CN107337632A - A kind of preparation method of CV-4093 - Google Patents
A kind of preparation method of CV-4093 Download PDFInfo
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- CN107337632A CN107337632A CN201710723859.9A CN201710723859A CN107337632A CN 107337632 A CN107337632 A CN 107337632A CN 201710723859 A CN201710723859 A CN 201710723859A CN 107337632 A CN107337632 A CN 107337632A
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- piperazine
- ether
- water
- ethoxys
- benzhydryl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention discloses a kind of preparation method of CV-4093, belong to technical field of medicine preparation.The synthesis of N (2 ethoxy) piperazine is synthesized using piperazine as initiation material, 1 benzhydryl 4 (2 ethoxy) piperazine is synthesized again, then 2 (piperazinyl of 4 benzhydryl 1) ethyl acetoacetic esters are synthesized again, by 2 (piperazinyl of 4 benzhydryl 1) ethyl acetoacetic esters, m-nitrobenzaldehyde and β amino ethyl crotonates are dissolved in isopropanol, it is heated to reflux, solvent is evaporated off, residue is dissolved in chloroform, with being filtered after anhydrous sodium sulfate drying, filtrate decompression recycling design, residue adds methanol to being completely dissolved, hydrogen chloride is passed through under ice bath, solvent is evaporated off, residue adds methanol, add activated carbon decolorizing filtering, filtrate cools down to obtain CV-4093.A kind of preparation method of CV-4093 of the present invention, technique is simple, and high income, cost is low, and obtained product purity is high.
Description
Technical field
The present invention relates to a kind of preparation method of CV-4093, belong to technical field of medicine preparation.
Background technology
CV-4093, Chinese nickname：1,4- dihydro -2,6- dimethyl -4- m-nitro base -3,5- pyridinedicarboxylic acids
Methyl esters -2- (4- benzhydryl -1- piperazinyls) carbethoxy hydrochloride, English name is MANIDIPINE DIHYDROCHLORIDE,
CAS is numbered：89226-75-5, molecular formula：C35H39ClN4O6, molecular weight：647.1604
It is anti-hypertension class, yellow or light yellow crystalline powder, fusing point：174~182 DEG C, single impurity：≤
0.5%, total impurities：≤ 1.0%, loss on drying：≤ 6.0%, sulphate residues≤0.1%, heavy metal：≤ 0.001%.
Existing CV-4093 preparation method is complicated, and the rate of recovery is low, and product purity is low.
The content of the invention
In view of this, the invention provides a kind of preparation method of CV-4093, technique is simple, high income, cost
Low, obtained product purity is high.
The present invention solves above-mentioned technical problem by following technological means：
A kind of preparation method of CV-4093 of the present invention, it comprises the following steps：
(1) synthesis of N- (2- ethoxys) piperazine, piperazine and water are added in reaction bulb, ice bath is cooled to 15-20 DEG C, adds
Enter oxirane, in 30-35 DEG C of stirring reaction 2 hours, be then slowly heated to temperature as 108-110 DEG C, to distilling out 90%
Water when stop reaction, be cooled to 10 DEG C, be filtered to remove unreacted piperazine after standing, filtrate decompression distillation, collecting temperature is
125-127 DEG C, cut of pressure when being 1.6kPa, obtain canescence viscous oily matter N- (2- ethoxys) piperazine；
(2) synthesis of 1- benzhydryls -4- (2- ethoxys) piperazine, by N- (2- ethoxys) piperazine, Anhydrous potassium carbonate powder
End and DMF are added in reaction bulb, lower point of 3 batches of addition benzhydryl bromides of stirring, are stirred at room temperature 3.5 hours, are added water, carried with ether
Take, ether is mutually washed 2 times with saturated nacl aqueous solution, and 1- benzhydryls -4- (2- ethoxys) piperazine is obtained after concentration；
(3) synthesis of 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, by 1- benzhydryls -4- (2- hydroxyls
Ethyl) piperazine and ketene dimer mixing, be again heated to after being stirred at room temperature 5 hours 70-80 DEG C react 1 hour, after vacuum distillation will
Residue is dissolved in chloroform, is washed 2 times with saturated nacl aqueous solution, and micro- brown oil 2- (4- bis- are obtained after solvent is evaporated off
Benzyl -1- piperazinyls) ethyl acetoacetic ester；
(4) by 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, m-nitrobenzaldehyde and beta-amino crotons
Sour methyl esters is dissolved in isopropanol, heating reflux reaction 8 hours, removes solvent under reduced pressure, residue is dissolved in chloroform, is washed with water
3 times, with being filtered after anhydrous sodium sulfate drying, filtrate decompression recycling design, residue adds methanol to being completely dissolved, and leads under ice bath
Enter hydrogen chloride to pH=2, continue stirring 0.5 hour, remove solvent under reduced pressure, residue adds methanol, after being heated to dissolving, then adds
Enter activated carbon decolorizing, filter, crystallization after filtrate cooling, filter to obtain pale yellow crystals, as CV-4093.
