CN107011197B - A method of continuously preparing Gabapentin - Google Patents
A method of continuously preparing Gabapentin Download PDFInfo
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- CN107011197B CN107011197B CN201710265987.3A CN201710265987A CN107011197B CN 107011197 B CN107011197 B CN 107011197B CN 201710265987 A CN201710265987 A CN 201710265987A CN 107011197 B CN107011197 B CN 107011197B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C263/00—Preparation of derivatives of isocyanic acid
- C07C263/12—Preparation of derivatives of isocyanic acid from or via nitrogen analogues of carboxylic acids, e.g. from hydroxamic acids, involving a Hofmann, Curtius or Lossen-type rearrangement
Abstract
The invention belongs to pharmaceutical chemicals to synthesize field, and in particular to a method of continuously prepare Gabapentin.The present invention passes through 1, Hoffmann rearrangement reaction occurs at relatively high temperatures for 1- cyclohexanediacetic acid monoamides, and the isocyanates direct hydrolysis of generation obtains DOPA spray fourth, the process for needing multistep temperature control originally is reduced to a step and is continuously prepared, process is simple, and reaction time is short；Temperature-controlled appliance is required lower；Due to pyroreaction, reaction rate is fast, does not need that much excessive sodium hypochlorite and sodium hydroxide is added to improve reaction rate, subsequent wastewater treatment pressure is effectively relieved in saving raw material；Continuous reaction is easy to that reaction process is monitored and controlled；Two fluids is realized in microreactor rapidly and efficiently to be mixed, and moment reaches uniform reaction environment, and reaction efficiency is high, and the amplification of this kind of microreactor is easy.
Description
Technical field
The invention belongs to pharmaceutical chemicals to synthesize field, and in particular to a method of continuously prepare Gabapentin.
Technical background
Gabapentin (Gabapentin), entitled 1- (aminomethyl) Cyclohexaneacetic acid of chemistry, by U.S. Warner-
The exploitation of Lanbert company listed in Britain in 1993, is a kind of novel antiepileptic, currently, this kind of bulk pharmaceutical chemicals are complete
The annual demand of ball is up to 1000 tons or more.
Precursor of the Gabapentin hydrochloride as Gabapentin, entitled 1- (aminomethyl) the Cyclohexaneacetic acid hydrochloride of chemistry,
The substance is prepared at present there are many route of synthesis (CN 104402744A, CN 105061241A, CN102093237B), wherein phase
It closes and reports that more method is: (1) with 1,1- cyclohexanediacetic acid monoamides (CDMA) for starting material, through Hoffmann rearrangement
Reaction, direct acidification reaction liquid obtain the method (CA 2478471A1) of Gabapentin hydrochloride；(2) Hoffmann rearrangement is first passed through
3,3- pentylidene butyrolactam is made in reaction, dehydrating condensation, then the side of Gabapentin hydrochloride is prepared through phase transfer acidic hydrolysis
Method (CN 102093237B, CN 104402744A).
The above method has used Hoffmann rearrangement reaction, for the practical operation major part patent (WO 02/ of the reaction
34709, WO 03/089403) using classical reaction method and condition, i.e., by tank reactor divide multistep temperature control into
Row intermittently operated is completed.This kind of method first at a lower temperature (- 5 DEG C~10 DEG C general), will contain 1,1- cyclohexanediacetic acid list
The solution of amide is slowly dropped in sodium hypochlorite alkaline solution, and isocyanates is made；Then higher temperature (general 20 DEG C with
On), isocyanate hydrolysis generates Gabapentin solution.Above-mentioned Hoffmann rearrangement reaction belongs to strong exothermal reaction, this kind of technique exists
There are temperature to be difficult to control in actual mechanical process, process is cumbersome, reaction time is long, amplification difficulty etc. is a series of intractable asks
Topic, has increased considerably the energy and material consumption of production process.Therefore it is very necessary to develop more efficient, inexpensive synthetic technology.
Summary of the invention
The purpose of the present invention is to propose to a kind of method for continuously preparing Gabapentin, specific technical solution is as follows:
A method of Gabapentin continuously being prepared, is included the following steps:
(1) the feed liquid A of the monoamides of cyclohexanediacetic acid containing 1,1- and sodium hydroxide is prepared；
(2) the feed liquid B containing sodium hypochlorite and sodium hydroxide is prepared；
(3) the feed liquid B in the feed liquid A and step (2) in step (1) is quickly mixed by micro-mixer, obtains reaction solution
C；
(4) reaction liquid C is reacted in reactor in step (3), obtains the alkaline solution containing Gabapentin；
(5) from extraction obtains Gabapentin in the alkaline solution containing Gabapentin in step (4).
