Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the invention relates to a continuous method for the synthesis of tadalafil from methyl ( 1 R,3R)- 1 -( 1 ,3 -benzodioxol-5 -y l)-2 ,3 ,4,9-tetrahydro-2-chloroacetyl- 1 H-pyrido [3 ,4-b] indole-3 - carboxy late .
• Tadalafil is an effective reversible selective inhibitor of specific phosphodiesterase type 5 (PDE5) of cyclic guanosine monophosphate (cGMP). It was first developed by GlaxoSmithKline (GSK) and approved by FDA in 2003 for the treatment of erectile dysfunction (ED) in men.
• PDE5 specific phosphodiesterase type 5
• cGMP cyclic guanosine monophosphate
• Erectile dysfunction is the inability to develop and/or maintain an erection sufficient during sexual activity.
• ED remains an important social and medical problem all over the world, and not only the condition of the working male population, but also the general family and social level depends on its solution. Therefore, taking into account the social status of the problem, this problem should be attributed to socially significant ones that require affordable medical care for all social groups of the population.
• Tadalafil was also approved by FDA in 2006 for the treatment of pulmonary arterial hypertension, and therefore, the need in a greater amount of the substance arose.
• Tadalafil (CAS 171596-29-5) is known as (6R, 12aR)-6-(1,3-benzodioxol-5- yl)-2,3,6,7, 12, 12a-hexahydro-2-methylpyrazino[1',2': 1 ,6]pyrido [3, 4-b] indole- 1 ,4- dione, and its chemical structure is presented below:
• tadalafil is synthesised from crystals of methyl (lR,3R)-l-(l,3-benzodioxol-5-yl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-lH- pyrido[3,4-b]indole-3-carboxylate using tetrahydrofuran (THF) as a solvent with addition of an aqueous solution of methylamine.
• THF tetrahydrofuran
• the new continuous method of obtaining tadalafil proposed by us will allow making synthesis of the product without hard-to-remove impurities, with stable quality and yield in a much shorter time at a lower temperature regardless of the weight of the lot.
• the aim of the invention is to obtain tadalafil (I) in a continuous manner in a flow reactor from methyl (lR,3R)-l-(l,3-benzodioxol-5-yl)-2- (chloroacetyl)-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole-3-carboxylate in a short time of reaction.
• Another feature of this invention is the possibility of using flow reactors, preferably micro- or millireactors, for continuous production of tadalafil.
• continuous and continuous method means that production processes are carried out in such a way that the supply of raw materials and the isolation of final products during these processes are carried out continuously or in portions without stopping the operation of the system as a whole. All stages of such a process at each point of the apparatus are carried out under the same conditions, which are unchanged for this point.
• the process of synthesis of tadalafil (I) is a continuous feed of the starting material - a solution of methyl (1R,3R)-1-(1 ,3- benzodioxol-5-yl)-2-(chloroacetyl)-2, 3 ,4,9-tetrahydro- lH-pyrido[3,4-b]indole-3- carboxylate (II) in an aprotic solvent and methylamine to the reactor at constant flow rates, temperature and pressure.
• the reaction time determined by the time of passage of the entire reactor volume remains constant.
• flow reactor means a reactor, in which the synthesis is possible in a continuous pattern, where all technological operations take place simultaneously.
• microreactor and “millireactor” mean a flow reactor characterized by high speed of mass transfer and heat transfer, with a small internal volume and small channel size, which allows working in a continuous mode, taking into account the constant parameters of the process over time and the possibility of its full automation. Intensive heat removal and heat transfer from the walls of the micro- and millireactor is explained by the large area of the channel with respect to its small internal volume, and therefore it is possible to conduct exothermic and endothermic reactions in such reactors under conditions that are nearly isothermal.
• Microreactors include flow reactors with an internal diameter/channel size in the range from 10-100 mm to 1 mm.
• the millireactors include flow reactors with an internal diameter/channel size in the range from 1 to 10 mm.
• the cross section of the micro- and milli-channel can be round, rectangular, and other shapes, while the channel can contain built-in static stirrers both along its entire length and only on one part of it, and the channel can also be made without static stirrers.
• Thermostating of reactors can be carried out using a liquid thermostat or using electrically heated elements, depending on the conditions of the reaction, the required temperature range and heat removal requirements.
