CN109988148A - 1-(3- cyanopyridine -2) -2- phenyl -4- methyl piperazine oxalates preparation method - Google Patents
1-(3- cyanopyridine -2) -2- phenyl -4- methyl piperazine oxalates preparation method Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine, it include: that (1) 2- chlorine nicotinic acid nitrile, potassium fluoride and -3 phenylpiperazine of 1- methyl are added in DMSO, heat temperature raising is reacted after nitrogen displacement；(2) by reaction product distillation under pressure, ethyl acetate is added in remaining residue, filters；(3) methanol and oxalic acid are added into filtrate, stirring and crystallizing, filtering, to obtain the final product.The present invention is optimized using DMSO as reaction dissolvent, and to the proportion of reaction temperature and raw material dosage, is substantially reduced the reaction time for preparing 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine, is effectively shortened the production cycle；The yield of 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine greatly improved, it is quality controllable；The post processing mode of the method for the present invention is simple, and entire synthesis process operation is simple, at low cost.
Description
Technical field
The present invention relates to the preparation method of Mirtazapine intermediate more particularly to Mirtazapine intermediate 1- (nicotinonitriles-
2) preparation method of -2- phenyl -4- methyl piperazine oxalates, belongs to the preparation field of Mirtazapine intermediate.
Background technique
Mirtazapine is the generic drug of Ou Jianong company Remeron (Mirtazapine).Mirtazapine is first, the whole world to going first
The secondary intake of adrenaline and serotonin has the antidepressant of double inhibition effect.Remeron1996 obtains beauty
State FDA approval, in more than 70 national clinical uses
US4062848, US6495685, JP2001/12287, CN1429819 have reported the synthetic route of Mirtazapine, wherein
The synthesis of intermediate 1- (nicotinonitrile -2) -2- phenyl -4- methyl is all referred to, document makees solvent with DMF, in temperature
140 DEG C, by 20 hours with 80% or so yield.
Find that DMF as solvent, has certain decomposition under experimental conditions, generates diethylamine, it is easy to is raw in experiment
At impurity E, the generation of impurity E not only influences the raising of yield, it is often more important that impurity E is difficult in subsequent each step intermediate
It removes；The reaction time of document is also too long, this reaction at high temperature, and reaction necessarily leads to various impurity for a long time, thus
The yield of reaction is reduced, while intermediate control is also relatively difficult, the post processing mode in document is also more complicated, needs a large amount of
Solvent extracted and need further to recrystallize.The shortcomings that in view of the above method, carry out process modification, find it is more economical,
Time is short, high-efficient, post processing mode is simple and is easy to the preparation process of practical operation is necessary.
Summary of the invention
Technical problem underlying to be solved by this invention is for existing Mirtazapine intermediate 1- (nicotinonitrile -2) -
Reaction time in the presence of the preparation method of 2- phenyl -4- methyl is too long, post processing mode is complicated, product yield is low etc. asks
Topic, provides that a kind of short reaction time, high production efficiency, post processing mode be simple, Mirtazapine intermediate 1- (3- of product yield high
Cyanopyridine -2) -2- phenyl -4- methyl preparation method,
The technical problem to be solved by the present invention is to what is be achieved through the following technical solutions:
A kind of preparation method of 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine, comprising:
(1) 2- chlorine nicotinic acid nitrile, potassium fluoride and -3 phenylpiperazine of 1- methyl are added in DMSO, heat temperature raising after nitrogen displacement
It is reacted；
(2) by reaction product distillation under pressure, ethyl acetate is added in remaining residue, filters；
(3) methanol and oxalic acid are added into filtrate, stirring and crystallizing, filtering, to obtain the final product.