Piperazine, water, the mass ratio of oxirane are 190-200 in the step (1):380-420:25-30, it is unreacted
Piperazine adds ether and washed, and is filtrated to get pure piperazine return and is used as raw material.
N- (2- ethoxys) piperazine in the step (2), Anhydrous potassium carbonate, DMF, the mass ratio of benzhydryl bromide and water are
45-50:50-55:400-550:90-100:950-1050, the ether volume of addition are 2-3 times of water volume, extracted by ether mistake
Journey is to mix ether with the aqueous solution, mixes 10-20min at normal temperatures, stirs to water droplet and be dispersed in ether, the grain of water droplet
Footpath is 0.1-0.2mm, is then stood, and layering obtains ether phase and aqueous phase, and obtained aqueous phase reclaims to obtain bromine by condensing crystallizing
Change potassium crystal, then saturated nacl aqueous solution and ether mix process, the volume ratio of saturated nacl aqueous solution and ether phase is 2-
3:1, temperature during concentration is 50-80 DEG C, and the solvent evaporated during concentration obtains ether by 20-30 DEG C of condensation recovery.
1- benzhydryls -4- (2- ethoxys) piperazine, ketene dimer, the mass ratio of chloroform are in the step (3)
90-95:25-30:500-700, vapo(u)rizing temperature is 80-150 DEG C during vacuum distillation, and pressure during distillation is 0.5-1kPa,.
2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, m-nitrobenzaldehyde, β in the step (4) -
Amino ethyl crotonate, isopropanol, the mass ratio of chloroform are 85-90:35-40:25-30:350-450:400-500, add
Heating-up temperature during heat backflow is 90-120 DEG C, and the addition of anhydrous sodium sulfate is 2-3 times of water quality in chloroform soln,
Temperature during ice bath is 5-10 DEG C.
The chemical equation of the present invention is as follows：
The present invention is synthesized by four steps, and using cheap piperazine, cost is low, and step is simple, simultaneously for initiation material
High income, the yield of each step are all higher than 70%, and comprehensive yield is higher than 35%, and solvent for use can largely reclaim profit again
With, reduce further cost, the reaction condition of each step is gentle, in preparation process without introduce heavy metal substance, avoid
The content of beary metal of final products is high.
Beneficial effects of the present invention：Technique is simple, and high income, cost is low, and obtained product purity is high.
Brief description of the drawings
The invention will be further described with reference to the accompanying drawings and examples.
Fig. 1 is the reacting flow chart of the present invention；
Fig. 2 is the reaction equation that the first step of the present invention prepares N- (2- ethoxys) piperazine；
Fig. 3 is the reaction equation that second step of the present invention prepares 1- benzhydryls -4- (2- ethoxys) piperazine；
Fig. 4 is the reaction side that the 3rd step of the invention prepares 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester
Formula；
Fig. 5 is the reaction equation that the 4th step of the invention prepares CV-4093.
