CN110143887A - A kind of preparation method of ebutol - Google Patents
A kind of preparation method of ebutol Download PDFInfo
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- CN110143887A CN110143887A CN201810143574.2A CN201810143574A CN110143887A CN 110143887 A CN110143887 A CN 110143887A CN 201810143574 A CN201810143574 A CN 201810143574A CN 110143887 A CN110143887 A CN 110143887A
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- ebutol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
This application discloses a kind of preparation method of ebutol, includes the following steps: that S- (+) -2- amino-n-butyl alcohol and 1 for being 1)+8.3 ° to+9.3 ° by specific rotation, 2- dichloroethanes mix in the reactor, react, obtain reaction discharging；2) reaction discharging is transferred to separation system, alkali is added, S- (+) -2- amino-n-butyl alcohol is then demultiplex out, and S- (+) -2- amino-n-butyl alcohol isolated is returned in reactor；3) alcohol is added into separation system again, obtains the alcoholic solution containing ethambutol；4) alcoholic solution containing ethambutol by the alcoholic solution for obtaining ethambutol by being separated off salt, after obtained desalination；5) the alcoholic solution cooling containing ethambutol after desalination is separated off impurity, the alcoholic solution of the ethambutol after being cleaned；6) water regulation system water content is added in the alcoholic solution of ethambutol and adds pure and mild hydrogen chloride, obtain the alcoholic solution containing ebutol；7) by Crystallization Separation ebutol, the ebutol is obtained.
Description
Technical field
The application belongs to pharmaceutical formulation techniques chemical field, and more specifically, this application involves a kind of ebutols
Preparation method.
Background technique
Ebutol be widely used in pulmonary tuberculosis caused by other anti-tubercular drug combination therapy tubercle bacilluses, also may be used
Treatment for tubercular meningitis and atypical mycobacterial infection.The drug accounts for the 13% of the anti-tuberculosis drugs market share
More than.
Ebutol (the entitled Ethambutol Hydrochloride of English), its chemical name is [2R, 2 [S-
(R*,R*)-R] (+) -2,2,-(1,2- second diyl diimino)-bis--n-butyl alcohol dihydrochloride, molecular formula C10H24N2O2·
HCl, molecular weight 277.23, No. CAS is 1070-11-7, structural formula are as follows:
The synthetic method reported at present includes with 1,2- epoxy -3- butylene, (S) -2-amino-butyric acid ethyl ester, S- (+) -2- ammonia
Base-n-butyl alcohol etc. is the synthesis technology of starting material.
And had the drawback that using 1,2- epoxy -3- butylene as the method that starting material prepares ebutol because
1,2- epoxy -3- butylene is gas, the degree that increases that the device is complicated, the more difficult control of inventory, and synthesis procedure is excessive.
The shortcomings that using (S) -2-amino-butyric acid ethyl ester as the method for starting material are as follows: the more difficult acquisition of raw material, price costly,
Production cost is excessively high.
And there is also following deficiencies for the method as being first condensed amido protecting again: raw material variety is excessive, operation is relative complex,
Impurity in products is more, is difficult to scale application.
The method that current ethambutol prepares ebutol is that dry HCl gas is passed through into ethambutol, into
Row obtains ebutol at salt.But the time that such method leads to HCl gas is considerably long, needs can be only achieved within 18-25 hours
Required pH value.Therefore this method occupancy equipment time is long, and energy loss is very big, limits production when mass production rolling feeds intake
Progress.And the bad transport of HCl gas can generate a large amount of highly acid waste liquids if it is self-control, and waste liquid is more intractable.Cause
This method limit the applications of large-scale production for this.
Therefore, in order to overcome the above-mentioned deficiency in the presence of the prior art, spy proposes this application.
Summary of the invention
The purpose of the application is, provides a kind of preparation method of ebutol.