The molar ratio of 1,1- cyclohexanediacetic acid monoamides and sodium hydroxide is 1:(1~5 in step (1)), the feed liquid A
In 1,1- cyclohexanediacetic acid monoamides molar concentration be 0.5~3mol/L, prepare 0~25 DEG C of temperature carry out.
In step (2) molar ratio of sodium hypochlorite and sodium hydroxide be 1:(0.5~3.5), the sodium hypochlorite it is effective
Chlorinity is 5~20%, and the molar concentration of sodium hypochlorite is 0.5~6mol/L in the feed liquid B, is prepared at 0~25 DEG C of temperature
It carries out.
The flow-rate ratio that feed liquid A and feed liquid B passes through the microreactor in step (3) is 1:(0.5~5).
In step (3) in reaction liquid C sodium hypochlorite, 1,1- cyclohexanediacetic acid monoamides and sodium hydroxide initial molar
Than for (1-4): 1:(2-5).
Micro-mixer is micro-channel mixer, film dispersion micro-mixer or Microtraps hole mixer in step (3).
Step quickly mixes described in (3), and mixing temperature is 0 DEG C~60 DEG C, and incorporation time is 0.1~1s.
Reactor described in step (4) be coil pipe or temperature control stirring kettle, reaction temperature be 0 DEG C~60 DEG C, preferably 20 DEG C~
50 DEG C, the reaction time is 0.5min~60min, preferably 1min~10min.
Reaction liquid C is in disk inner reaction tube in step (4), and the reaction time is 0.5min~10min, and reaction temperature is 0 DEG C~
60 DEG C, then reaction solution is imported in temperature control stirring kettle, the reaction time is 1min~5h, and reaction temperature is 0 DEG C~50 DEG C.
The step (5) is to be added in reducing agent into the alkaline solution containing Gabapentin described in step (4) with remnants'
Sodium hypochlorite obtains Gabapentin after then acidified, filtering, recrystallization, drying；The reducing agent is thiosulfate, Asia
Sulfate or bisulfites.
The invention has the benefit that
By 1,1- cyclohexanediacetic acid monoamides Hoffmann rearrangement reaction occurs at relatively high temperatures for the present invention, generation
Isocyanates direct hydrolysis obtains DOPA spray fourth, and the process for needing multistep temperature control originally is reduced to a step and is continuously prepared, process
Simply, reaction time is short；Temperature-controlled appliance is required lower；Due to pyroreaction, reaction rate is fast, does not need to be added remote
Remote excessive sodium hypochlorite and sodium hydroxide improve reaction rate, save raw material, subsequent wastewater treatment pressure is effectively relieved；Even
Continuousization reaction, is easy to that reaction process is monitored and controlled；Two fluids is realized in microreactor rapidly and efficiently to be mixed, and moment reaches
Uniform reaction environment, reaction efficiency is high, and the amplification of this kind of microreactor is easy.
Detailed description of the invention
Fig. 1 is the process flow chart of embodiment 1,2,5 and 7.
Fig. 2 is the process flow chart of embodiment 3.
Fig. 3 is the process flow chart of embodiment 4.
Specific implementation method
The invention proposes a kind of methods for continuously preparing Gabapentin, do further below with reference to embodiment to the present invention
Illustrate, but is not limited to the present invention.
Micro-mixer of the present invention is micro-channel mixer or patent ZL00105779.0, ZL 200510012114.9
Described in microreactor, which is able to achieve the efficient mixing between two fluids, and moment reaches uniform reaction ring
Border, other, which are able to achieve the device quickly mixed, can also be used for the present invention.
Embodiment 1
(1) under 10~15 DEG C of water-bath temperature controls and stirring, slowly by 88g 1,1- cyclohexanediacetic acid monoamides adds
Enter in the sodium hydroxide solution for being 10% to 195g mass fraction, feed liquid A is made in dissolved clarification.
(2) under 5~10 DEG C of water-bath temperature controls and stirring, 53g sodium hydrate solid is slowly added to 450g effective chlorine
In the liquor natrii hypochloritis that content is 8.4%, feed liquid B is made in dissolved clarification.