The prior art is mostly made when synthesizing Mirtazapine intermediate 1- (nicotinonitrile -2) -2- phenyl -4- methyl with DMF
Solvent, reaction temperature are 140 DEG C, and the reaction time after 20 hours is needed to can be only achieved 80% or so yield.The present invention is non-
It is often found surprisingly that, using DMSO as reaction dissolvent, reaction temperature is 150 DEG C, it is only necessary to 2 hours or so reaction time,
The yield of reaction product can reach 90% or more, this not only substantially reduces the reaction time, shortens the production cycle, also effectively mention
The high yield of product.
The present invention is by experiment it has furthermore been found that reaction temperature influences also more to show for the yield of product in step (1)
It writes；Wherein, it can guarantee that the yield of product reaches 90% or more when reaction temperature is 150-160 DEG C, when reaction temperature is lower than 150
DEG C or be higher than 160 DEG C, the yield of product is decreased obviously, and is below 90%.
In addition, the also further discovery of the present invention, reaction raw materials 2- chlorine nicotinic acid nitrile and the dosage of -3 phenylpiperazine of 1- methyl are matched
It is also more closely related than the yield for product；Wherein, by mol, 2- chlorine nicotinic acid nitrile and -3 phenylpiperazine of 1- methyl are according to 1:1.0-
The ratio of 1:1.1, which carries out compatibility, can effectively improve product yield, when reaction temperature is 150 DEG C, 2- chlorine nicotinic acid nitrile and 1- methyl-
When the molar ratio of 3 phenylpiperazines is 1:1.05, the yield of product reaches 99%
Preferably, the number of the displacement of nitrogen described in step (1) is 1-5 times, preferably 3 times；The reaction time
It can be 1-3 hours, preferably 2 hours.
Preferably, after reaction product distillation under pressure being steamed solvent in step (2), remaining residue is cooled to room temperature
Add ethyl acetate；Wherein, the room temperature is 20-30 DEG C.
Preferably, according to volume basis, it is added in the methanol from step (3) to filtrate and step (2) that are added in
The usage ratio of ethyl acetate is 1:3；According to mass ratio meter, oxalic acid and reaction raw materials 2- chlorine nicotinic acid nitrile that step (3) is added
Ratio is preferably 1:1.
Preferably, being stirred crystallization under the conditions of 15-25 DEG C of temperature in step (3).
The present invention is optimized using DMSO as reaction dissolvent, and to the proportion of reaction temperature and raw material dosage, significantly
The reaction time for preparing 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine is shortened, the production cycle is shortened；It greatly improves
The yield of 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine, it is quality controllable；Post processing mode is also fairly simple, entirely
Synthesis process operation is simple, cost is effectively reduced.
Detailed description of the invention
The structural formula of Fig. 1 Mirtazapine.
Fig. 2 present invention prepares the process route chart of 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine.
Specific embodiment
Further describe the present invention below in conjunction with specific embodiment, the advantages and features of the present invention will be with description and
It is apparent.But examples are merely exemplary for these, and it is not intended to limit the scope of the present invention in any way.Those skilled in the art
Member it should be understood that can modify without departing from the spirit and scope of the invention to details and form of the invention or
Replacement, but these modifications and replacement are fallen within the protection scope of the present invention.
Influence of the table 1 using different reaction dissolvent and response parameter for product yield
The preparation of comparative example 1 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine
2- chlorine nicotinic acid nitrile (6.93g, 50mmol) is added into the there-necked flask of 500ml, -3 phenylpiperazine of 1- methyl (8.82g,
50mmol), potassium fluoride (8.71g, 150mmol), n,N-Dimethylformamide (DMF) (100ml), nitrogen displacement are heated afterwards three times
140 DEG C are warming up to, is stirred 20 hours, TLC detects end of reaction, and crude product is added in 100ml ice water, ethyl acetate is used
(50ml) is extracted 3 times, merges organic phase, dry with anhydrous sodium sulfate, and solvent is removed under reduced pressure and obtains brown oil, 11.0g is received
Rate 79%.1H NMR (500M, d6-DMSO): δ 9.5-10.8 (br, 2H), 8.38-8.39 (dd, 1H), 8.15-8.18 (dd,
1H), 7.03-7.07 (dd, 1H), 7.10-7.35 (m, 5H), 3.86-4.00 (m, 1H), 3.58-3.59 (m, 2H), 3.22-
3.29 (m, 2H), 3.18-3.20 (m, 2H), 2.66 (s, 3H)；13C NMR (125M, d6-DMSO): 164.5,1612.2,
151.0,141.5,138.5,128.5,127.6,127.0,122.2,115.9,110.2,76.8,66.7,57.0,48.8,
47.1；ESI-MS:279.1528.