To achieve the goals above, the application adopts the following technical scheme that
A kind of preparation method of ebutol, which is characterized in that the preparation method includes the following steps:
1) by specific rotation be+8.3 ° to+9.3 ° S- (+) -2- amino-n-butyl alcohol and 1,2- dichloroethanes in the reactor
Mixing, reaction obtain reaction discharging；
2) the resulting reaction discharging of step 1) is transferred to separation system, alkali is added, S- (+) -2- amino -1- is then demultiplex out
Butanol, and S- (+) -2- amino-n-butyl alcohol isolated is returned in reactor；
3) alcohol is added into separation system again, obtains the alcoholic solution containing ethambutol；
4) alcoholic solution of ethambutol obtained in step 3) is contained into second after obtained desalination by being separated off salt
The alcoholic solution of amine butanol；
5) the alcoholic solution cooling containing ethambutol after the resulting desalination of step 4) is separated off impurity, is cleaned
The alcoholic solution of ethambutol afterwards；
6) water regulation system water content is added to the alcoholic solution of ethambutol obtained in step 5) and adds pure and mild chlorination
Hydrogen obtains the alcoholic solution containing ebutol；
7) by Crystallization Separation ebutol, the ebutol is obtained.
Preferably, in step 1), the temperature of reaction is 100 DEG C to 140 DEG C, and the reaction time is 2 hours to 5 hours.It is excellent
It is selected in step 1), the temperature to react is 120 DEG C to 140 DEG C, and the reaction time is 2 hours to 4 hours.
Preferably, in step 1), the pressure to react is 0.01~3Mpa, and gas-pressurized is nitrogen.It is preferred that in step
It is rapid 1) in, the pressure that reacts is 0.5~1.5Mpa, and gas-pressurized is nitrogen.
Preferably, the molar ratio of S- (+) -2- amino-n-butyl alcohol and 1, the 2- dichloroethanes is 8:1 to 12:1；
Preferably, S- (+) -2- amino-n-butyl alcohol and 1, the molar ratio of 2- dichloroethanes are 9:1 to 10:1.
Preferably, the alcohol described in step 3) includes at least one of methanol, ethyl alcohol, isopropanol and n-butanol；It is described
The molar ratio of 1,2- dichloroethanes and the alcohol is 1:12 to 1:19；Preferably, 1, the 2- dichloroethanes and the alcohol rub
You are than being 1:12 to 1:15.
Preferably, the condition in step 2) are as follows: 100 DEG C to 150 DEG C of temperature, the time 1 hour to 5 hours；Preferred steps 2)
In temperature condition be 120 DEG C to 150 DEG C, the time 3 hours to 5 hours.
Preferably, the condition in step 5) are as follows: 10~35 DEG C of temperature, preferably 15~20 DEG C.
Preferably, step 6) regulation system water content is 1~5%, preferably 3~4%；The pure and mild chlorine of addition in step 6)
Change the condition of hydrogen are as follows: 10 DEG C to 50 DEG C of temperature, the time 1 hour to 4 hours；Preferred steps 6) in temperature condition be 30 DEG C to 50
DEG C, the time 1 hour to 2 hours.
Preferably, in step 7), the temperature of Crystallization Separation ebutol is 0 DEG C to 30 DEG C, the time be 1 hour extremely
8 hours；It is preferred that the temperature of Crystallization Separation ebutol is 5 DEG C to 15 DEG C in step 7), the time is 2 hours to 4 small
When.
Preferably, after step 7) completion, after further including the mother liquor normal pressure concentration and recovery alcohol that will be obtained, by crystallizing
To the ebutol of the second mother liquor and precipitation, second mother liquor and ebutol are separated, by the ethylamine hydrochloride
Butanol return step 2) in separation system；Alkali is added into second mother liquor and adjusts pH value, then therefrom described in separation
S- (+) -2- amino-n-butyl alcohol not being kept completely separate out in pure and mild step 2), and S- (+) -2- ammonia that will be isolated in the step
It is returned in the step 1) reactor after base-n-butyl alcohol water removal；Be preferably added to alkali to pH be 7.5-8.5；Pass through air-distillation
Separate the methanol or ethyl alcohol；The isopropanol or n-butanol are separated by vacuum distillation；S- (+)-is separated by vacuum distillation
2- amino-n-butyl alcohol.
