CN108218723A - A kind of method of synthetic hydrochloric acid ethambutol - Google Patents
A kind of method of synthetic hydrochloric acid ethambutol Download PDFInfo
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- CN108218723A CN108218723A CN201611191696.6A CN201611191696A CN108218723A CN 108218723 A CN108218723 A CN 108218723A CN 201611191696 A CN201611191696 A CN 201611191696A CN 108218723 A CN108218723 A CN 108218723A
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- Prior art keywords
- alcohol
- amino
- hours
- butyl alcohol
- mother liquor
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- 238000000034 method Methods 0.000 title claims abstract description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims description 40
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 title claims description 18
- 229960000285 ethambutol Drugs 0.000 title claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 51
- AUAHHJJRFHRVPV-BZDVOYDHSA-N ethambutol dihydrochloride Chemical compound [Cl-].[Cl-].CC[C@@H](CO)[NH2+]CC[NH2+][C@@H](CC)CO AUAHHJJRFHRVPV-BZDVOYDHSA-N 0.000 claims abstract description 28
- 239000012452 mother liquor Substances 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000002425 crystallisation Methods 0.000 claims abstract description 10
- 230000008025 crystallization Effects 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 238000007599 discharging Methods 0.000 claims abstract description 5
- 238000011084 recovery Methods 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 235000019441 ethanol Nutrition 0.000 claims description 40
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 16
- 230000001476 alcoholic effect Effects 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 10
- 238000005292 vacuum distillation Methods 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 claims 3
- 125000001340 2-chloroethyl group Chemical class [H]C([H])(Cl)C([H])([H])* 0.000 claims 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 abstract 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 239000000047 product Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- JCBPETKZIGVZRE-UHFFFAOYSA-N 2-aminobutan-1-ol Chemical compound CCC(N)CO JCBPETKZIGVZRE-UHFFFAOYSA-N 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000010583 slow cooling Methods 0.000 description 8
- 230000002378 acidificating effect Effects 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 238000004064 recycling Methods 0.000 description 7
- 150000001298 alcohols Chemical class 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 238000009413 insulation Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- GXBYFVGCMPJVJX-UHFFFAOYSA-N Epoxybutene Chemical group C=CC1CO1 GXBYFVGCMPJVJX-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000011144 upstream manufacturing Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- OZHIYEINSCNALY-UHFFFAOYSA-N 1-aminobutan-1-ol Chemical class CCCC(N)O OZHIYEINSCNALY-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- KXSBWGSJFSEIED-YFKPBYRVSA-N ethyl (2s)-2-aminobutanoate Chemical compound CCOC(=O)[C@@H](N)CC KXSBWGSJFSEIED-YFKPBYRVSA-N 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 206010003754 Atypical mycobacterial infections Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000219000 Populus Species 0.000 description 1
- 208000022971 Tuberculous meningitis Diseases 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940124976 antitubercular drug Drugs 0.000 description 1
- WQONFASRIIZLSA-UHFFFAOYSA-N butan-1-ol ethanamine hydrochloride Chemical compound C(CCC)O.C(C)N.Cl WQONFASRIIZLSA-UHFFFAOYSA-N 0.000 description 1
- OPQCEZJIHDNSLT-UHFFFAOYSA-N butan-1-ol;n-ethylethanamine Chemical compound CCCCO.CCNCC OPQCEZJIHDNSLT-UHFFFAOYSA-N 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960001618 ethambutol hydrochloride Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000001223 meningeal tuberculosis Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
This application discloses a kind of technique for preparing ebutol, including step：1) 2 amino of S (+), 1 butanol and 1, the mixing of 2 dichloroethanes, the two react to form reaction discharging；2) reaction discharging is isolated 2 amino of S (+), 1 butanol in piece-rate system and is returned in reactor；3) HCl is added in into piece-rate system；4) the first mother liquor and the ebutol being precipitated are obtained by crystallization；5) from first mother liquor after normal pressure concentration and recovery alcohol, the second mother liquor and the ebutol being precipitated is obtained by crystallization, the ebutol is returned in piece-rate system；6) alkali is added in into second mother liquor and adjusts pH value, then 2 amino of S (+), 1 butanol not being kept completely separate out in the alcohol and step 2) is therefrom detached, and is returned in reactor after 2 amino of S (+), 1 butanol isolated in the step is removed water.
Description
Technical field
This application involves a kind of methods of synthetic hydrochloric acid ethambutol.
Background technology
Ebutol be widely used in the pulmonary tuberculosis caused by other anti-tubercular drug combination therapy tubercle bacilluses, also may be used
For the treatment of 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, and structural formula is:
The synthetic method reported at present is included 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 it is had as a drawback that in the method that 1,2- epoxy -3- butylene prepares ebutol as starting material：Because
1,2- epoxy -3- butylene is gas, increases equipment complexity, the more difficult control of inventory, and synthesis procedure is excessive.
It is using (S) -2-amino-butyric acid ethyl ester as the shortcomings that method of starting material：The more difficult acquisition of raw material, price costly,
Production cost is excessively high.