Embodiment
Below with reference to accompanying drawing, the present invention is described in detail, as shown in figure 1, a kind of hydrochloric acid horse Buddhist nun of the present embodiment
Flat preparation method, it comprises the following steps：
(1) synthesis of N- (2- ethoxys) piperazine, piperazine and water are added in reaction bulb, ice bath is cooled to 15-20 DEG C, adds
Enter oxirane, in 30-35 DEG C of stirring reaction 2 hours, be then slowly heated to temperature as 108-110 DEG C, to distilling out 90%
Water when stop reaction, be cooled to 10 DEG C, be filtered to remove unreacted piperazine after standing, filtrate decompression distillation, collecting temperature is
125-127 DEG C, cut of pressure when being 1.6kPa, obtain canescence viscous oily matter N- (2- ethoxys) piperazine, as shown in Figure 2；
(2) synthesis of 1- benzhydryls -4- (2- ethoxys) piperazine, by N- (2- ethoxys) piperazine, Anhydrous potassium carbonate powder
End and DMF are added in reaction bulb, lower point of 3 batches of addition benzhydryl bromides of stirring, are stirred at room temperature 3.5 hours, are added water, carried with ether
Take, ether is mutually washed 2 times with saturated nacl aqueous solution, and 1- benzhydryls -4- (2- ethoxys) piperazine, such as Fig. 3 is obtained after concentration
It is shown；
(3) synthesis of 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, by 1- benzhydryls -4- (2- hydroxyls
Ethyl) piperazine and ketene dimer mixing, be again heated to after being stirred at room temperature 5 hours 70-80 DEG C react 1 hour, after vacuum distillation will
Residue is dissolved in chloroform, is washed 2 times with saturated nacl aqueous solution, and micro- brown oil 2- (4- bis- are obtained after solvent is evaporated off
Benzyl -1- piperazinyls) ethyl acetoacetic ester, as shown in Figure 4；
(4) by 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, m-nitrobenzaldehyde and beta-amino crotons
Sour methyl esters is dissolved in isopropanol, heating reflux reaction 8 hours, removes solvent under reduced pressure, residue is dissolved in chloroform, is washed with water
3 times, with being filtered after anhydrous sodium sulfate drying, filtrate decompression recycling design, residue adds methanol to being completely dissolved, and leads under ice bath
Enter hydrogen chloride to pH=2, continue stirring 0.5 hour, remove solvent under reduced pressure, residue adds methanol, after being heated to dissolving, then adds
Enter activated carbon decolorizing, filter, crystallization after filtrate cooling, filter to obtain pale yellow crystals, as CV-4093, as shown in Figure 5.
Piperazine, water, the mass ratio of oxirane are 190-200 in the step (1):380-420:25-30, it is unreacted
Piperazine adds ether and washed, and is filtrated to get pure piperazine return and is used as raw material.
N- (2- ethoxys) piperazine in the step (2), Anhydrous potassium carbonate, DMF, the mass ratio of benzhydryl bromide and water are
45-50:50-55:400-550:90-100:950-1050, the ether volume of addition are 2-3 times of water volume, extracted by ether mistake
Journey is to mix ether with the aqueous solution, mixes 10-20min at normal temperatures, stirs to water droplet and be dispersed in ether, the grain of water droplet
Footpath is 0.1-0.2mm, is then stood, and layering obtains ether phase and aqueous phase, and obtained aqueous phase reclaims to obtain bromine by condensing crystallizing
Change potassium crystal, then saturated nacl aqueous solution and ether mix process, the volume ratio of saturated nacl aqueous solution and ether phase is 2-
3:1, temperature during concentration is 50-80 DEG C, and the solvent evaporated during concentration obtains ether by 20-30 DEG C of condensation recovery.
1- benzhydryls -4- (2- ethoxys) piperazine, ketene dimer, the mass ratio of chloroform are in the step (3)
90-95:25-30:500-700, vapo(u)rizing temperature is 80-150 DEG C during vacuum distillation, and pressure during distillation is 0.5-1kPa.
2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, m-nitrobenzaldehyde, β in the step (4) -
Amino ethyl crotonate, isopropanol, the mass ratio of chloroform are 85-90:35-40:25-30:350-450:400-500, add
Heating-up temperature during heat backflow is 90-120 DEG C, and the addition of anhydrous sodium sulfate is 2-3 times of water quality in chloroform soln,
Temperature during ice bath is 5-10 DEG C.