The beneficial effect that the application generates includes but is not limited to:
(1) the present processes are used, S- (+) -2- amino that can be 8.3~9.3 ° with specific rotation-n-butyl alcohol production
Meet ChP2015 editions qualified finished products out, relatively with S- (+) -2- amino-n-butyl alcohol of high specific rotation (+9.3o extremely+10.9o) at
This is lower.
(2) the application uses compressive reaction in S- (+) -2- amino-n-butyl alcohol and 1 when 2- dichloroethanes reacts, more existing
The synthesis under normal pressure yield of technology can be improved 3~5%.
(3) process that the application has step cooling to remove impurity before at salt, i.e. reaction step 5), it can be with by the step
Remove the impurity of the overwhelming majority.
Detailed description of the invention
Fig. 1 is the process flow chart for preparing ebutol.
Specific embodiment
The application is described in detail below with reference to embodiment, but the application is not limited to these embodiments.
Unless otherwise instructed, the raw material in embodiments herein is bought by commercial sources, wherein
S- (+) -2- amino-n-butyl alcohol is purchased from Hebei Kai Liang Biotechnology Co., Ltd.
1,2- dichloroethanes is purchased from Chemical Co., Ltd., Wuxi City poplar city.
Acidic alcohol is purchased from Changzhou to long Chemical Co., Ltd..
Ethyl alcohol is purchased from Chongqing Chuan Dong chemical industry (group) Co., Ltd.
Methanol is purchased from Zaoyang City Ke Li Environmental Protection Technology Co., Ltd.
Isopropanol is purchased from Poole chemistry Science and Technology Ltd., Yancheng City Soviet Union.
N-butanol is purchased from Kunshan Kun Hua Co., Ltd.
It using device model is UltiMate 3000 that purity detecting, which is high performance liquid chromatography detection result,
Embodiment 1
In S- (+) -2- amino of 295kg (3309.4mol)-n-butyl alcohol (+8.3 ° of specific rotation) investment 500L reaction kettle,
In the case where being sufficiently stirred, (amino butanol and 1,2- dichloroethanes feed ratio are 1, the 2- dichloroethanes of addition 35kg (353.7mol)
9.36:1), it is forced into 1Mpa with nitrogen, stirring is warming up to 110 DEG C, and control temperature is reacted 2 hours at 120 DEG C -130 DEG C.Drop
The sodium hydroxide of 24.6kg (615mol) is added to 90 DEG C of emptying for temperature, keeps the temperature 30min, and vacuum distillation recycling is used at 150 DEG C
S- (+) -2- amino-n-butyl alcohol 251.5kg (2821.4mol), control vacuum pressure are -0.09MPa.70 DEG C are cooled to, is added
Dehydrated alcohol 200kg stirs 30min, and filters pressing enters 500L reaction kettle, and filtrate is cooled to 15~20 DEG C, and filters pressing 500L reaction kettle is mended
Add water 8kg, be warming up to 30 DEG C or so, be added dropwise 37.3kg acidic alcohol (HCl content 30%), stirring, control pH 3 to 3.5 it
Between.Slow cooling is to 8 DEG C to 10 DEG C, and being centrifugally separating to obtain ebutol 83.6kg, (yield 85.3%, m.p.199 DEG C extremely
204 DEG C), purity 99.8%.
The first mother liquor obtained after suction filtration is concentrated, solid is precipitated and is centrifuged to obtain the hydrochloric acid of the second mother liquor and 1.8kg
Ethambutol；Sodium hydroxide is added in the second mother liquor after separation and is neutralized to pH after 8 or so, 100 DEG C of air-distillation ethyl alcohol add
Enter toluene azeotropic water removing, S- (+) -2- amino-n-butyl alcohol 9.5kg is recycled in 150 DEG C of vacuum distillations.
Table 1S- (+) -2- amino-n-butyl alcohol and 1, influence table of the 2- dichloroethanes feed ratio to product yield
Embodiment 2
Referring to the reaction condition of embodiment 1, changing setting-up point and condensation reaction time, other conditions are constant, with
It determines the influence to product yield, is shown in Table 2.
The influence table of 2 setting-up point of table and reaction time on yield
Embodiment 3
Referring to the reaction condition of embodiment 1, individually change the alcohol of dissolution distillation gains, other conditions are constant, with determination
Influence to product yield, is shown in Table 3.
