence time was 60 min.

[0067] 5) Neutralization reaction

[0068] The neutralization reactor received the reaction liquid from tubular reactor R4. 10% ammonia water was used as the alkali solution. Metering pump P9 was started to pump 10% ammonia water solution into the neutralization reactor C. The pH value was continuously monitored and the addition of alkali solution was stopped when the pH value was about 3.5. The neutralized reaction liquid was filtered, the filter cake was washed with pure water and dried to obtain white solid 89.93 g. The total yield was 79.5% and the purity was 99% based on methyl dopa methyl ester as the starting material. The filtrate was separated to recover toluene and cyclohexanone.

[0069] Example 2

[0070] 1) Synthesis of 1-oxa-2-azaspiro[2.5]octane

[0071] Take cyclohexanone 200.0 g, add toluene 370.00 mL, stir evenly to get mixed solution 1, use 25% ammonia water as solution 2, use sodium hypochlorite with effective chlorine content of 13% as solution 3. Set the flow rate of metering pumps P1, P2, P3 so that the flow molar ratio of cyclohexanone:ammonia water:sodium hypochlorite is 1:2:2. Turn on metering pumps P1, P2, and deliver solution 1 and solution 2 to tubular reactor R1 (inner diameter 4.35 mm) containing fine glass beads (diameter 2 mm) using metering pumps P1 and P2 respectively, the T1 temperature in the tubular reactor R1 is 5°C, the residence time in the tubular reactor R1 is 15 min, after 15 min, turn on metering pump P3, and pump solution 3 into tubular reactor R2 (inner diameter 4.35 mm) containing fine glass beads (diameter 2 mm) to react with the reaction liquid from tubular reactor R1. The T2 temperature in the tubular reactor R2 is 5°C, and the residence time in the tubular reactor R2 is 60 s. The reaction liquid coming out of the tubular reactor R2 is separated into phases by a gas-liquid-liquid phase separator, and the organic phase from the organic phase outlet D3 is collected, and the organic phase is recorded as solution 4 and stored in a low-temperature storage tank B, and the temperature in the storage tank B is 0°C. The continuously obtained organic phase is sampled and titrated, and the product yield is 35.35%.

[0072] 2) Synthesis of 2-[(cyclohexylidene)hydrazino]-3-(3,4-dihydroxyphenyl)-2- methylpropanoic acid methyl ester

[0073] Take methyl dopa methyl ester 112.62 g, add methanol 791.8 g, heat to dissolve, and prepare solution 5. Deliver solution 4 using metering pump P5, and deliver solution 5 using metering pump P6, and set the flow rate of metering pumps P5, P6 so that the flow molar ratio of methyl dopa methyl ester:1-oxa-2-azaspiro[2.5]octane is 1:2.0, turn on metering pumps P5, P6, and deliver solution 4 and solution 5 to tubular reactor R3 (inner diameter 2.175 mm), and the reaction temperature T3 in the tubular reactor R3 is 55°C, and the reaction residence time is 5 min.

[0074] 3) Distillation of reaction liquid to remove methanol

[0075] The reaction liquid is delivered from tubular reactor R3 to distillation module S4, and the distillation temperature is set to 55°C, and the gauge pressure is -0.05 MPa, and after distilling off the methanol, reaction liquid 7 is obtained. The distilled off methanol is reused.

[0076] 4) Hydrolysis reaction

[0077] The solution 7 from which methanol was removed was delivered by metering pump P7 and the solution 8 was delivered by metering pump P8. The solution 8 was a 10% hydrochloric acid solution. The flow rates of the metering pumps P7 and P8 were set so that the molar ratio of methyl dopa methyl ester: HCl = 1 : 1.5. The metering pumps were started and the metering pump P7 pumped the solution 7 from which methanol was removed into the tubular reactor R4 and the metering pump P8 pumped the 10% hydrochloric acid solution into the tubular reactor R4 (internal diameter 2.175 mm). The pressure of the back pressure valve was adjusted so that the internal pressure of the tubular reactor R4 was 0.5 MPa. The reaction temperature T4 of the tubular reactor R4 was 150°C and the reaction residence time was 60 min.