(3) feed liquid A and feed liquid B in step (2) is passed through water-bath respectively with the flow of 5mL/min and 8mL/min in step (1)
In the micro-reactor apparatus that temperature is 40 DEG C, realizes quickly mixing, obtain reaction liquid C.Wherein feed liquid A is continuous phase, and feed liquid B is point
Dephasing.Micro-reactor apparatus is mainly made of microreactor and coil pipe, microreactor structure referring to patent ZL200510012114.9,
Containing 2 parallel channels, using 10 microns of stainless steel perforated membrane as decentralized medium.Residence time of the reaction liquid C in coil pipe be
5min is obtained to 1mol/L sodium thiosulfate being added dropwise from the solution connect in micro-reactor apparatus to neutralize remaining sodium hypochlorite
It is 98.5% by the yield that high performance liquid chromatography measures Gabapentin to the solution of the spray fourth of DOPA containing product.Containing Gabapentin
Solution is acidified, filtering, recrystallization, it is dry after, Gabapentin is prepared.
Embodiment 2
(1) under 10~15 DEG C of water-bath temperature controls and stirring, slowly by 71g1,1- cyclohexanediacetic acid monoamides is added
In the sodium hydroxide solution for being 9.5% to 164g mass fraction, feed liquid A is made in dissolved clarification.
(2) under 5~10 DEG C of water-bath temperature controls and stirring, 34g sodium hydrate solid is slowly added to 390g effective chlorine
In the liquor natrii hypochloritis that content is 8.4%, feed liquid B is made in dissolved clarification.
(3) feed liquid A and feed liquid B in step (2) is passed through water respectively with the flow of 5mL/min and 8.5mL/min in step (1)
In the micro-reactor apparatus that bath temperature is 45 DEG C, realizes quickly mixing, obtain reaction liquid C.Wherein feed liquid A is continuous phase, and feed liquid B is
Dispersed phase.Micro-reactor apparatus is mainly made of microreactor and coil pipe.Microreactor structure is referring to patent
ZL200510012114.9 contains 2 parallel channels, using 10 microns of stainless steel perforated membrane as decentralized medium.Reaction liquid C is in disk
Residence time in pipe is 4.8min, to 1mol/L sodium thiosulfate being added dropwise from the solution connect in micro-reactor apparatus to neutralize
Remaining sodium hypochlorite obtains the solution of the spray fourth of DOPA containing product, can be measured by high performance liquid chromatography, the production of Gabapentin
Rate is 99.0%.Solution containing Gabapentin is acidified, filtering, recrystallizes, after drying, and Gabapentin is prepared.
Embodiment 3
(1) under 10~15 DEG C of water-bath temperature controls and stirring, slowly by 71g1,1- cyclohexanediacetic acid monoamides is added
In the sodium hydroxide solution for being 9.5% to 164g mass fraction, feed liquid A is made in dissolved clarification.
(2) under 5~10 DEG C of water-bath temperature controls and stirring, 43g sodium hydrate solid is slowly added to 330g effective chlorine
In the liquor natrii hypochloritis that content is 8.2%, feed liquid B is made in dissolved clarification.
(3) feed liquid A and feed liquid B in step (2) is passed through water-bath respectively with the flow of 6mL/min and 9mL/min in step (1)
In the micro-reactor apparatus that temperature is 40 DEG C, realizes quickly mixing, obtain reaction liquid C.Wherein feed liquid A is continuous phase, and feed liquid B is point
Dephasing.Micro-reactor apparatus is mainly made of microreactor and coil pipe.Microreactor structure referring to patent ZL200510012114.9,
Containing 2 parallel channels, using 20 microns of stainless steel filter membrane as decentralized medium.Residence time of the reaction liquid C in coil pipe be
2.0min。
(4) reaction solution in step (3) is imported into 40 DEG C of temperature control stirring kettles, 5min is stirred to react, to from stirred tank
1mol/L sodium thiosulfate is added dropwise in obtained solution to neutralize remaining sodium hypochlorite, obtains the molten of the spray fourth of DOPA containing product
Liquid can be measured by high performance liquid chromatography, and the yield for just going out Gabapentin in the reaction solution of micro-reactor apparatus is 94.5%, most
The yield of Gabapentin is 99.5% in end reaction liquid.Solution containing Gabapentin is acidified, filtering, recrystallizes, after drying, system
It is standby to obtain Gabapentin.
