CN103224476A - New process for preparing 1-[2-(2-hydroxyethoxy)ethyl]piperazine through diethanolamine method - Google Patents
New process for preparing 1-[2-(2-hydroxyethoxy)ethyl]piperazine through diethanolamine method Download PDFInfo
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- CN103224476A CN103224476A CN2013101977635A CN201310197763A CN103224476A CN 103224476 A CN103224476 A CN 103224476A CN 2013101977635 A CN2013101977635 A CN 2013101977635A CN 201310197763 A CN201310197763 A CN 201310197763A CN 103224476 A CN103224476 A CN 103224476A
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Abstract
The invention provides a new process route for preparing 1-[2-(2-hydroxyethoxy)ethyl]piperazine through a diethanolamine method, which takes diethanolamine as an initial material and performs brand new three-step reaction of halogen replacement, acylation and cyclization. Compared with a chloroethanol method conventionally used in the current industry, the new process provided by the invention has the advantages of high reaction activity, low toxicity, easily controlled reaction system, cheap and accessible reaction kettle and the like; and the whole reaction process does not need high-temperature operation, the post treatment is simple, and the production operation difficulty and the potential safety hazard are greatly reduced. The invention creatively adopts a diglycolamine method to successfully realize the cyclization of an intermediate compound (N-bis(2-chloroethyl)acetamide) of a project product; the conversion rate is up to 80% or above; the production process is safe and non-toxic; the process is simple; no expensive catalyst needs to be used; and the technology fills up the blank in China.
Description
Technical field
The present invention relates to a kind of atypical chlorpromazine quetiapine fumarate intermediate 1-[2-(2-hydroxyl-oxethyl) ethyl] production technique of piperazine, be specifically related to a kind of diethanolamine method and prepare 1-[2-(2-hydroxyl-oxethyl) ethyl] novel process of piperazine, belong to chemical field of medicaments.
Background technology
Quetiapine fumarate is an atypical chlorpromazine of new generation, is gone on the market in Britain first in November, 1997 by Britain Zeneca company, and is clinical in a schizoid line medicine.This medicine is at present uniquely both to have been can be used for treating the manic acute attack of two-phase by FDA confirmation sheet medicine, can treat the atypical antipsychotic of the depressed acute attack of two-phase again.At present, the synthetic quetiapine fumarate of industrialization is the female cyclic cpds 10H-of earlier synthetic key intermediate dibenzo [b, f] [1,4] sulphur azatropylidene-11-ketone and side chain compound 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine, obtain quetiapine fumarate by side chain and female ring reaction again, its technological line is as follows:
The quality of synthetic quetiapine fumarate operational path depends on female cyclic cpds and side chain 1-[2-(2-hydroxyl-oxethyl) ethyl to a great extent] piperazine synthetic.
At present, intermediate 1-[2-(2-hydroxyl-oxethyl) ethyl] preparation method of piperazine has following two kinds: 1, piperazine and 2-(2-chloroethoxy) are ethanol condensed:
2, piperazinecarboxylic acid ethyl ester and 2-(2-chloroethoxy) are ethanol condensed:
Method 1,2 all relates to the preparation of intermediate 2-(2-chloroethoxy) alcoholic acid, and its synthetic method mainly contains three kinds: 1) glycol ether chlorination process: this method side reaction is more, and purification difficult is not suitable for suitability for industrialized production,
2) chloroethanol method: under the boron trifluoride diethyl etherate catalysis, with the chloroethanol is that starting raw material and reacting ethylene oxide obtain, this method is industrialized common process, but used raw material chloroethanol, oxyethane are highly toxic product, low 10.4 ℃ of oxyethane boiling point, inflammable, explosive characteristics are arranged, potential safety hazard is very big, the easy etching apparatus of while boron trifluoride, and equipment claimed is often changed, increased production cost
3) reaction of glycol ether and SULPHURYL CHLORIDE obtains mono-substituted glycol ether sulphonate, again with piperazine condensation,
This method prepares mono-substituted glycol ether sulphonate condition and is not easy control, is easy to generate disubstituted glycol ether sulphonate, and yield is low.