[0078] 5) Neutralization reaction

[0079] The neutralization reactor received the reaction solution from the tubular reactor R4. The base solution was 15% ammonia water. The pump P9 was started and the 15% ammonia water solution was pumped into the neutralization reactor C. The solution was continuously stirred and the addition of the base solution was stopped when the pH value was about 3.5. The neutralized reaction solution was filtered and the filter cake was washed with pure water and dried to obtain a light yellow solid 101.69 g. The total yield was 89.9% and the purity was 96% based on the methyl dopa methyl ester as the starting material. The filtrate was separated and the toluene and cyclohexanone were recovered.

[0080] Example 3

[0081] 1) Synthesis of 1-oxa-2-azaspiro[2.5]octane

[0082] Cyclohexanone 200.0 g was weighed and toluene 370.00 mL was added to obtain a mixed solution 1. 25% ammonia water was used as the solution 2 and sodium hypochlorite with an available chlorine content of 13% was used as the solution 3. The flow rates of the metering pumps P1, P2 and P3 were set so that the molar ratio of cyclohexanone: ammonia water: sodium hypochlorite = 1 : 2 : 2. The metering pumps P1 and P2 were started and the solution 1 and the solution 2 were delivered by the metering pumps P1 and P2 respectively into the tubular reactor R1 (internal diameter 2.175 mm) which was provided with fine glass beads (diameter 1 mm). The T1 temperature in the tubular reactor R1 was -5°C and the residence time in the tubular reactor R1 was 15 min. After 15 min, the metering pump P3 was started and the solution 3 was pumped into the tubular reactor R2 (internal diameter 2.175 mm) which was provided with fine glass beads (diameter 1 mm) and reacted with the reaction solution from the tubular reactor R1. The T2 temperature in the tubular reactor R2 was -5°C and the residence time in the tubular reactor R2 was 18 s. The reaction solution from the tubular reactor R2 was separated into phases by a gas-liquid-liquid phase separator and the organic phase from the outlet D3 was collected. The organic phase was temporarily stored in the low temperature storage tank B which had a temperature of -1°C. The continuously obtained organic phase was sampled and titrated and the product content yield was 47.89%.

[0083] 2) Synthesis reaction of 2-[(cyclohexylidene)hydrazino]-3-(3,4-dihydroxyphenyl)-2- methylpropanoic acid methyl ester

[0084] Methyl dopa methyl ester 112.62 g was weighed, added to methanol 791.8 g, heated and dissolved to prepare solution 5. Solution 4 was delivered by metering pump P5 and solution 5 was delivered by metering pump P6. The flow rates of metering pumps P5 and P6 were set so that the flow molar ratio of methyl dopa methyl ester: 1-oxa-2-azaspiro[2.5]octane = 1:1.4. Metering pumps P5 and P6 were started and solutions 4 and 5 were delivered to tubular reactor R3 (inner diameter 2.175 mm). The reaction temperature T3 in tubular reactor R3 was 65°C and the reaction residence time was 2 min.

[0085] 3) Distillation of reaction liquid to remove methanol

[0086] The reaction liquid was delivered from tubular reactor R3 to distillation module S4. The distillation temperature was set to 40°C and the pressure was set to -0.08 MPa. After distillation of methanol, reaction liquid 7 was obtained. The distilled methanol was reused.

[0087] 4) Hydrolysis reaction

[0088] Metering pump P7 delivered reaction liquid 7 from which methanol had been removed and metering pump P8 delivered solution 8 which was 36% hydrochloric acid solution. The flow rates of metering pumps P7 and P8 were set so that the flow molar ratio of methyl dopa methyl ester: HC1 = 1:1.5. Metering pumps were started and metering pump P7 delivered reaction liquid from which methanol had been removed to tubular reactor R4 and metering pump P8 delivered 36% hydrochloric acid solution to tubular reactor R4 (inner diameter 2.175 mm). The pressure of back pressure valve was adjusted so that the internal pressure of tubular reactor R4 was 0.5 MPa. The reaction temperature T4 of tubular reactor R4 was 160°C and the reaction residence time was 45 min.

[0089] 5) Neutralization reaction

[0090] The neutralization reactor received the reaction liquid from tubular reactor R4. 20% ammonia water was used as the alkali solution. Pump P9 was started and 20% ammonia water solution was pumped into the neutralization reactor C. The pH value was continuously monitored and the addition of alkali solution was stopped when the pH value was about 3.5. The neutralized reaction liquid was filtered, the filter cake was washed with pure water and dried to obtain white solid 101.92. The total yield was 90.1% and the purity was 99.0% based on methyl dopa methyl ester. The filtrate was separated and toluene and cyclohexanone were recovered

[0091] Example 4

[0092] Example 4 was carried out in the same way as Example 3 except that the following two conditions of step 4) hydrolysis reaction were changed:

[0093] 1) Adjust the delivery flow rate of metering pump P8 so that the flow molar ratio of methyl dopa methyl ester: HCl = 1:2.