• the invention proposes a continuous method for the production of tadalafil from methyl ( 1 R,3R)- 1 -( 1 ,3-benzodioxol-5-yl)-2-(chloroacetyl)-2,3 ,4,9-tetrahydro- 1 H-pyrido [3, 4-b] indole-3 -carboxylate (II).
• a solution of methyl (lR,3R)-l-(l,3-benzodioxol-5-yl)-2- (chloroacetyl)-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole-3-carboxylate (II) in an aprotic solvent is used as an initial solution in vessel V-l (Fig. 1 and 2).
• Methylamine a solution of methylamine or an aqueous solution of methylamine, preferably an aqueous solution of methylamine, is used as the starting reagent.
• the use of methylamine solution in the vessel for reagents V-2 is shown in Figure 1.
• the use of gaseous methylamine in the flask B is shown in Figure 2.
• Dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide, preferably dimethylformamide, is used as an aprotic solvent.
• the flow rates for the initial solution and reagent for pumps P-1 and P-2 are selected on the basis of the reaction time and are indicated in specific examples.
• the flow rates of the initial solution and gaseous methylamine are selected based on the time of the reaction and are indicated in specific examples.
• the operating time, the weight of the resulting product are particular cases for the continuous synthesis and are indicated in specific examples.
• Methylamine was used at stage 2 as the base which catalyzed the cyclization reaction by feeding it to the micro- or millireactor in excess at stage 1.
• the selection of reagents used in the invention and their concentrations allow using only two pumps and one micro- or millireactor in the continuous method of the production of tadalafil without the need for an additional supply of reagents at stage 2.
• the reaction was carried out using the isothermal method at a temperature selected for stages 1 and 2.
• the total reaction time at stages 1 and 2 in the micro- or millireactor is from 1 to 60 minutes, preferably from 2 to 20 minutes, even more preferably from 3 to 4.5 minutes.
• the pressure range used in the micro- or millireactor is from 1 to 40 bar, preferably in the range from 3 to 10 bar.
• Figure 1 presents a schematic view of the micro- or millireactor installation, which includes vessels V-l and V-2 for the initial solutions, pumps P-1 and P-2 for supplying these solutions, micro- or millireactor R, vessel V-3 for collecting the product.
• Syringe pumps with two syringes connected via a T-shaped mixer were used as pumps. Pump heads and syringes are made of materials resistant to corrosion.
• the micro- or millireactor R is made of Hastelloy, which is one of the most corrosion resistant alloys. Flows mixing occurs inside the micro- or millireactor.
• any commercially available micro- or millireactor can be used, in which reactions can be carried out in specified ranges of time, temperature and pressure.
• Figure 2 presents a schematic view of the micro- or millireactor installation, which includes a vessel V-l for the initial solution, a pump P for supplying this solution, a micro- or millireactor R, a cylinder with gaseous methylamine B, a gas flow regulator FC, a vessel V-2 for collecting the product.
• a syringe pump with two syringes connected via a T-shaped mixer was used as a pump. Pump heads and syringes are made of materials resistant to corrosion.
• the micro- or millireactor R is made of Hastelloy, which is one of the most corrosion-resistant alloys, the flows mixing occurs inside the micro- or millireactor.
• any commercially available micro- or millireactor can be used, in which reactions can be carried out in specified ranges of time, temperature and pressure.
• Flow 1 is created by the pump P-1, the flow rate is 7.5 ml/min.
• Flows 1 and 2 are fed into the millireactor and mixed directly in the millireactor.
• the temperature of the reaction mixture is maintained at 40 °C, the isothermal synthesis is carried out during the entire time of production. Thermostating is carried out by a liquid thermostat.
• the pressure in the millireactor is 8 bar.
• the exposure time of the reaction mixture in the millireactor was 3 min 42 sec.
• the product was collected at the outlet of the millireactor into the collector at room temperature, simultaneously a flow of methanol was added to the product stream at the rate of 30 ml/min, and the mixture was stirred at room temperature. After the end of the lot production, the mixture was fed to the Schott filter, the product was separated on the filter, after washing the product it was dried to constant weight, the mother liquor was collected and subjected to additional purification/evaporation to isolate the product residue.
• Flow 1 is created by the pump P-1, the flow rate is 7.5 ml/min.
• Flows 1 and 2 are fed into the millireactor and mixed directly in the millireactor.
• the temperature of the reaction mixture is maintained at 35 °C, the isothermal synthesis is carried out during the entire time of production. Thermostating is carried out by a liquid thermostat.
• the pressure in the millireactor is 8 bar.
