CN105949102A - Production method of azelnidipine intermediate - Google Patents
Production method of azelnidipine intermediate Download PDFInfo
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- CN105949102A CN105949102A CN201610441451.8A CN201610441451A CN105949102A CN 105949102 A CN105949102 A CN 105949102A CN 201610441451 A CN201610441451 A CN 201610441451A CN 105949102 A CN105949102 A CN 105949102A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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Abstract
The invention discloses a production method of an azelnidipine intermediate. The production method comprises the following steps of 1 an esterification reaction; 2 a Pinner reaction, wherein a solvent A is added into a microreactor through a pump with the flow velocity of 100-200 ml/min, heating is conducted until the temperature is 220 DEG C-260 DEG C, absolute ethyl alcohol and dichloromethane are slowly and dropwise added into the microreactor, stirring is conducted for 3-5 h, liquid nitrogen is introduced, cooling is conducted until the temperature is 15 DEG C-25 DEG C, dry hydrogen chloride gas is introduced for 2-6 h, the microreactor is sealed, stirring is conducted for 20-30 h, and mixed liquid B is prepared for standby application; 3 a neutralization reaction; 4 an amidine generation reaction, wherein the azelnidipine intermediate-3-amino-3-aminoproionic acid-1-(diphenylmethyl)-3-azetidinyl ester acetate compound is obtained. According to the production method, the temperature state of a reaction system and the usage quantity of the reactants in all the steps are strictly controlled, synthesis of the intermediate is stable, the product yield is increased, the product purity is improved, side reactions are decreased, the purpose sof reducing the production cost and shortening the reaction cycle are achieved, and the production method is more suitable for industrialized large-scale production.
Description
Technical field
The present invention relates to medicine synthesis technical field, be specifically related to the production method of a kind of azelnidipine intermediate.
Background technology
Azelnidipine (azelnidipine) is jointly to be ground by Sankyo and Ube Industries company of Japan
A kind of novel dihydropyridine calcium channel blocker of system exploitation, is approved to list in Japan, commodity the last ten-days period in May, 2003
Entitled Calblock.Azelnidipine has selectivity retardation to arterial smooth muscle cell calcium channel, and it can expand blood vessel, fall
Low peripheral vascular resistance and arterial pressure, be widely used in clinically slight or Moderate Essential Hypertension, renal insufficiency accompanied with hypertension with
And the treatment of severe hypertension etc..Azelnidipine compared with the dihydropyridine calcium channel blocker such as nicardipine, nifedipine,
Have that selectivity is high, hypotensive effect strong and persistently, to advantages such as heart stimulation are little；At present, relevant azelnidipine preparation method with
Epoxychloropropane and .alpha.-aminodiphenylmethane. are initiation material, synthesize through N-alkylation, cyclization, esterification, Pinner, neutralize, become amidine
Reaction first prepares intermediate 3-amino-3-imino group propanoic acid-1-(benzhydryl)-3-azacyclo-butyl ester acetic acid
Salt, then prepares azelnidipine with 2-(3-nitrobenzal) isopropyl acetoacetate through Hantzsch condensation；On this road
Line is esterified, Pinner synthesis and neutralize reaction dissolvent and reaction condition in three-step reaction control it is critical that.But
Being, this complex operation, purity is poor, not easy purification, it is difficult to obtain solid product, and productivity is low, have a strong impact on the matter of finished product
Amount, makes production cost be greatly improved；Therefore, in view of being necessary it to be improved further above, improve azelnidipine intermediate
Yield and quality etc..
Summary of the invention
Because the drawbacks described above of prior art, present invention aim to overcome that above-mentioned the deficiencies in the prior art provide one
Plant the production method of azelnidipine intermediate.