The preparation of comparative example 2 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine
2- chlorine nicotinic acid nitrile (6.93g, 50mmol) is added into the there-necked flask of 500ml, -3 phenylpiperazine of 1- methyl (8.82g,
50mmol), potassium fluoride (8.71g, 150mmol), n,N-Dimethylformamide (DMF) (100ml), nitrogen displacement are heated afterwards three times
150 DEG C are warming up to, is stirred 4 hours, TLC detects end of reaction, and crude product is added in 100ml ice water, ethyl acetate is used
(50ml) is extracted 3 times, merges organic phase, dry with anhydrous sodium sulfate, and solvent is removed under reduced pressure and obtains brown oil, 11.6g is received
Rate 83%.
The preparation of comparative example 3 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine
2- chlorine nicotinic acid nitrile (6.93g, 50mmol) is added into the there-necked flask of 500ml, -3 phenylpiperazine of 1- methyl (8.82g,
50mmol), potassium fluoride (8.71g, 150mmol), n,N-Dimethylformamide (DMF) (100ml), nitrogen displacement are heated afterwards three times
160 DEG C are warming up to, is stirred 2 hours, TLC detects end of reaction, and crude product is added in 100ml ice water, ethyl acetate is used
(50ml) is extracted 3 times, merges organic phase, dry with anhydrous sodium sulfate, and solvent is removed under reduced pressure and obtains brown oil, 11.8g is received
Rate 85%.
The preparation of embodiment 1 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine
2- chlorine nicotinic acid nitrile (6.93g, 50mmol) is added into the there-necked flask of 500ml, -3 phenylpiperazine of 1- methyl (8.82g,
50mmol), potassium fluoride (8.71g, 150mmol), dimethyl sulfoxide (DMSO) (100ml), nitrogen displacement heat to afterwards three times
It 150 DEG C, stirs 2 hours, TLC detects end of reaction, directly progress distillation under pressure, and ethyl acetate 30ml, mistake is added in residue
It filters, addition methanol 10ml in filtrate, oxalic acid (6.3g, 50mmol), is stirred 4 hours at 15-25 DEG C, pale yellow colored solid is obtained by filtration
Body, 16.6g, yield 90%.
1H NMR (500M, d6-DMSO): δ 9.4-10.8 (br, 2H), 8.36-8.38 (dd, 1H), 8.16-8.17 (dd,
1H), 7.01-7.06 (dd, 1H), 7.10-7.36 (m, 5H), 3.85-4.01 (m, 1H), 3.55-3.58 (m, 2H), 3.20-
3.26 (m, 2H), 3.15-3.18 (m, 2H), 2.63 (s, 3H)；13C NMR (125M, d6-DMSO): 164.3,1612.4,
151.2,141.6,138.8,128.2,127.3,127.3,122.1,115.9,110.1,76.5,66.3,57.4,48.7,
47.3；ESI-MS:279.1526.
The preparation of embodiment 2 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine
2- chlorine nicotinic acid nitrile (6.93g, 50mmol) is added into the there-necked flask of 500ml, -3 phenylpiperazine of 1- methyl (9.70g,
55mmol), potassium fluoride (8.71g, 150mmol), dimethyl sulfoxide (DMSO) (100ml), nitrogen displacement heat to afterwards three times
It 150 DEG C, stirs 2 hours, TLC detects end of reaction, directly progress distillation under pressure, and ethyl acetate 30ml, mistake is added in residue
It filters, addition methanol 10ml in filtrate, oxalic acid (6.3g, 50mmol), is stirred 4 hours at 15-25 DEG C, pale yellow colored solid is obtained by filtration
Body, 17.68g, yield 96%.