[0094] 2) Adjust the back pressure valve pressure so that the internal pressure of tubular reactor R4 is 1 MPa, the reaction temperature T4 of tubular reactor R4 is 180°C, and the reaction residence time is 30 min.

[0095] The neutralization reaction process of Example 4 is the same as that of Example 3. After the neutralization reaction of Example 4 is completed, the reaction solution is filtered, the filter cake is washed and dried, and the reaction results are: 96.94 g of white solid is obtained, with a total yield of 85.7% and a purity of 98.1% based on methyl dopa methyl ester. The filtrate is separated, and toluene and cyclohexanone are recovered.

[0096] Example 5

[0097] The experimental process of Example 5 is the same as that of Example 3, except that the following conditions are changed in step 1):

[0098] 1) The cyclohexanone and toluene used in the preparation of solution 1 are both recovered. 200.0 g of recovered cyclohexanone and 370.00 mL of recovered toluene are weighed, and after stirring uniformly, a mixed solution 1 is obtained.

[0099] 2) The T1 temperature in tubular reactor R1 is 5°C, the R1 reactor residence time is 15 min, and after 15 min, metering pump P3 is opened to pump solution 3 into tubular reactor R2 (inner diameter 2.175 mm) containing fine glass beads (diameter 1 mm) to react with the reaction solution from tubular reactor R1. The T2 temperature in tubular reactor R2 is 5°C, and the residence time in tubular reactor R2 is 18 s. The reaction solution from tubular reactor R2 is separated by a gas-liquid-liquid phase separator, and the organic phase from outlet D3 is collected. The organic phase is temporarily stored in low-temperature tank B, and the temperature in tank B is -1°C. The continuously obtained organic phase is sampled and titrated, and the yield of 1-oxa-2-azaspiro[2.5]octane product is 46.47%.

[0100] The remaining operations of Example 5 are the same as those of Example 3, and after the operations are completed, 100.90 g of white solid is obtained, with a total yield of 89.2% and a purity of 98.0% based on methyl dopa methyl ester.

[0101] Example 6

[0102] The experimental process is the same as that of Example 3, except that the solvent used in the preparation of solution 5 is recovered methanol. 112.62 g of methyl dopa methyl ester is weighed and added to 791.8 g of recovered methanol, and after heating and dissolving, solution 5 is prepared. The remaining operations are the same as those of Example 3, and after the operations are completed, 99.88 g of white solid is obtained, with a total yield of 88.3% and a purity of 98.6% based on methyl dopa methyl ester.

Claims

1. A process for the preparation of carbidopa in continuous flow reaction characterized in that, The method comprises the following steps: 1) dissolving cyclohexanone in an organic solvent to obtain solution 1, and conveying the solution 1 and an ammonia solution to a tubular reactor R1 respectively for reaction, and conveying the reaction liquid flowing out of the tubular reactor R1 and a sodium hypochlorite solution to a tubular reactor R2 respectively for reaction; 2) continuously separating the reaction liquid generated in the step 1) through a gas-liquid-liquid phase separator to obtain an organic phase containing 1-oxa-2-azaspiro[2.5]octane, and conveying the organic phase to a storage tank B for storage; 3) dissolving methyl dopa methyl ester in an organic solvent to obtain a methyl dopa methyl ester solution, and conveying the organic phase stored in the step 2) and the methyl dopa methyl ester solution to a tubular reactor R3 respectively for reaction, and recovering the solvent through distillation to obtain a 2-[(cyclohexylidene)hydrazino]-3-(3,4-dihydroxyphenyl)-2-methylpropionic acid methyl ester solution; 4) conveying the 2-[(cyclohexylidene)hydrazino]-3-(3,4-dihydroxyphenyl)-2-methylpropionic acid methyl ester solution and a concentrated hydrochloric acid solution to a tubular reactor R4 respectively for reaction to obtain a carbidopa reaction liquid, and receiving the carbidopa reaction liquid in a reaction kettle C; 5) conveying a lye to the reaction kettle C to adjust the pH value of the carbidopa reaction liquid to obtain carbidopa precipitate, and finally filtering, washing and drying to obtain carbidopa pure product.