Summary of the invention
Deficiency at above-mentioned similar technology existence; the purpose of this invention is to provide a kind is starting raw material with the diethanolamine; prepare 1-[2-(2-hydroxyl-oxethyl) ethyl through halogen displacement, acidylate, the brand-new diethanolamine method of cyclization] novel process of piperazine; to reduce potential safety hazard; simplify the operation; reduce production costs stabilized product quality.
Technical scheme of the present invention is: diethanolamine method prepares 1-[2-(2-hydroxyl-oxethyl) ethyl] the piperazine novel process, it is characterized in that: realize by following three-step reaction:
1, halogen replacement(metathesis)reaction: behind reactant sulfur oxychloride and reaction solvent adding reactor, be cooled to 20～25 ℃; Drip the raw material diethanolamine again, diethanolamine and sulfur oxychloride mol ratio are 1:2.4, and the control temperature of reaction system is less than 50 ℃; After dripping, reaction soln was 20～25 ℃ of insulations 5 hours, and this process is separated out a large amount of solids; Afterwards, reactor slowly is warming up to 60 ℃, is incubated 3 hours; Cool to room temperature filters again, promptly obtains two-(2-chloroethyl) amine hydrochlorates; Productive rate reaches 90%.
2, acetylization reaction: halogen substitution product two-(2-chloroethyl) amine hydrochlorate, water, methylene dichloride are added reactor, drip acetylizing agent and 30% aqueous sodium hydroxide solution simultaneously, the control reactor temperature is at 20～30 ℃; Reaction is told lower floor's methylene dichloride after finishing, and uses anhydrous magnesium sulfate drying, filters, and filtrate concentrating reclaimed methylene dichloride, and the residuum recrystallization promptly obtains two (2-chloroethyl) ethanamides of N-, productive rate 71%.
3, ring-closure reaction: in reactor, add diglycolamine, two (2-chloroethyl) ethanamide and the water of acetylization reaction product N-, with this mixed reactant reflux, after reaction finishes, concentrating under reduced pressure; Add methyl alcohol in the concentrated solution,, add 50-65 ℃ of insulation in back 3 hours at 50-65 ℃ of dropwise liquid; After reaction was finished, normal pressure reclaimed methyl alcohol, adds methyl alcohol in the residuum again, is cooled to 0-5 ℃, filtered; Earlier the filtrate normal pressure is reclaimed methyl alcohol, then the filtrate decompression distillation is obtained target product 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine, productive rate 86%.
As a preferred version, the reaction solvent in the described halogen replacement(metathesis)reaction is preferably ethylene dichloride, chloroform, toluene, halogeno-benzene, ethers.
As a preferred version, described acetylizing agent is preferably Acetyl Chloride 98Min., diacetyl oxide or Glacial acetic acid.
Technological line of the present invention is as follows:
Compare with the commercial like product, the project product that adopts diethanolamine method production to obtain has advantages such as purity height, look shape are good, conversion rate of products height, and my company's product only is the 70-80% of like product price, this price has played crucial effects for the market value that reduces its main derived product antipsychotic drug quetiapine fumarate, has the market competition advantage that can not be substituted.
The following advantage that the present invention has: 1, compare with the conventional chloroethanol method of using of present industry, the diethanolamine method of independent research has many advantages such as reactive behavior is higher, toxicity is little, reaction system is easy to control, reactor is cheap and easy to get; 2, entire reaction course does not need high-temperature operation, and aftertreatment is simple, has greatly reduced the difficulty and the potential safety hazard of production operation, has the incomparable technical superiority of traditional technology; 3, original creation adopts the diglycolamine method successfully to realize the cyclization of two (2-chloroethyl) ethanamides of project product intermediate N, and transformation efficiency is up to more than 80%, the production process safety non-toxic, and technology is simple, need not to use expensive catalyst, and technology fills the domestic gaps; 4, compare with the commercial like product, the project product that adopts diethanolamine method production to obtain has advantages such as purity height, look shape are good, conversion rate of products height.