1H NMR (500M, d6-DMSO): δ 9.4-10.8 (br, 2H), 8.36-8.38 (dd, 1H), 8.16-8.17 (dd,
1H), 7.01-7.06 (dd, 1H), 7.10-7.36 (m, 5H), 3.85-4.01 (m, 1H), 3.55-3.58 (m, 2H), 3.20-
3.26 (m, 2H), 3.15-3.18 (m, 2H), 2.63 (s, 3H)；13C NMR (125M, d6-DMSO): 164.3,1612.4,
151.2,141.6,138.8,128.2,127.3,127.3,122.1,115.9,110.1,76.5,66.3,57.4,48.7,
47.3；ESI-MS:279.1526.
The preparation of embodiment 3 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine
2- chlorine nicotinic acid nitrile (13.86kg, 100mol) is added into 300L reaction kettle, -3 phenylpiperazine of 1- methyl (18.51kg,
105mol), potassium fluoride (17.42kg, 300mol), dimethyl sulfoxide (DMSO) (100L), nitrogen displacement heat to afterwards three times
It 150 DEG C, stirs 2 hours, TLC detects end of reaction, directly progress distillation under pressure, and ethyl acetate 60L, centrifugation is added in residue
It separates, addition methanol 20L in filtrate, oxalic acid (12.6kg, 100mol), stirs 6 hours, be obtained by filtration faint yellow at 15-25 DEG C
Solid, 36.5kg, yield 99%.
1H NMR (500M, d6-DMSO): δ 9.4-10.8 (br, 2H), 8.36-8.38 (dd, 1H), 8.16-8.17 (dd,
1H), 7.01-7.06 (dd, 1H), 7.10-7.36 (m, 5H), 3.85-4.01 (m, 1H), 3.55-3.58 (m, 2H), 3.20-
3.26 (m, 2H), 3.15-3.18 (m, 2H), 2.63 (s, 3H)；13C NMR (125M, d6-DMSO): 164.3,1612.4,
151.2,141.6,138.8,128.2,127.3,127.3,122.1,115.9,110.1,76.5,66.3,57.4,48.7,
47.3；ESI-MS:279.1526.
The preparation of embodiment 4 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine
2- chlorine nicotinic acid nitrile (6.93g, 50mmol) is added into the there-necked flask of 500ml, -3 phenylpiperazine of 1- methyl (8.82g,
50mmol), potassium fluoride (8.71g, 150mmol), dimethyl sulfoxide (DMSO) (100ml), nitrogen displacement heat to afterwards three times
It 140 DEG C, stirs 24 hours, TLC detects end of reaction, directly progress distillation under pressure, and ethyl acetate 30ml, mistake is added in residue
It filters, addition methanol 10ml in filtrate, oxalic acid (6.3g, 50mmol), is stirred 4 hours at 15-25 DEG C, pale yellow colored solid is obtained by filtration
Body, 11.42g, yield 62%.
1H NMR (500M, d6-DMSO): δ 9.4-10.8 (br, 2H), 8.36-8.38 (dd, 1H), 8.16-8.17 (dd,
1H), 7.01-7.06 (dd, 1H), 7.10-7.36 (m, 5H), 3.85-4.01 (m, 1H), 3.55-3.58 (m, 2H), 3.20-
3.26 (m, 2H), 3.15-3.18 (m, 2H), 2.63 (s, 3H)；13C NMR (125M, d6-DMSO): 164.3,1612.4,
151.2,141.6,138.8,128.2,127.3,127.3,122.1,115.9,110.1,76.5,66.3,57.4,48.7,
47.3；ESI-MS:279.1526.