Influence table of the alcohol of the dissolution distillation gains of table 3 to product yield
Embodiment 4
Referring to the reaction condition of embodiment 1, individually change the dosage of dehydrated alcohol, other conditions are constant, to determine to production
The influence of object yield, is shown in Table 4.
Influence table of the dosage of 4 dehydrated alcohol of table to product yield
Embodiment 5
Referring to the reaction condition of embodiment 1, individually changing the rotation of S- (+) -2- amino-n-butyl alcohol ratio, other conditions are constant,
To determine the influence to product yield and quality, it is shown in Table 5.
The ratio of table 5S- (+) -2- amino-n-butyl alcohol is revolved to the influence table to product yield and quality
Embodiment 6
Referring to the reaction condition of embodiment 1, individually change pressure when insulation reaction, other conditions are constant, with determining pair
The influence of product yield and quality, is shown in Table 6.
Influence of the pressure to product yield and quality when 6 insulation reaction of table
Embodiment 7
Referring to the reaction condition of embodiment 1, it is individually changed to the temperature for the removal of impurities that cools down before salt, other conditions are constant, with true
The fixed influence to product yield and quality, is shown in Table 7.
Influence of the table 7 at the temperature for the removal of impurities that cools down before salt to product yield and quality
The above is only several embodiments of the application, not does any type of limitation to the application, although this Shen
Please disclosed as above with preferred embodiment, however not to limit the application, any person skilled in the art is not taking off
In the range of technical scheme, a little variation or modification are made using the technology contents of the disclosure above and is equal to
Case study on implementation is imitated, is belonged in technical proposal scope.
Claims (10)
1. a kind of preparation method of ebutol, which is characterized in that the preparation method includes the following steps:
1) S- (+) -2- amino-n-butyl alcohol that specific rotation is+8.3 ° to+9.3 ° is mixed in the reactor with 1,2- dichloroethanes
It closes, reaction, obtains reaction discharging；
2) the resulting reaction discharging of step 1) is transferred to separation system, alkali is added, S- (+) -2- amino-n-butyl alcohol is then demultiplex out,
And S- (+) -2- amino-n-butyl alcohol isolated is returned in reactor；
3) alcohol is added into separation system again, obtains the alcoholic solution containing ethambutol；
4) by the alcoholic solution of ethambutol obtained in step 3) by being separated off salt, contain ethamine fourth after obtained desalination
The alcoholic solution of alcohol；
5) the alcoholic solution cooling containing ethambutol after the resulting desalination of step 4) is separated off impurity, after being cleaned
The alcoholic solution of ethambutol；
6) water regulation system water content is added to the alcoholic solution of ethambutol obtained in step 5) and adds pure and mild hydrogen chloride, obtain
To the alcoholic solution containing ebutol；
7) by Crystallization Separation ebutol, the ebutol is obtained.
2. the preparation method of ebutol according to claim 1, which is characterized in that in step 1), reaction
Temperature is 100 DEG C to 140 DEG C, and the reaction time is 2 hours to 5 hours；It is preferred that the temperature to react is 120 in step 1)
DEG C to 140 DEG C, the reaction time is 2 hours to 4 hours.
3. the preparation method of ebutol described in -2 any one according to claim 1, which is characterized in that in step 1)
In, the pressure to react is 0.01~3Mpa, and gas-pressurized is nitrogen；It is preferred that in step 1), the pressure to react is
0.5~1.5Mpa, gas-pressurized are nitrogen.
4. the preparation method of ebutol described in any one of -3 according to claim 1, which is characterized in that the S-
The molar ratio of (+) -2- amino-n-butyl alcohol and the 1,2- dichloroethanes is 8:1 to 12:1；Preferably, S- (+) -2- ammonia
The molar ratio of base-n-butyl alcohol and 1,2- dichloroethanes is 9:1 to 10:1.
5. the preparation method of ebutol described in any one of -4 according to claim 1, which is characterized in that in step
3) alcohol described in includes at least one of methanol, ethyl alcohol, isopropanol and n-butanol；The 1,2- dichloroethanes and the alcohol
Molar ratio is 1:12 to 1:19；Preferably, the molar ratio of 1, the 2- dichloroethanes and the alcohol is 1:12 to 1:15.