• the exposure time of the reaction mixture in the millireactor was 3 min 42 sec.
• the product was collected at the outlet of the millireactor in the collector at room temperature. After collecting the product for 1 hour, methanol was added to the product in the collector. The volume ratio of methanol to the collected product solution comprised 4: 1, the mixture was stirred for 1 hour. The mixture was fed to the Schott filter, the product was separated on the filter, after washing the product it was dried to constant weight, the mother liquor was collected and subjected to additional purification/evaporation to isolate the product residue.
• Flow 1 is created by the pump P-1, the flow rate is 6.25 ml/min.
• Flows 1 and 2 are fed to the millireactor and are stirred there.
• the temperature of the reaction mixture is maintained at 40 °C, the isothermal synthesis is carried out during the entire time of production. Thermostating is carried out by a liquid thermostat.
• the pressure is 3 bar.
• the exposure time of the reaction mixture in millireactor is 4 min 18 sec.
• the product was collected at the outlet from the millireactor into the collector at room temperature, Flow 3 of methanol was simultaneously added to the product flow at the rate of 24 ml/min, the mixture was stirred at room temperature, then the mixture was fed to the Schott filter, the product was separated on the filter, after washing the product it was dried to constant weight, the mother liquor was collected and subjected to additional purification/evaporation to isolate residues of the product.
• Flow 1 is created by the pump P- 1 , the flow rate is 7.5 ml/min.
• Flows 1 and 2 are fed into the millireactor and mixed directly in the millireactor.
• the temperature of the reaction mixture is maintained at 30 °C, the isothermal synthesis is carried out during the entire time of production. Thermostating is carried out by a liquid thermostat.
• the pressure in the millireactor is 12 bar.
• the exposure time of the reaction mixture in the millireactor was 3 min 42 sec.
• the product was collected at the outlet of the millireactor in the collector at room temperature, at the same time methanol was added to the product flow, and the mixture was stirred at room temperature. After the end of the lot production, the mixture was fed to the Schott filter, the product was separated on the filter, after washing the product it was dried to constant weight, the mother liquor was collected and subjected to additional purification/evaporation to isolate the product residue.
• Flow 1 is created by the pump P-1, the flow rate is 3.75 ml/min.
• Flow 2 is created by the pump P-2, the flow rate is 0.85 ml/min.
• Flows 1 and 2 are fed into the microreactor and mixed directly in the microreactor.
• the temperature of the reaction mixture is maintained at 35 °C, the isothermal synthesis is carried out during the entire time of production. Thermostating is carried out by a liquid thermostat.
• the pressure in the microreactor is 2.5 bar.
• the exposure time of the reaction mixture in the microreactor was 1 min 44 sec.
• the product was collected at the outlet of the microreactor in the collector at room temperature, at the same time methanol was added to the product flow, and the mixture was stirred at room temperature. After the end of the lot production, the mixture was fed to the Schott filter, the product was separated on the filter, after washing the product it was dried to constant weight, the mother liquor was collected and subjected to additional purification/evaporation to isolate the product residue.
• Flow 1 is created by the pump P-1, the flow rate is 1.8 ml/min.
• Flows 1 and 2 are fed into the microreactor and mixed directly in the microreactor.
• the temperature of the reaction mixture is maintained at 40 °C, the isothermal synthesis is carried out during the entire time of production. Thermostating is carried out by a liquid thermostat.
• the pressure in the microreactor is 3.5 bar.
• the exposure time of the reaction mixture in the microreactor was 3 min 28 sec.
• the product was collected at the outlet of the microreactor in the collector at room temperature, at the same time methanol flow was added to the product flow, and the mixture was stirred at room temperature. After the end of the lot production, the mixture was fed to the Schott filter, the product was separated on the filter, after washing the product it was dried to constant weight, the mother liquor was collected and subjected to additional purification/evaporation to isolate the product residue.
• Flow 1 is created by the pump P-1, the flow rate is 2.5 ml/min.
• Flows 1 and 2 are fed into the microreactor and mixed directly in the microreactor.
• the temperature of the reaction mixture is maintained at 35 °C, the isothermal synthesis is carried out during the entire time of production. Thermostating is carried out by a liquid thermostat.
• the pressure in the microreactor is 2.5 bar.
• the exposure time of the reaction mixture in the microreactor was 2 min 36 sec.