The preparation of embodiment 5 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine
2- chlorine nicotinic acid nitrile (6.93g, 50mmol) is added into the there-necked flask of 500ml, -3 phenylpiperazine of 1- methyl (8.82g,
50mmol), potassium fluoride (8.71g, 150mmol), dimethyl sulfoxide (DMSO) (100ml), nitrogen displacement heat to afterwards three times
It 145 DEG C, stirs 20 hours, TLC detects end of reaction, directly progress distillation under pressure, and ethyl acetate 30ml, mistake is added in residue
It filters, addition methanol 10ml in filtrate, oxalic acid (6.3g, 50mmol), is stirred 4 hours at 15-25 DEG C, pale yellow colored solid is obtained by filtration
Body, 11.83g, yield 64%.
1H NMR (500M, d6-DMSO): δ 9.4-10.8 (br, 2H), 8.36-8.38 (dd, 1H), 8.16-8.17 (dd,
1H), 7.01-7.06 (dd, 1H), 7.10-7.36 (m, 5H), 3.85-4.01 (m, 1H), 3.55-3.58 (m, 2H), 3.20-
3.26 (m, 2H), 3.15-3.18 (m, 2H), 2.63 (s, 3H)；13C NMR (125M, d6-DMSO): 164.3,1612.4,
151.2,141.6,138.8,128.2,127.3,127.3,122.1,115.9,110.1,76.5,66.3,57.4,48.7,
47.3；ESI-MS:279.1526.
The preparation of embodiment 6 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine
2- chlorine nicotinic acid nitrile (6.93g, 50mmol) is added into the there-necked flask of 500ml, -3 phenylpiperazine of 1- methyl (9.70g,
55mmol), potassium fluoride (8.71g, 150mmol), dimethyl sulfoxide (DMSO) (100ml), nitrogen displacement heat to afterwards three times
It 160 DEG C, stirs 2 hours, TLC detects end of reaction, directly progress distillation under pressure, and ethyl acetate 30ml, mistake is added in residue
It filters, addition methanol 10ml in filtrate, oxalic acid (6.3g, 50mmol), is stirred 4 hours at 15-25 DEG C, pale yellow colored solid is obtained by filtration
Body, 16.94g, yield 92%.
1H NMR (500M, d6-DMSO): δ 9.4-10.8 (br, 2H), 8.36-8.38 (dd, 1H), 8.16-8.17 (dd,
1H), 7.01-7.06 (dd, 1H), 7.10-7.36 (m, 5H), 3.85-4.01 (m, 1H), 3.55-3.58 (m, 2H), 3.20-
3.26 (m, 2H), 3.15-3.18 (m, 2H), 2.63 (s, 3H)；13C NMR (125M, d6-DMSO): 164.3,1612.4,
151.2,141.6,138.8,128.2,127.3,127.3,122.1,115.9,110.1,76.5,66.3,57.4,48.7,
47.3；ESI-MS:279.1526.
The preparation of embodiment 7 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine
2- chlorine nicotinic acid nitrile (6.93g, 50mmol) is added into the there-necked flask of 500ml, -3 phenylpiperazine of 1- methyl (9.70g,
55mmol), potassium fluoride (8.71g, 150mmol), dimethyl sulfoxide (DMSO) (100ml), nitrogen displacement heat to afterwards three times
It 165 DEG C, stirs 2 hours, TLC detects end of reaction, directly progress distillation under pressure, and ethyl acetate 30ml, mistake is added in residue
It filters, addition methanol 10ml in filtrate, oxalic acid (6.3g, 50mmol), is stirred 4 hours at 15-25 DEG C, pale yellow colored solid is obtained by filtration
Body, 16.38g, yield 89%.
1H NMR (500M, d6-DMSO): δ 9.4-10.8 (br, 2H), 8.36-8.38 (dd, 1H), 8.16-8.17 (dd,
1H), 7.01-7.06 (dd, 1H), 7.10-7.36 (m, 5H), 3.85-4.01 (m, 1H), 3.55-3.58 (m, 2H), 3.20-
3.26 (m, 2H), 3.15-3.18 (m, 2H), 2.63 (s, 3H)；13C NMR (125M, d6-DMSO): 164.3,1612.4,
151.2,141.6,138.8,128.2,127.3,127.3,122.1,115.9,110.1,76.5,66.3,57.4,48.7,
47.3；ESI-MS:279.1526.