6. the preparation method of ebutol described in any one of -5 according to claim 1, which is characterized in that step 2)
In condition are as follows: 100 DEG C to 150 DEG C of temperature, the time 1 hour to 5 hours；Preferred steps 2) in temperature condition be 120 DEG C extremely
150 DEG C, the time 3 hours to 5 hours.
7. the preparation method of ebutol described in any one of -6 according to claim 1, which is characterized in that step 5)
In condition are as follows: 10~35 DEG C of temperature, preferably 15~20 DEG C.
8. the preparation method of ebutol according to any one of claims 1-7, which is characterized in that step 6)
Regulation system water content is 1~5%, preferably 3~4%；The condition of pure and mild hydrogen chloride is added in step 6) are as follows: 10 DEG C of temperature is extremely
50 DEG C, the time 1 hour to 4 hours；Preferred steps 6) in temperature condition be 30 DEG C to 50 DEG C, the time 1 hour to 2 hours.
9. the preparation method of ebutol described in any one of -8 according to claim 1, which is characterized in that in step
7) in, the temperature of Crystallization Separation ebutol is 0 DEG C to 30 DEG C, and the time is 1 hour to 8 hours；It is preferred that in step 7),
The temperature of Crystallization Separation ebutol is 5 DEG C to 15 DEG C, and the time is 2 hours to 4 hours.
10. the preparation method of ebutol described in any one of -9 according to claim 1, which is characterized in that in step
It further include obtaining the second mother liquor and precipitation by crystallizing after the mother liquor normal pressure concentration and recovery alcohol that will be obtained after rapid 7) completion
Ebutol separates second mother liquor and ebutol, by the ebutol return step 2) in
In separation system；Alkali is added into second mother liquor and adjusts pH value, then therefrom separates incomplete in the pure and mild step 2)
S- (+) -2- amino-n-butyl alcohol isolated, and will be returned after S- (+) -2- amino isolated in the step-n-butyl alcohol water removal
Into reactor described in step 1)；Be preferably added to alkali to pH be 7.5-8.5；The methanol or ethyl alcohol are separated by air-distillation；
The isopropanol or n-butanol are separated by vacuum distillation；S- (+) -2- amino-n-butyl alcohol is separated by vacuum distillation.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3769347A (en) * | 1971-02-11 | 1973-10-30 | American Cyanamid Co | Production of d,d'-2,2'-(ethylenediimino) di-1-butanol hydrochloride |
| GB1365473A (en) * | 1972-06-01 | 1974-09-04 | Mitsui Toatsu Chemicals | Production of a butanol derivate and its salts |
| RU2220949C1 (en) * | 2002-04-03 | 2004-01-10 | Федеральное государственное унитарное предприятие "Государственный научный центр "Научно-исследовательский институт органических полупродуктов и красителей" | Method for purification of ethambutol |
| CN103772214A (en) * | 2012-10-25 | 2014-05-07 | 北大方正集团有限公司 | Methods for preparing ethambutol and ethambutol hydrochloride |
-
2018
- 2018-02-12 CN CN201810143574.2A patent/CN110143887A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3769347A (en) * | 1971-02-11 | 1973-10-30 | American Cyanamid Co | Production of d,d'-2,2'-(ethylenediimino) di-1-butanol hydrochloride |
| GB1365473A (en) * | 1972-06-01 | 1974-09-04 | Mitsui Toatsu Chemicals | Production of a butanol derivate and its salts |
| RU2220949C1 (en) * | 2002-04-03 | 2004-01-10 | Федеральное государственное унитарное предприятие "Государственный научный центр "Научно-исследовательский институт органических полупродуктов и красителей" | Method for purification of ethambutol |
| CN103772214A (en) * | 2012-10-25 | 2014-05-07 | 北大方正集团有限公司 | Methods for preparing ethambutol and ethambutol hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 孙福强等: "盐酸乙胺丁醇的合成工艺改进", 《广州化工》 * |
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Application publication date: 20190820 |