Embodiment 1
1) synthesis of N- (2- ethoxys) piperazine
Piperazine (i.e. MNDP-0) 194g and water 400ml are added in reaction bulb, ice bath is cooled to 15-20 degree, adds epoxy
Ethane 26.5g, in 30-35 degree stirring reaction 2 hours, interior temperature 108-110 degree is then slowly heated to, to distilling water outlet 360ml
When stop reaction, be cooled to 10 degree, be filtered to remove unreacted piperazine after standing, filtrate decompression distillation, collect 125-127 degree/
1.6kPa cuts, obtain canescence viscous oily matter 1- benzhydryls -4- (2- ethoxys) piperazine 48.4g (i.e. MNDP-1), yield
81.7%, as shown in Figure 2.
2) synthesis of 1- benzhydryls -4- (2- ethoxys) piperazine
48.4g MNDP-1,51.5g Anhydrous potassium carbonate powder and 500mlDMF is added in reaction bulb, and stirring lower point 3 batches adds
Enter benzhydryl bromide 91.4g, be stirred at room temperature 3.5 hours, go in water 1000ml, with extracted by ether, ether mutually uses saturation chlorination
Sodium solution is washed 2 times, and product 1- benzhydryls -4- (2- ethoxys) piperazine 93.5g (i.e. MNDP-2), yield are obtained after concentration
85.4%, as shown in Figure 3.
3) synthesis of 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester
93.5g MNDP-2 and 29.2g ketene dimers mixing, is again heated to 70-80 degree reaction 1 after being stirred at room temperature 5 hours
Hour, residue is dissolved in chloroform 400ml after vacuum distillation, wash 2 times with saturated nacl aqueous solution, and being evaporated off after solvent must be micro-
Brown oil 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester 86.5g (i.e. MNDP-3), yield 72.3%,
As shown in Figure 4.
4) synthesis of CV-4093
86.5g MNDP-3,37.9g m-nitrobenzaldehyde and 28.8g beta-amino ethyl crotonates is dissolved in isopropanol 500ml
In, heating reflux reaction 8 hours, remove solvent under reduced pressure, residue is dissolved in chloroform 300ml, is washed with water 3 times, anhydrous sulphur
Sour sodium filters after drying, filtrate decompression recycling design, and residue adds methanol 1000ml to being completely dissolved, and chlorination is passed through under ice bath
Hydrogen continues stirring 0.5 hour, removes solvent under reduced pressure, residue adds methanol 900ml, is heated to molten rear addition activity to PH=2
Carbon decoloring, filtering, crystallization after filtrate cooling, filter to obtain pale yellow crystals CV-4093 118.1g (i.e. MNDP), yield
75.8%, as shown in Figure 5.
Embodiment 2
A kind of preparation method of CV-4093, it comprises the following steps：
(1) synthesis of N- (2- ethoxys) piperazine, piperazine and water are added in reaction bulb, ice bath is cooled to 18 DEG C, adds
Oxirane, in 32 DEG C of stirring reactions 2 hours, temperature is then slowly heated to as 109 DEG C, to stopping when distilling out 90% water
Reaction, is cooled to 10 DEG C, unreacted piperazine is filtered to remove after standing, filtrate decompression distillation, it is 126 DEG C, pressure to collect temperature
For 1.6kPa when cut, obtain canescence viscous oily matter N- (2- ethoxys) piperazine, as shown in Figure 2；
(2) synthesis of 1- benzhydryls -4- (2- ethoxys) piperazine, by N- (2- ethoxys) piperazine, Anhydrous potassium carbonate powder
End and DMF are added in reaction bulb, lower point of 3 batches of addition benzhydryl bromides of stirring, are stirred at room temperature 3.5 hours, are added water, carried with ether
Take, ether is mutually washed 2 times with saturated nacl aqueous solution, and 1- benzhydryls -4- (2- ethoxys) piperazine, such as Fig. 3 is obtained after concentration
It is shown；
(3) synthesis of 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, by 1- benzhydryls -4- (2- hydroxyls
Ethyl) piperazine and ketene dimer mixing, be again heated to after being stirred at room temperature 5 hours 75 DEG C react 1 hour, by residue after vacuum distillation
Thing is dissolved in chloroform, is washed 2 times with saturated nacl aqueous solution, and micro- brown oil 2- (4- hexichol first is obtained after solvent is evaporated off
Base -1- piperazinyls) ethyl acetoacetic ester, as shown in Figure 4；
(4) by 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, m-nitrobenzaldehyde and beta-amino crotons
Sour methyl esters is dissolved in isopropanol, heating reflux reaction 8 hours, removes solvent under reduced pressure, residue is dissolved in chloroform, is washed with water
3 times, with being filtered after anhydrous sodium sulfate drying, filtrate decompression recycling design, residue adds methanol to being completely dissolved, and leads under ice bath
Enter hydrogen chloride to pH=2, continue stirring 0.5 hour, remove solvent under reduced pressure, residue adds methanol, after being heated to dissolving, then adds
Enter activated carbon decolorizing, filter, crystallization after filtrate cooling, filter to obtain pale yellow crystals, as CV-4093, as shown in Figure 5.