Embodiment 4
(1) under 10~15 DEG C of water-bath temperature controls and stirring, slowly by 71g1,1- cyclohexanediacetic acid monoamides is added
In the sodium hydroxide solution for being 9.5% to 164g mass fraction, feed liquid A is made in dissolved clarification.
(2) under 5~10 DEG C of water-bath temperature controls and stirring, 43g sodium hydrate solid is slowly added to 330g effective chlorine
In the liquor natrii hypochloritis that content is 8.2%, feed liquid B is made in dissolved clarification.
(3) in step (1) in feed liquid A and step (2) feed liquid B be passed through respectively with the flow of 6mL/min and 9mL/min it is micro- anti-
Device is answered, microreactor structure contains 3 parallel channels, be with 20 microns of Microtraps hole referring to patent ZL 200510012114.9
Decentralized medium, feed liquid A are dispersed phase, and feed liquid B is continuous phase, are introduced directly into 20 DEG C of temperature control stirring kettles, are stirred to react after mixing
60min leads to 1mol/L sodium thiosulfate being added dropwise from solution obtained in temperature control stirring kettle to neutralize remaining sodium hypochlorite
Crossing high performance liquid chromatography and measuring the yield of Gabapentin is 95.2%.Solution containing Gabapentin is acidified, filtering, recrystallization,
After drying, Gabapentin is prepared.
Embodiment 5
(1) under 10~15 DEG C of water-bath temperature controls and stirring, slowly by 140g1,1- cyclohexanediacetic acid monoamides adds
Enter in the sodium hydroxide solution for being 19% to 360g mass fraction, feed liquid A is made in dissolved clarification.
(2) under 5~10 DEG C of water-bath temperature controls and stirring, 30g sodium hydrate solid is slowly added to 700g effective chlorine
In the liquor natrii hypochloritis that content is 8.6%, feed liquid B is made in dissolved clarification.
(3) feed liquid A and feed liquid B in step (2) is passed through water respectively with the flow of 11mL/min and 15mL/min in step (1)
Quickly mixing is realized in the micro-reactor apparatus that bath temperature is 45 DEG C, obtains reaction liquid C.Wherein feed liquid A is continuous phase, and feed liquid B is
Dispersed phase.Micro-reactor apparatus is mainly made of microreactor and coil pipe.Microreactor structure is referring to patent
ZL200510012114.9 contains 5 parallel channels, using 50 microns of stainless steel perforated membrane as decentralized medium.Reaction liquid C is in disk
Residence time in pipe is 3.8min, to 1mol/L sodium thiosulfate is added dropwise from the solution connect in micro-reactor apparatus in
It with remaining sodium hypochlorite, is measured by high performance liquid chromatography, the yield of Gabapentin is 98.2%.Solution containing Gabapentin
After acidified, filtering, recrystallization, drying, Gabapentin is prepared.
Embodiment 6
(1) under 10~15 DEG C of water-bath temperature controls and stirring, slowly by 568g1,1- cyclohexanediacetic acid monoamides adds
Enter in the sodium hydroxide solution for being 9.5% to 1312g mass fraction, feed liquid A is made in dissolved clarification.
(2) under 5~10 DEG C of water-bath temperature controls and stirring, it is effective that 272g sodium hydrate solid is slowly added to 3120g
In the liquor natrii hypochloritis that chlorinity is 8.4%, feed liquid B is made in dissolved clarification.
(3) feed liquid A and feed liquid B in step (2) is passed through water respectively with the flow of 40mL/min and 68mL/min in step (1)
In the micro-reactor apparatus that bath temperature is 45 DEG C, realizes quickly mixing, obtain reaction liquid C.Wherein feed liquid A is continuous phase, and feed liquid B is
Dispersed phase.Micro-reactor apparatus is mainly made of microreactor and coil pipe.Microreactor structure is referring to patent
ZL200510012114.9 contains 10 parallel channels, using 2 microns of porous ceramic film as decentralized medium.Reaction liquid C is in coil pipe
The interior residence time is 5min, is remained to 1mol/L sodium thiosulfate is added dropwise from the solution connect in micro-reactor apparatus with neutralizing
Sodium hypochlorite, by high performance liquid chromatography measure Gabapentin yield be 99.4%.Solution containing Gabapentin is acidified,
After filtering, recrystallization, drying, Gabapentin is prepared.