Description of drawings
Fig. 1 is the schema of novel process of the present invention.
Embodiment
Now in conjunction with the accompanying drawings and following concrete enforcement, the invention will be further described.
1) halogen replacement(metathesis)reaction
In the 1000L reactor, add 238kg sulfur oxychloride, 1200kg ethylene dichloride, be cooled to 20～25 ℃; Drip the 88kg diethanolamine again, controlled temperature is less than 50 ℃; After dripping, reaction soln is separated out a large amount of solids 20～25 ℃ of insulations 5 hours; Afterwards, reactor slowly is warming up to 60 ℃, is incubated 3 hours; Cool to room temperature filters again, obtains 136kg two-(2-chloroethyl) amine hydrochlorate.
2) acetylization reaction
Add 178.5kg two-(2-chloroethyl) amine hydrochlorate, 400kg water, 320kg methylene dichloride in the 1000L still, drip 85kg Acetyl Chloride 98Min. and 72kg30% aqueous sodium hydroxide solution simultaneously, the control reactor temperature is at 20～30 ℃; Reaction is told lower floor's methylene dichloride after finishing, and uses anhydrous magnesium sulfate drying, filters, and filtrate concentrating reclaimed methylene dichloride, and the residuum recrystallization obtains two (2-chloroethyl) ethanamides of 130kg N-.
3) ring-closure reaction
In the 1000L still, add 105kg diglycolamine, two (2-chloroethyl) ethanamides of 184kg N-, 500kg water, with this mixed reactant reflux; After reaction finishes, concentrating under reduced pressure; Add 500kg methyl alcohol in the concentrated solution, drip the 150kg30% liquid caustic soda, add 50-65 ℃ of insulation in back 3 hours at 50-65 ℃; After reaction was finished, normal pressure reclaimed methyl alcohol, adds 200kg methyl alcohol in the residuum again, is cooled to 0-5 ℃, filtered; Earlier the filtrate normal pressure is reclaimed methyl alcohol, underpressure distillation gets 150kg1-[2-(2-hydroxyl-oxethyl) ethyl then] piperazine.
Above content is to further specifying that the present invention did in conjunction with concrete preferred implementation; can not assert that concrete enforcement of the present invention is confined to these explanations; for the general technical staff of the technical field of the invention; under the prerequisite that does not break away from design of the present invention; can also do some simple deductions and replacement, all should be considered as belonging to protection scope of the present invention.
Claims (3)
1. diethanolamine method prepares 1-[2-(2-hydroxyl-oxethyl) ethyl] the piperazine novel process, it is characterized in that: realize by following three-step reaction:
1) halogen replacement(metathesis)reaction: behind reactant sulfur oxychloride and reaction solvent adding reactor, be cooled to 20～25 ℃; Drip the raw material diethanolamine again, diethanolamine and sulfur oxychloride mol ratio are 1:2.4, and the control temperature of reaction system is less than 50 ℃; After dripping, reaction soln was 20～25 ℃ of insulations 5 hours, and this process is separated out a large amount of solids; Afterwards, reactor slowly is warming up to 60 ℃, is incubated 3 hours; Cool to room temperature filters again, promptly obtains two-(2-chloroethyl) amine hydrochlorates;
2) acetylization reaction: halogen substitution product two-(2-chloroethyl) amine hydrochlorate, water, methylene dichloride are added reactor, drip acetylizing agent and 30% aqueous sodium hydroxide solution simultaneously, the control reactor temperature is at 20～30 ℃; Reaction is told lower floor's methylene dichloride after finishing, and uses anhydrous magnesium sulfate drying, filters, and filtrate concentrating reclaimed methylene dichloride, and the residuum recrystallization promptly obtains two (2-chloroethyl) ethanamides of N-;
3) ring-closure reaction: in reactor, add diglycolamine, two (2-chloroethyl) ethanamide and the water of acetylization reaction product N-, with this mixed reactant reflux, after reaction finishes, concentrating under reduced pressure; Add methyl alcohol in the concentrated solution,, add 50-65 ℃ of insulation in back 3 hours at 50-65 ℃ of dropwise liquid; After reaction was finished, normal pressure reclaimed methyl alcohol, adds methyl alcohol in the residuum again, is cooled to 0-5 ℃, filtered; Earlier the filtrate normal pressure is reclaimed methyl alcohol, then the filtrate decompression distillation is obtained target product 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine.