The preparation of embodiment 8 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine
2- chlorine nicotinic acid nitrile (6.93g, 50mmol) is added into the there-necked flask of 500ml, -3 phenylpiperazine of 1- methyl (9.70g,
55mmol), potassium fluoride (8.71g, 150mmol), dimethyl sulfoxide (DMSO) (100ml), nitrogen displacement heat to afterwards three times
It 155 DEG C, stirs 2 hours, TLC detects end of reaction, directly progress distillation under pressure, and ethyl acetate 30ml, mistake is added in residue
It filters, addition methanol 10ml in filtrate, oxalic acid (6.3g, 50mmol), is stirred 4 hours at 15-25 DEG C, pale yellow colored solid is obtained by filtration
Body, 16.94g, yield 94%.
1H NMR (500M, d6-DMSO): δ 9.4-10.8 (br, 2H), 8.36-8.38 (dd, 1H), 8.16-8.17 (dd,
1H), 7.01-7.06 (dd, 1H), 7.10-7.36 (m, 5H), 3.85-4.01 (m, 1H), 3.55-3.58 (m, 2H), 3.20-
3.26 (m, 2H), 3.15-3.18 (m, 2H), 2.63 (s, 3H)；13C NMR (125M, d6-DMSO): 164.3,1612.4,
151.2,141.6,138.8,128.2,127.3,127.3,122.1,115.9,110.1,76.5,66.3,57.4,48.7,
47.3；ESI-MS:279.1526.
Claims (10)
1. a kind of preparation method of 1- (nicotinonitrile -2) -2- phenyl -4- methyl piperazine characterized by comprising
(1) 2- chlorine nicotinic acid nitrile, potassium fluoride and -3 phenylpiperazine of 1- methyl are added in DMSO, nitrogen displacement after heat temperature raising into
Row reaction；
(2) by reaction product distillation under pressure, ethyl acetate is added in remaining residue, filters；
(3) methanol and oxalic acid are added in filtrate, stirring and crystallizing, filtering, to obtain the final product.
2. preparation method described in accordance with the claim 1, which is characterized in that reaction temperature 150-160 described in step (1)
℃。
3. preparation method according to claim 2, which is characterized in that reaction temperature 150-155 described in step (1)
℃。
4. preparation method described in accordance with the claim 1, which is characterized in that by mol, 2- chlorine nicotinic acid nitrile and -3 phenyl of 1- methyl
The ratio of piperazine is 1:1.0-1:1.1.
5. preparation method according to claim 4, which is characterized in that the ratio of -3 phenylpiperazine of 2- chlorine nicotinic acid nitrile and 1- methyl
For 1:1.05.
6. preparation method described in accordance with the claim 1, which is characterized in that nitrogen described in step (1) displacement number be
1-5 times, preferably 3 times.
7. preparation method described in accordance with the claim 1, which is characterized in that the reaction time described in step (1) is that 1-3 is small
When, preferably 2 hours.
8. preparation method described in accordance with the claim 1, which is characterized in that step steams reaction product distillation under pressure in (2)
After solvent, remaining residue is cooled to room temperature and adds ethyl acetate.
9. preparation method described in accordance with the claim 1, which is characterized in that according to volume basis, in step (3) into filtrate institute
The usage ratio for the ethyl acetate being added in the methanol and step (2) of addition is 1:3；The oxalic acid that is added in step (3) with
The mass ratio of 2- chlorine nicotinic acid nitrile in step (1) is 1:1.
10. preparation method described in accordance with the claim 1, which is characterized in that in step (3) under the conditions of 15-25 DEG C of temperature
It is stirred crystallization.
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