Claims (4)
1. a kind of method for continuously preparing Gabapentin, which comprises the steps of:
(1) the feed liquid A of the monoamides of cyclohexanediacetic acid containing 1,1- and sodium hydroxide is prepared；Wherein, 1,1- cyclohexanediacetic acid in
The molar ratio of monoamides and sodium hydroxide is 1:(1~5), 1,1- cyclohexanediacetic acid monoamides is mole dense in the feed liquid A
Degree is 0.5~3mol/L, prepares and carries out at 0~25 DEG C of temperature；
(2) the feed liquid B containing sodium hypochlorite and sodium hydroxide is prepared；Wherein, the molar ratio of sodium hypochlorite and sodium hydroxide is 1:
(0.5~3.5), the available chlorine content of the sodium hypochlorite are 5~20%, and the molar concentration of sodium hypochlorite is in the feed liquid B
0.5~6mol/L is prepared and is carried out at 0~25 DEG C of temperature；
(3) the feed liquid B in the feed liquid A and step (2) in step (1) is quickly mixed by micro-mixer, obtains reaction liquid C；Its
The flow-rate ratio that middle feed liquid A and feed liquid B passes through the micro-mixer is 1:(0.5~5)；The quick mixing, mixing temperature are 0 DEG C
~60 DEG C, incorporation time 0.1-1s, sodium hypochlorite in reaction liquid C, 1,1- cyclohexanediacetic acid monoamides and sodium hydroxide
Initial molar ratio is (1-4): 1:(2-5)；
(4) reaction liquid C is reacted in reactor in step (3), obtains the alkaline solution containing Gabapentin；The reactor is disk
Pipe or temperature control stirring kettle, reaction temperature are 0 DEG C~60 DEG C, and the reaction time is 0.5min~60min；Sodium hypochlorite in reaction liquid C,
The initial molar ratio of 1,1- cyclohexanediacetic acid monoamides and sodium hydroxide is (1-4): 1:(2-5)；
(5) from extraction obtains Gabapentin in the alkaline solution containing Gabapentin in step (4).
2. the method according to claim 1, wherein micro-mixer is micro-channel mixer, film point in step (3)
Dissipate micro-mixer or Microtraps hole mixer.
3. the method according to claim 1, wherein reaction liquid C is in disk inner reaction tube, reaction in step (4)
Between be 0.5min~10min, reaction temperature is 0 DEG C~60 DEG C, is then imported reaction solution in temperature control stirring kettle, the reaction time is
1min~60min, reaction temperature are 0 DEG C~60 DEG C.
4. adding a bar spray to containing described in step (4) the method according to claim 1, wherein the step (5) is
Sodium hypochlorite in reducing agent and remaining is added in the alkaline solution of fourth, then acidified, filtering after recrystallizing, being dry, obtains
Gabapentin；The reducing agent is thiosulfate, sulphite or bisulfites.
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| JP7114109B2 (en) * | 2017-10-05 | 2022-08-08 | ノボマー， インコーポレイテッド | Isocyanate, derivative and method for producing same |
| WO2019073476A1 (en) * | 2017-10-13 | 2019-04-18 | Hikal Limited | Continuous process for the preparation of gabapentin salt |
| CN108794307B (en) * | 2018-07-18 | 2022-11-11 | 山东道可化学有限公司 | Micro-reaction system and method for synthesizing 4-bromo-3-methylanisole by solvent method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004110342A2 (en) * | 2003-06-12 | 2004-12-23 | Matrix Laboratories Ltd | Novel polymorph of gabapentin and its conversion to gabapentin form-ii |
| CN1861579A (en) * | 2006-06-12 | 2006-11-15 | 浙江手心医药化学品有限公司 | Preparation process of 3,3-imyl butyrolactam |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004110342A2 (en) * | 2003-06-12 | 2004-12-23 | Matrix Laboratories Ltd | Novel polymorph of gabapentin and its conversion to gabapentin form-ii |
| CN1861579A (en) * | 2006-06-12 | 2006-11-15 | 浙江手心医药化学品有限公司 | Preparation process of 3,3-imyl butyrolactam |
Non-Patent Citations (1)
| Title |
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| 微通道反应器在合成反应中的应用;穆金霞 等;《化学进展》;20080131;第20卷(第1期);60-75 |
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