2. diethanolamine method according to claim 1 prepares 1-[2-(2-hydroxyl-oxethyl) ethyl] the piperazine novel process, it is characterized in that: the reaction solvent in the described halogen replacement(metathesis)reaction is preferably ethylene dichloride, chloroform, toluene, halogeno-benzene, ethers.
3. diethanolamine method according to claim 1 and 2 prepares 1-[2-(2-hydroxyl-oxethyl) ethyl] the piperazine novel process, it is characterized in that: described acetylizing agent is preferably Acetyl Chloride 98Min., diacetyl oxide or Glacial acetic acid.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108033931A (en) * | 2017-12-28 | 2018-05-15 | 山东铂源药业有限公司 | A kind of synthetic method of N-Boc piperazines |
| CN108191791A (en) * | 2018-01-10 | 2018-06-22 | 山东铂源药业有限公司 | A kind of synthetic method of Dasatinib intermediate |
| CN113477052A (en) * | 2021-07-15 | 2021-10-08 | 大连理工大学 | Aminoethylated piperazine, preparation method thereof, carbon dioxide absorbent and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102471260A (en) * | 2009-06-30 | 2012-05-23 | 盖尔德马研究及发展公司 | Novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics |
| WO2012116586A1 (en) * | 2011-03-02 | 2012-09-07 | 华中科技大学 | 2-aminothiazole derivative, preparation method, and use |
| CN102786497A (en) * | 2012-07-13 | 2012-11-21 | 常州大学 | Preparation method of piperazine compound and intermediate thereof |
| CN103044356A (en) * | 2011-10-13 | 2013-04-17 | 湖南九典制药有限公司 | New method for synthesizing levocetirizine and key intermediate thereof |
-
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102471260A (en) * | 2009-06-30 | 2012-05-23 | 盖尔德马研究及发展公司 | Novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics |
| WO2012116586A1 (en) * | 2011-03-02 | 2012-09-07 | 华中科技大学 | 2-aminothiazole derivative, preparation method, and use |
| CN103044356A (en) * | 2011-10-13 | 2013-04-17 | 湖南九典制药有限公司 | New method for synthesizing levocetirizine and key intermediate thereof |
| CN102786497A (en) * | 2012-07-13 | 2012-11-21 | 常州大学 | Preparation method of piperazine compound and intermediate thereof |
Non-Patent Citations (2)
| Title |
|---|
| VOLOVEL"SKII, L. N 等: "Potential antitumor compounds. II.Dichlorodiethylamides of some aliphatic acids", 《ZHURNAL OBSHCHEI KHIMII》 * |
| 蔡进 等: "多巴胺D3受体部分激动剂BP897的合成", 《中国新药杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108033931A (en) * | 2017-12-28 | 2018-05-15 | 山东铂源药业有限公司 | A kind of synthetic method of N-Boc piperazines |
| CN108033931B (en) * | 2017-12-28 | 2020-03-10 | 山东铂源药业有限公司 | Synthesis method of N-Boc piperazine |
| CN108191791A (en) * | 2018-01-10 | 2018-06-22 | 山东铂源药业有限公司 | A kind of synthetic method of Dasatinib intermediate |
| CN108191791B (en) * | 2018-01-10 | 2020-04-28 | 山东铂源药业有限公司 | Synthesis method of dasatinib intermediate |
| CN113477052A (en) * | 2021-07-15 | 2021-10-08 | 大连理工大学 | Aminoethylated piperazine, preparation method thereof, carbon dioxide absorbent and application thereof |
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