For achieving the above object, the production method of a kind of azelnidipine intermediate, comprise the following steps:
(1) esterification: a, in inert gas shielding downhill reaction still, it is slowly added to dimethylaniline, epoxychloropropane and has
Machine solvent is mixed in proportion, and mixing time is 2-8h, and temperature controls at 80-100 DEG C；
B, dropping cyanoacetic acid and N, N-dicyclohexylcarbodiimide continue reaction 3-5h；
C, react complete cooling, sucking filtration, filtrate, washing, prepare solvent orange 2 A standby；
(2) Pinner reaction:
Solvent orange 2 A is added in microreactor by a, the pump using flow velocity to be 100-200ml/min, is heated to 220-260 DEG C；
B, slowly dripping in dehydrated alcohol, dichloromethane in microreactor, mixing time is 3-5h；
C, it is passed through liquid nitrogen, is cooled to 15-25 DEG C, be passed through dry hydrogen chloride gas 2-6h, seal stirring 20-30h, prepare mixed
Close liquid B standby；
(3) reaction is neutralized:
Dripping sodium bicarbonate in mixed liquid B, control pH value is 8.2-8.4, stirring 60-80min, sucking filtration, filtrate steaming removal solvent,
Dried prepared powder C is standby；
(4) amidine is become to react:
By adding ammonium carbonate after powder C toluene, xylene soluble, being warming up to 100-150 DEG C, pressure 0-2MPa, reaction is completely
After, isolated and purified white crystal, obtain azelnidipine intermediate 3-amino-3-imino group propanoic acid-1-(benzhydryl
)-3-azacyclo-butyl ester acetate compounds.
Further, in step (1), the volume ratio of toluidines, epoxychloropropane and organic solvent is 1:(0.6-
0.8):(1.5-2.5)。
Further, in step (1) volume of dropping cyanoacetic acid and N, N-dicyclohexylcarbodiimide be 25ml,
45ml。
Further, step (2) slowly drips dehydrated alcohol in microreactor, the volume of dichloromethane is 60ml,
70ml。
Further, step (3) controls pH value is 8.3.
Further, in step (1), described organic solvent is ethyl acetate.
Due to the utilization of such scheme technology, the present invention invents relatively prior art and possesses following beneficial effect: the present invention exists
Transforming in the production method of tradition azelnidipine intermediate, in each step of strict control, the state of temperature of reaction system is with anti-
Answer the usage amount of thing, intermediate synthesizing stable, improve product yield and purity, decrease side reaction, reduce production cost,
Shorten the purpose of reaction time, be more suitable for industrialization large-scale production.
Detailed description of the invention
Embodiments of the present invention are described in detail, whereby to the present invention how application technology hands below with reference to embodiment
Section solves technical problem, and the process that realizes reaching technique effect can fully understand and implement according to this.
The present invention discloses the production method of a kind of azelnidipine intermediate, below in conjunction with the example structure proposed to this
Bright further illustrate.
The production method of 1 one kinds of azelnidipine intermediate of embodiment
The production method of a kind of azelnidipine intermediate, comprises the following steps:
(1) esterification: a, in inert gas shielding downhill reaction still, it is slowly added to dimethylaniline, epoxychloropropane and has
Machine solvent is mixed in proportion, and mixing time is 2h, and temperature controls at 80 DEG C；
B, dropping cyanoacetic acid and N, N-dicyclohexylcarbodiimide continue reaction 3h；
C, react complete cooling, sucking filtration, filtrate, washing, prepare solvent orange 2 A standby；
(2) Pinner reaction:
Solvent orange 2 A is added in microreactor by a, the pump using flow velocity to be 100ml/min, is heated to 220 DEG C；
B, slowly dripping in dehydrated alcohol, dichloromethane in microreactor, mixing time is 3h；
C, it is passed through liquid nitrogen, is cooled to 15 DEG C, be passed through dry hydrogen chloride gas 2h, seal stirring 20h, prepare mixed liquid B standby
With；
(3) reaction is neutralized:
Dripping sodium bicarbonate in mixed liquid B, controlling pH value is 8.2, stirring 60min, sucking filtration, filtrate steaming removal solvent, after drying
Prepare powder C standby；
(4) amidine is become to react:
By adding ammonium carbonate after powder C toluene, xylene soluble, it is warming up to 100 DEG C, pressure 1MPa, after reaction completely, point
Obtain white crystal from purification, obtain azelnidipine intermediate 3-amino-3-imino group propanoic acid-1-(benzhydryl)-3-
Azacyclo-butyl ester acetate compounds；
Preferred version as the present invention: in step (1), the volume ratio of toluidines, epoxychloropropane and organic solvent is
1:0.6:1.5；
Preferred version as the present invention: in step (1), the volume of dropping cyanoacetic acid and N, N-dicyclohexylcarbodiimide is
25ml、45ml；
Preferred version as the present invention: slowly drip dehydrated alcohol, the volume of dichloromethane in step (2) in microreactor
For 60ml, 70ml；
Preferred version as the present invention: in step (1), described organic solvent is ethyl acetate.