2. A process for the preparation of carbidopa in continuous flow reaction as claimed in claim 1 wherein, In the step 1), the organic solvent is one or more of benzene, toluene, xylene and dichloromethane, and toluene is preferred; the mass fraction of cyclohexanone is 10% to 40%, the ammonia water concentration is 10% to 25%, and the effective chlorine content of the sodium hypochlorite is 6% to 13%; the molar flow rate ratio of cyclohexanone, ammonia water and sodium hypochlorite is 1:0.1 to 5:0.1 to 5, and 1:1 to 2:1 to 2 is preferred.

3. A process for the preparation of carbidopa in continuous flow reaction as claimed in claim 1 wherein, In the step 1), the material residence time in the tubular reactor R1 is 1 to 15 minutes, and 5 to 15 minutes is preferred; the material residence time in the tubular reactor R2 is 1 to 120 seconds, and 10 to 60 seconds is preferred; The reaction temperature in the tubular reactor R1 and the tubular reactor R2 is-10 to 10 ℃, and-5 to 5 ℃ is preferred; The inner diameter of the tubes of the tubular reactor R1 and the tubular reactor R2 is 1 to 10 mm.

4. A process for the preparation of carbidopa in continuous flow reaction as claimed in claim 1 wherein, In the step 2), the gas-liquid-liquid phase separator is a cross four-way pipe structure with one inlet and three outlets, one side horizontal inlet receives the reaction liquid flowing out of the tubular reactor R2, the opposite side horizontal outlet discharges the separated organic phase, the upper vertical outlet discharges gas, and the lower vertical outlet discharges water phase; The storage temperature in the storage tank B in the step 2) is-10 to 10 ℃, and-1 to 1 ℃ is preferred.

5. A process for the preparation of carbidopa in continuous flow reaction as claimed in claim 1 wherein, In the step 3), the organic solvent for dissolving the methyl dopa methyl ester is one or both of methanol and ethanol, the concentration of the methyl dopa methyl ester solution in the step 3) is 0.1 to 5 mol / L, and the molar flow rate ratio of the methyl dopa methyl ester and 1-oxa-2-azaspiro[2.5]octane is 1:1 to 5, and 1:1 to 2 is preferred.

6. A process for the preparation of carbidopa in continuous flow reaction as claimed in claim 1 wherein, In the step 3), the reaction temperature in the tubular reactor R3 is 20 to 90 ℃, and 40 to 58 ℃ is preferred; the material residence time in the tubular reactor R3 is 0.5 to 15 minutes, and 1 to 3 minutes is preferred; and the inner diameter of the tube of the tubular reactor R3 is 1.7 mm to 12 mm.

7. A process for the preparation of carbidopa in continuous flow reaction as claimed in claim 1 wherein, The concentration of the concentrated hydrochloric acid in step 4) is 20% to 37%, preferably 30% to 37%; the molar flow ratio of the concentrated hydrochloric acid to the methyl dopa methyl ester is 1 to 2:1, preferably 1 to 1.5:

1.

8. A process for the preparation of carbidopa in continuous flow reaction as claimed in claim 1 wherein, In step 4), the reaction temperature in the tubular reactor R4 is 80 to 180°C, preferably 120 to 160°C; the residence time of the material in the tubular reactor R4 is 0.5 to 10 h, preferably 0.5 to 2 h; The inner diameter of the tubular reactor R4 is 1.7 mm to 21 mm, and the reaction pressure in the tubular reactor R4 is 0.3 to 2 MPa.

9. A process for the preparation of carbidopa in continuous flow reaction as claimed in claim 1 wherein, In step 5), the alkali solution as the pH regulator is selected from one or more of sodium hydroxide, ammonia, and potassium hydroxide, preferably ammonia; the concentration of the ammonia is 10% to 25%; the pH value is adjusted to 1 to 5 in step 5), preferably 3 to 4, and after cooling and crystallization, filtration, washing, and drying, the pure carbidopa is obtained.

10. The process according to claim 1, wherein the reaction apparatus used in the process is characterized by, The reaction system comprises, in sequence, a tubular reactor R1, a tubular reactor R2, a gas-liquid-liquid phase separator, a storage tank B, a tubular reactor R3, a distillation device, a tubular reactor R4, and a reaction kettle C.

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