Piperazine, water, the mass ratio of oxirane are 195 in the step (1):395:28, unreacted piperazine adds second
Ether is washed, and is filtrated to get pure piperazine return and is used as raw material.
N- (2- ethoxys) piperazine in the step (2), Anhydrous potassium carbonate, DMF, the mass ratio of benzhydryl bromide and water are
48:53:495:98:980, the ether volume of addition is 2.3 times of water volume, and extracted by ether process is to mix ether and the aqueous solution
Closing, mix 18min at normal temperatures, stir to water droplet and be dispersed in ether, the particle diameter of water droplet is 0.15mm, is then stood, point
Layer obtains ether phase and aqueous phase, and obtained aqueous phase reclaims to obtain potassium bromide crystal, then saturated nacl aqueous solution by condensing crystallizing
Process is mixed with ether, and the volume ratio of saturated nacl aqueous solution and ether phase is 2.5:1, temperature during concentration is 75 DEG C, dense
The solvent evaporated during contracting obtains ether by 25 DEG C of condensation recovery.
1- benzhydryls -4- (2- ethoxys) piperazine, ketene dimer, the mass ratio of chloroform are in the step (3)
93:28:600, vapo(u)rizing temperature is 89 DEG C during vacuum distillation, and pressure during distillation is 0.8kPa.
2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, m-nitrobenzaldehyde, β in the step (4) -
Amino ethyl crotonate, isopropanol, the mass ratio of chloroform are 88:38:28:380:480, heating-up temperature when being heated to reflux
For 102 DEG C, the addition of anhydrous sodium sulfate is 2.5 times of water quality in chloroform soln, and temperature during ice bath is 8 DEG C.
Embodiment 3
A kind of preparation method of CV-4093, it comprises the following steps：
(1) synthesis of N- (2- ethoxys) piperazine, piperazine and water are added in reaction bulb, ice bath is cooled to 18 DEG C, adds
Oxirane, in 32 DEG C of stirring reactions 2 hours, temperature is then slowly heated to as 108 DEG C, to stopping when distilling out 90% water
Reaction, is cooled to 10 DEG C, unreacted piperazine is filtered to remove after standing, filtrate decompression distillation, it is 125 DEG C, pressure to collect temperature
For 1.6kPa when cut, obtain canescence viscous oily matter N- (2- ethoxys) piperazine, as shown in Figure 2；
(2) synthesis of 1- benzhydryls -4- (2- ethoxys) piperazine, by N- (2- ethoxys) piperazine, Anhydrous potassium carbonate powder
End and DMF are added in reaction bulb, lower point of 3 batches of addition benzhydryl bromides of stirring, are stirred at room temperature 3.5 hours, are added water, carried with ether
Take, ether is mutually washed 2 times with saturated nacl aqueous solution, and 1- benzhydryls -4- (2- ethoxys) piperazine, such as Fig. 3 is obtained after concentration
It is shown；
(3) synthesis of 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, by 1- benzhydryls -4- (2- hydroxyls
Ethyl) piperazine and ketene dimer mixing, be again heated to after being stirred at room temperature 5 hours 75 DEG C react 1 hour, by residue after vacuum distillation
Thing is dissolved in chloroform, is washed 2 times with saturated nacl aqueous solution, and micro- brown oil 2- (4- hexichol first is obtained after solvent is evaporated off
Base -1- piperazinyls) ethyl acetoacetic ester, as shown in Figure 4；
(4) by 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, m-nitrobenzaldehyde and beta-amino crotons
Sour methyl esters is dissolved in isopropanol, heating reflux reaction 8 hours, removes solvent under reduced pressure, residue is dissolved in chloroform, is washed with water
3 times, with being filtered after anhydrous sodium sulfate drying, filtrate decompression recycling design, residue adds methanol to being completely dissolved, and leads under ice bath
Enter hydrogen chloride to pH=2, continue stirring 0.5 hour, remove solvent under reduced pressure, residue adds methanol, after being heated to dissolving, then adds
Enter activated carbon decolorizing, filter, crystallization after filtrate cooling, filter to obtain pale yellow crystals, as CV-4093, as shown in Figure 5.