The production method of 2 one kinds of azelnidipine intermediate of embodiment
The production method of a kind of azelnidipine intermediate, comprises the following steps:
(1) esterification: a, in inert gas shielding downhill reaction still, it is slowly added to dimethylaniline, epoxychloropropane and has
Machine solvent is mixed in proportion, and mixing time is 2-8h, and temperature controls at 90 DEG C；
B, dropping cyanoacetic acid and N, N-dicyclohexylcarbodiimide continue reaction 4h；
C, react complete cooling, sucking filtration, filtrate, washing, prepare solvent orange 2 A standby；
(2) Pinner reaction:
Solvent orange 2 A is added in microreactor by a, the pump using flow velocity to be 150ml/min, is heated to 240 DEG C；
B, slowly dripping in dehydrated alcohol, dichloromethane in microreactor, mixing time is 3-5h；
C, it is passed through liquid nitrogen, is cooled to 20 DEG C, be passed through dry hydrogen chloride gas 4h, seal stirring 25h, prepare mixed liquid B standby
With；
(3) reaction is neutralized:
Dripping sodium bicarbonate in mixed liquid B, controlling pH value is 8.3, stirring 70min, sucking filtration, filtrate steaming removal solvent, after drying
Prepare powder C standby；
(4) amidine is become to react:
By adding ammonium carbonate after powder C toluene, xylene soluble, it is warming up to 125 DEG C, pressure 1.5MPa, after reaction completely, point
Obtain white crystal from purification, obtain azelnidipine intermediate 3-amino-3-imino group propanoic acid-1-(benzhydryl)-3-
Azacyclo-butyl ester acetate compounds；
Preferred version as the present invention: in step (1), the volume ratio of toluidines, epoxychloropropane and organic solvent is
1:0.7:2；
Preferred version as the present invention: in step (1), the volume of dropping cyanoacetic acid and N, N-dicyclohexylcarbodiimide is
25ml、45ml；
Preferred version as the present invention: slowly drip dehydrated alcohol, the volume of dichloromethane in step (2) in microreactor
For 60ml, 70ml；
Preferred version as the present invention: in step (1), described organic solvent is ethyl acetate.
The production method of 3 one kinds of azelnidipine intermediate of embodiment
The production method of a kind of azelnidipine intermediate, comprises the following steps:
(1) esterification: a, in inert gas shielding downhill reaction still, it is slowly added to dimethylaniline, epoxychloropropane and has
Machine solvent is mixed in proportion, and mixing time is 8h, and temperature controls at 100 DEG C；
B, dropping cyanoacetic acid and N, N-dicyclohexylcarbodiimide continue reaction 5h；
C, react complete cooling, sucking filtration, filtrate, washing, prepare solvent orange 2 A standby；
(2) Pinner reaction:
Solvent orange 2 A is added in microreactor by a, the pump using flow velocity to be 200ml/min, is heated to 260 DEG C；
B, slowly dripping in dehydrated alcohol, dichloromethane in microreactor, mixing time is 5h；
C, it is passed through liquid nitrogen, is cooled to 25 DEG C, be passed through dry hydrogen chloride gas 6h, seal stirring 30h, prepare mixed liquid B standby
With；
(3) reaction is neutralized:
Dripping sodium bicarbonate in mixed liquid B, controlling pH value is 8.4, stirring 80min, sucking filtration, filtrate steaming removal solvent, after drying
Prepare powder C standby；
(4) amidine is become to react:
By adding ammonium carbonate after powder C toluene, xylene soluble, it is warming up to 150 DEG C, pressure 2MPa, after reaction completely, point
Obtain white crystal from purification, obtain azelnidipine intermediate 3-amino-3-imino group propanoic acid-1-(benzhydryl)-3-
Azacyclo-butyl ester acetate compounds；
Preferred version as the present invention: in step (1), the volume ratio of toluidines, epoxychloropropane and organic solvent is
1:0.8:2.5；
Preferred version as the present invention: in step (1), the volume of dropping cyanoacetic acid and N, N-dicyclohexylcarbodiimide is
25ml、45ml；
Preferred version as the present invention: slowly drip dehydrated alcohol, the volume of dichloromethane in step (2) in microreactor
For 60ml, 70ml；
Preferred version as the present invention: in step (1), described organic solvent is ethyl acetate.