• the product was collected at the outlet of the microreactor in the collector at room temperature, at the same time methanol was added to the product flow, and the mixture was stirred at room temperature. After the end of the lot production, the mixture was fed to the Schott filter, the product was separated on the filter, after washing the product it was dried to constant weight, the mother liquor was collected and subjected to additional purification/evaporation to isolate the product residue.
• Flow 1 is created by the pump P-1, the flow rate is 2.5 ml/min.
• Flows 1 and 2 are fed into the microreactor and mixed directly in the microreactor.
• the temperature of the reaction mixture is maintained at 35 °C, the isothermal synthesis is carried out during the entire time of production. Thermostating is carried out by a liquid thermostat.
• the pressure in the microreactor is 2.5 bar.
• the exposure time of the reaction mixture in the microreactor was 2 min 36 sec.
• the product was collected at the outlet of the microreactor in the collector at room temperature, at the same time methanol was added to the product flow, and the mixture was stirred at room temperature. After the end of the lot production, the mixture was fed to the Schott filter, the product was separated on the filter, after washing the product it was dried to constant weight, the mother liquor was collected and subjected to additional purification/evaporation to isolate the product residue.
• the temperature of the reaction mixture is maintained at 35 °C, the isothermal synthesis is carried out during the entire time of production. Thermostating is carried out by a liquid thermostat.
• the exposure time of the reaction mixture in millireactor is 4 min 30 sec. Flows 1 and 2 were fed to the millireactor for 1 hour and collected in the collector V-3.
• the product was collected at the outlet of the millireactor in the collector at room temperature. After collecting the product for 1 hour, methanol was added to the product in the collector. The volume ratio of methanol to the collected product solution comprised 4: 1, the mixture was stirred for 1 hour. The mixture was fed to the Schott filter, the product was separated on the filter, after washing the product it was dried to constant weight, the mother liquor was collected and subjected to additional purification/evaporation to isolate the product residue.
• the temperature of the reaction mixture is maintained at 40 °C, the isothermal synthesis is carried out during the entire time of production. Thermostating is carried out by a liquid thermostat.
• the exposure time of the reaction mixture in the microreactor was 3 min 12 sec.
• the product was collected at the outlet of the microreactor in the collector at room temperature. After collecting the product for 1 hour, methanol was added to the product in the collector. The volume ratio of methanol to the collected product solution comprised 4:1, the mixture was stirred for 1 hour. The mixture was fed to the Schott filter, the product was separated on the filter, after washing the product it was dried to constant weight, the mother liquor was collected and subjected to additional purification/evaporation to isolate the product residue.
• Flow 1 is created by the pump P-1, the flow rate is 0.83 ml/min.
• Flow 2 is created by the pump P-2, the flow rate is 0.19 ml/min.
• Flows 1 and 2 are fed into the millireactor and mixed directly in the millireactor.
• the temperature of the reaction mixture is maintained at 32 °C, the isothermal synthesis is carried out during the entire time of production. Thermostating is carried out by a liquid thermostat.
• the pressure in the millireactor is 7 bar.
• the exposure time of the reaction mixture in millireactor is 33 min 18 sec.
• the product was collected at the outlet of the millireactor in the collector at room temperature, at the same time methanol was added to the product flow, and the mixture was stirred at room temperature. After the end of the lot production, the mixture was fed to the Schott filter, the product was separated on the filter, after washing the product it was dried to constant weight, the mother liquor was collected and subjected to additional purification/evaporation to isolate the product residue.
• Flow 1 is created by the pump P-1, the flow rate is 2.5 ml/min.
• Flows 1 and 2 are fed into the microreactor and mixed directly in the microreactor.
• the temperature of the reaction mixture is maintained at 40 °C, the isothermal synthesis is carried out during the entire time of production. Thermostating is carried out by a liquid thermostat.
• the pressure in the microreactor is 2.8 bar.
• the exposure time of the reaction mixture in the microreactor was 2 min 36 sec.
• the product was collected at the outlet of the microreactor in the collector at room temperature, at the same time methanol was added to the product flow, and the mixture was stirred at room temperature. After the end of the lot production, the mixture was fed to the Schott filter, the product was separated on the filter, after washing the product it was dried to constant weight, the mother liquor was collected and subjected to additional purification/evaporation to isolate the product residue.

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• 2019
  • 2019-04-26 RU RU2019112922A patent/RU2692764C1/ru active
  • 2019-07-29 WO PCT/RU2019/000529 patent/WO2020218941A1/en active Application Filing

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