Piperazine, water, the mass ratio of oxirane are 195 in the step (1):395:28, unreacted piperazine adds second
Ether is washed, and is filtrated to get pure piperazine return and is used as raw material.
N- (2- ethoxys) piperazine in the step (2), Anhydrous potassium carbonate, DMF, the mass ratio of benzhydryl bromide and water are
48:52:495:98:985, the ether volume of addition is 2.3 times of water volume, and extracted by ether process is to mix ether and the aqueous solution
Closing, mix 18min at normal temperatures, stir to water droplet and be dispersed in ether, the particle diameter of water droplet is 0.15mm, is then stood, point
Layer obtains ether phase and aqueous phase, and obtained aqueous phase reclaims to obtain potassium bromide crystal, then saturated nacl aqueous solution by condensing crystallizing
Process is mixed with ether, and the volume ratio of saturated nacl aqueous solution and ether phase is 2.5:1, temperature during concentration is 75 DEG C, dense
The solvent evaporated during contracting obtains ether by 25 DEG C of condensation recovery.
1- benzhydryls -4- (2- ethoxys) piperazine, ketene dimer, the mass ratio of chloroform are in the step (3)
94:27:600, vapo(u)rizing temperature is 89 DEG C during vacuum distillation, and pressure during distillation is 0.8kPa.
2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, m-nitrobenzaldehyde, β in the step (4) -
Amino ethyl crotonate, isopropanol, the mass ratio of chloroform are 88:38:28:380:480, heating-up temperature when being heated to reflux
For 102 DEG C, the addition of anhydrous sodium sulfate is 2.5 times of water quality in chloroform soln, and temperature during ice bath is 8 DEG C.
Embodiment 4
A kind of preparation method of CV-4093, it comprises the following steps：
(1) synthesis of N- (2- ethoxys) piperazine, piperazine and water are added in reaction bulb, ice bath is cooled to 18 DEG C, adds
Oxirane, in 32 DEG C of stirring reactions 2 hours, temperature is then slowly heated to as 109 DEG C, to stopping when distilling out 90% water
Reaction, is cooled to 10 DEG C, unreacted piperazine is filtered to remove after standing, filtrate decompression distillation, it is 127 DEG C, pressure to collect temperature
For 1.6kPa when cut, obtain canescence viscous oily matter N- (2- ethoxys) piperazine, as shown in Figure 2；
(2) synthesis of 1- benzhydryls -4- (2- ethoxys) piperazine, by N- (2- ethoxys) piperazine, Anhydrous potassium carbonate powder
End and DMF are added in reaction bulb, lower point of 3 batches of addition benzhydryl bromides of stirring, are stirred at room temperature 3.5 hours, are added water, carried with ether
Take, ether is mutually washed 2 times with saturated nacl aqueous solution, and 1- benzhydryls -4- (2- ethoxys) piperazine, such as Fig. 3 is obtained after concentration
It is shown；
(3) synthesis of 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, by 1- benzhydryls -4- (2- hydroxyls
Ethyl) piperazine and ketene dimer mixing, be again heated to after being stirred at room temperature 5 hours 75 DEG C react 1 hour, by residue after vacuum distillation
Thing is dissolved in chloroform, is washed 2 times with saturated nacl aqueous solution, and micro- brown oil 2- (4- hexichol first is obtained after solvent is evaporated off
Base -1- piperazinyls) ethyl acetoacetic ester, as shown in Figure 4；
(4) by 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, m-nitrobenzaldehyde and beta-amino crotons
Sour methyl esters is dissolved in isopropanol, heating reflux reaction 8 hours, removes solvent under reduced pressure, residue is dissolved in chloroform, is washed with water
3 times, with being filtered after anhydrous sodium sulfate drying, filtrate decompression recycling design, residue adds methanol to being completely dissolved, and leads under ice bath
Enter hydrogen chloride to pH=2, continue stirring 0.5 hour, remove solvent under reduced pressure, residue adds methanol, after being heated to dissolving, then adds
Enter activated carbon decolorizing, filter, crystallization after filtrate cooling, filter to obtain pale yellow crystals, as CV-4093, as shown in Figure 5.