The preferred embodiment of the present invention described in detail above.Should be appreciated that those of ordinary skill in the art without
Need creative work just can make many modifications and variations according to the design of the present invention.Therefore, all technology in the art
Personnel are available by logical analysis, reasoning, or a limited experiment the most on the basis of existing technology
Technical scheme, all should be in the protection domain being defined in the patent claims.
Claims (6)
1. the production method of an azelnidipine intermediate, it is characterised in that comprise the following steps:
(1) esterification: a, in inert gas shielding downhill reaction still, it is slowly added to dimethylaniline, epoxychloropropane and has
Machine solvent is mixed in proportion, and mixing time is 2-8h, and temperature controls at 80-100 DEG C；
B, dropping cyanoacetic acid and N, N-dicyclohexylcarbodiimide continue reaction 3-5h；
C, react complete cooling, sucking filtration, filtrate, washing, prepare solvent orange 2 A standby；
(2) Pinner reaction:
Solvent orange 2 A is added in microreactor by a, the pump using flow velocity to be 100-200ml/min, is heated to 220-260 DEG C；
B, slowly dripping in dehydrated alcohol, dichloromethane in microreactor, mixing time is 3-5h；
C, it is passed through liquid nitrogen, is cooled to 15-25 DEG C, be passed through dry hydrogen chloride gas 2-6h, seal stirring 20-30h, prepare mixed
Close liquid B standby；
(3) reaction is neutralized:
Dripping sodium bicarbonate in mixed liquid B, control pH value is 8.2-8.4, stirring 60-80min, sucking filtration, filtrate steaming removal solvent,
Dried prepared powder C is standby；
(4) amidine is become to react:
By adding ammonium carbonate after powder C toluene, xylene soluble, being warming up to 100-150 DEG C, pressure 0-2MPa, reaction is completely
After, isolated and purified white crystal, obtain azelnidipine intermediate 3-amino-3-imino group propanoic acid-1-(benzhydryl
)-3-azacyclo-butyl ester acetate compounds.
2. according to the production method of a kind of azelnidipine intermediate described in claim 1, it is characterised in that in step (1)
The volume ratio of toluidines, epoxychloropropane and organic solvent is 1:(0.6-0.8): (1.5-2.5).
3. according to the production method of a kind of azelnidipine intermediate described in claim 1, it is characterised in that in step (1)
The volume of dropping cyanoacetic acid and N, N-dicyclohexylcarbodiimide is 25ml, 45ml.
4. according to the production method of a kind of azelnidipine intermediate described in claim 1, it is characterised in that in step (2)
Slowly drip dehydrated alcohol in microreactor, the volume of dichloromethane is 60ml, 70ml.
5. according to the production method of a kind of azelnidipine intermediate described in claim 1, it is characterised in that step (3) is controlled
PH value processed is 8.3.
6. according to the production method of a kind of azelnidipine intermediate described in claim 1, it is characterised in that in step (1),
Described organic solvent is ethyl acetate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106543061A (en) * | 2016-10-20 | 2017-03-29 | 威海迪素制药有限公司 | The preparation method of 3 alcohol of N benzhydryl ring fourths heterocycle |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102453023A (en) * | 2010-10-21 | 2012-05-16 | 大丰市天生药业有限公司 | Process for producing azelnidipine |
| CN103130700A (en) * | 2013-03-14 | 2013-06-05 | 沈阳中海药业有限公司 | Preparation method of azelnidipine intermediate |
-
2016
- 2016-06-20 CN CN201610441451.8A patent/CN105949102A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102453023A (en) * | 2010-10-21 | 2012-05-16 | 大丰市天生药业有限公司 | Process for producing azelnidipine |
| CN103130700A (en) * | 2013-03-14 | 2013-06-05 | 沈阳中海药业有限公司 | Preparation method of azelnidipine intermediate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106543061A (en) * | 2016-10-20 | 2017-03-29 | 威海迪素制药有限公司 | The preparation method of 3 alcohol of N benzhydryl ring fourths heterocycle |
| CN106543061B (en) * | 2016-10-20 | 2019-08-16 | 威海迪素制药有限公司 | The preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol |
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Application publication date: 20160921 |