Piperazine, water, the mass ratio of oxirane are 195 in the step (1):395:27, unreacted piperazine adds second
Ether is washed, and is filtrated to get pure piperazine return and is used as raw material.
N- (2- ethoxys) piperazine in the step (2), Anhydrous potassium carbonate, DMF, the mass ratio of benzhydryl bromide and water are
48:51:495:98:980, the ether volume of addition is 2.3 times of water volume, and extracted by ether process is to mix ether and the aqueous solution
Closing, mix 18min at normal temperatures, stir to water droplet and be dispersed in ether, the particle diameter of water droplet is 0.15mm, is then stood, point
Layer obtains ether phase and aqueous phase, and obtained aqueous phase reclaims to obtain potassium bromide crystal, then saturated nacl aqueous solution by condensing crystallizing
Process is mixed with ether, and the volume ratio of saturated nacl aqueous solution and ether phase is 2.5:1, temperature during concentration is 75 DEG C, dense
The solvent evaporated during contracting obtains ether by 25 DEG C of condensation recovery.
1- benzhydryls -4- (2- ethoxys) piperazine, ketene dimer, the mass ratio of chloroform are in the step (3)
93:29:600, vapo(u)rizing temperature is 89 DEG C during vacuum distillation, and pressure during distillation is 0.8kPa.
2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, m-nitrobenzaldehyde, β in the step (4) -
Amino ethyl crotonate, isopropanol, the mass ratio of chloroform are 87:38:26:380:480, heating-up temperature when being heated to reflux
For 102 DEG C, the addition of anhydrous sodium sulfate is 2.5 times of water quality in chloroform soln, and temperature during ice bath is 9 DEG C.
Finally illustrate, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to compared with
The present invention is described in detail good embodiment, it will be understood by those within the art that, can be to the skill of the present invention
Art scheme is modified or equivalent substitution, and without departing from the objective and scope of technical solution of the present invention, it all should cover at this
Among the right of invention.
Claims (5)
1. a kind of preparation method of CV-4093, it is characterised in that comprise the following steps：
(1) synthesis of N- (2- ethoxys) piperazine, piperazine and water are added in reaction bulb, ice bath is cooled to 15-20 DEG C, adds ring
Oxidative ethane, in 30-35 DEG C of stirring reaction 2 hours, temperature is then slowly heated to as 108-110 DEG C, to the water for distilling out 90%
When stop reaction, be cooled to 10 DEG C, be filtered to remove unreacted piperazine after standing, filtrate decompression distillation, it is 125- to collect temperature
127 DEG C, cut of pressure when being 1.6kPa, obtain canescence viscous oily matter N- (2- ethoxys) piperazine；
(2) synthesis of 1- benzhydryls -4- (2- ethoxys) piperazine, by N- (2- ethoxys) piperazine, Anhydrous potassium carbonate powder and
DMF is added in reaction bulb, and stirring lower point 3 batches adds benzhydryl bromides, is stirred at room temperature 3.5 hours, addition water, with extracted by ether,
Ether is mutually washed 2 times with saturated nacl aqueous solution, and 1- benzhydryls -4- (2- ethoxys) piperazine is obtained after concentration；
(3) synthesis of 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, by 1- benzhydryls -4- (2- hydroxyl second
Base) piperazine and ketene dimer mixing, 70-80 DEG C is again heated to after being stirred at room temperature 5 hours and is reacted 1 hour, will be surplus after vacuum distillation
Excess is dissolved in chloroform, is washed 2 times with saturated nacl aqueous solution, and micro- brown oil 2- (4- hexichol is obtained after solvent is evaporated off
Methyl isophthalic acid-piperazinyl) ethyl acetoacetic ester；
(4) by 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, m-nitrobenzaldehyde and beta-amino crotonic acid first
Ester is dissolved in isopropanol, heating reflux reaction 8 hours, removes solvent under reduced pressure, and residue is dissolved in chloroform, is washed with water 3 times,
With being filtered after anhydrous sodium sulfate drying, filtrate decompression recycling design, residue adds methanol to being completely dissolved, and chlorine is passed through under ice bath
Change hydrogen to pH=2, continue stirring 0.5 hour, remove solvent under reduced pressure, residue adds methanol, after being heated to dissolving, adds work
Property carbon decoloring, filtering, filtrate cooling after crystallization, filter to obtain pale yellow crystals, as CV-4093.
A kind of 2. preparation method of CV-4093 according to claim 1, it is characterised in that：In the step (1)
Piperazine, water, the mass ratio of oxirane are 190-200:380-420:25-30, unreacted piperazine add ether and washed,
Pure piperazine return is filtrated to get to use as raw material.
A kind of 3. preparation method of CV-4093 according to claim 1, it is characterised in that：In the step (2)
N- (2- ethoxys) piperazine, Anhydrous potassium carbonate, DMF, the mass ratio of benzhydryl bromide and water are 45-50:50-55:400-550:
90-100:950-1050, the ether volume of addition are 2-3 times of water volume, and extracted by ether process is to mix ether and the aqueous solution
Close, mix 10-20min at normal temperatures, stir to water droplet and be dispersed in ether, the particle diameter of water droplet is 0.1-0.2mm, Ran Houjing
Put, layering obtains ether phase and aqueous phase, and obtained aqueous phase reclaims to obtain potassium bromide crystal, then saturated sodium-chloride by condensing crystallizing
Solution and ether mix process, and the volume ratio of saturated nacl aqueous solution and ether phase is 2-3:1, temperature during concentration is 50-
80 DEG C, the solvent evaporated during concentration obtains ether by 20-30 DEG C of condensation recovery.
A kind of 4. preparation method of CV-4093 according to claim 1, it is characterised in that：In the step (3)
1- benzhydryls -4- (2- ethoxys) piperazine, ketene dimer, the mass ratio of chloroform are 90-95:25-30:500-700, subtract
Vapo(u)rizing temperature is 80-150 DEG C during pressure distillation, and pressure during distillation is 0.5-1kPa.
A kind of 5. preparation method of CV-4093 according to claim 1, it is characterised in that：In the step (4)
2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, m-nitrobenzaldehyde, beta-amino ethyl crotonate, isopropanol,
The mass ratio of chloroform is 85-90:35-40:25-30:350-450:400-500, heating-up temperature when being heated to reflux are 90-
120 DEG C, the addition of anhydrous sodium sulfate is 2-3 times of water quality in chloroform soln, and temperature during ice bath is 5-10 DEG C.
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| CN108218765A (en) * | 2017-11-24 | 2018-06-29 | 扬子江药业集团北京海燕药业有限公司 | A kind of production method for improving manidipine hydrochloride II crystal forms |
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| CN102875451A (en) * | 2012-04-05 | 2013-01-16 | 常州制药厂有限公司 | Improved method for synthesis process of manidipine hydrochloride |
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| CN102875451A (en) * | 2012-04-05 | 2013-01-16 | 常州制药厂有限公司 | Improved method for synthesis process of manidipine hydrochloride |
| CN104292150A (en) * | 2013-07-19 | 2015-01-21 | 许昌恒生制药有限公司 | Synthetic process of manidipine hydrochloride |
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| CN108218765A (en) * | 2017-11-24 | 2018-06-29 | 扬子江药业集团北京海燕药业有限公司 | A kind of production method for improving manidipine hydrochloride II crystal forms |
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