It is that S- (+) -2- amino-n-butyl alcohol and 1,2- dichloroethanes are directly condensed with widest method at present
Ethambutol is prepared, needs the HCl generated with NaOH come neutralization reaction after the completion of condensation, yield is relatively low, and NaOH is to equipment
Corrode larger.
And as first by the method that amido protecting is condensed again, there is also following deficiencies：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 gases are passed through into ethambutol, into
Row obtains ebutol into salt.But the time that such method leads to HCl gases 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 big production rolling feeds intake
Progress.And the bad transport of HCl gases, if if self-control, a large amount of highly acid waste liquids can be generated, waste liquid is more intractable.Cause
This method limit the applications of large-scale production for this.
Invention content
In order to overcome problems of the prior art, the present invention provides a kind of technique for preparing ebutol,
The technique includes the following steps：1) S- (+) -2- amino-n-butyl alcohol and 1,2- dichloroethanes mix in the reactor, the two hair
Raw reaction is discharged with forming reaction；
2) the reaction discharging obtained in step 1) is remained after S- (+) -2- amino-n-butyl alcohol is isolated in piece-rate system
Excess material, and S- (+) -2- amino-n-butyl alcohol isolated is returned in the reactor；
3) after completing step 2), the surplus material is transferred in another reactor, is added in into the reactor
HCl；
4) ebutol of the precipitation of the first mother liquor is obtained by crystallization, detaches first mother liquor and ethylamine hydrochloride
Butanol；
5) from first mother liquor after normal pressure concentration and recovery alcohol, ebutol and the second mother are obtained by crystallization
Liquid, by the ebutol return to step 2) in piece-rate system in；
6) alkali is added in into second mother liquor and adjusts pH value, then therefrom detached in the alcohol and step 2) and do not divide completely
S- (+) -2- amino-n-butyl alcohol separated out, and will be returned to after S- (+) -2- amino isolated in the step-n-butyl alcohol water removal
In the step 1) reactor.
In a specific embodiment, in step 1), the temperature to react is 100 DEG C to 140 DEG C, the reaction time
It is 2 hours to 5 hours.
In a specific embodiment, preferably in step 1), the temperature to react is 120 DEG C to 140 DEG C, reaction
Time is 2 hours to 4 hours.
In a specific embodiment, the specific rotation of S- (+) -2- amino-n-butyl alcohol is+9.3 ° to+10.9 °.
In a specific embodiment, it is preferable that the specific rotation of S- (+) -2- amino-n-butyl alcohol for+10.0 ° to+
10.9°。
In a specific embodiment, mole of S- (+) -2- amino-n-butyl alcohol and 1, the 2- dichloroethanes
Than being 8:1 to 12:1.
In a specific embodiment, it is preferable that S- (+) -2- amino-n-butyl alcohol and 1,2- dichloroethanes rub
You are than being 9:1 to 10:1.
In a specific embodiment, the alcohol in step 3) is included in methanol, ethyl alcohol, isopropanol and n-butanol
At least one.
In a specific embodiment, it is preferable that the alcohol wherein in step 3) is ethyl alcohol.
In a specific embodiment, the molar ratio of 1, the 2- dichloroethanes and the alcohol is 1:12 to 1:19.
The molar ratio of the 1,2- dichloroethanes and the alcohol is 1:12 to 1:15.
In a specific embodiment, in step 3), to the reactor can add in pure HCl gases or
The alcoholic solution of HCl can be added in.
In a specific embodiment, the alcoholic solution of HCl is preferably added to, and the HCl contents of the alcoholic solution are
28wt% to 37wt%.
In a specific embodiment, in step 3), the alcohol is first added in the reactor, adds HCl, with
Form the first alcoholic solution containing HCl；Or the second alcoholic solution is obtained after first mixing the alcohol and HCl, it is then added to described
In reactor, to form the first alcoholic solution containing HCl；And the pH value of first alcoholic solution in reactor is 2 to 4.
In a specific embodiment, the HCl contents of second alcoholic solution are 28wt% to 37wt%.
In a specific embodiment, the condition in step 2) is：100 DEG C to 150 DEG C of temperature, time are 1 hour to 5 small
When.
In a specific embodiment, preferred steps 2) in temperature put forward condition as 120 DEG C to 150 DEG C, 3 hours time
To 5 hours.
In a specific embodiment, the condition in step 3) is：10 DEG C to 50 DEG C of temperature, time are 1 hour to 4 small
When.
In a specific embodiment, preferred steps 3) in temperature condition for 30 DEG C to 50 DEG C, 1 hour to 2 time
Hour.
In a specific embodiment, in step 4), the temperature of Crystallization Separation ebutol is 0 DEG C to 30
DEG C, the time is 1 hour to 8 hours.
In a specific embodiment, preferably in step 4), the temperature of Crystallization Separation ebutol for 5 DEG C extremely
15 DEG C, the time is 2 hours to 4 hours.
In a specific embodiment, in step 2), S- (+) -2- amino -1- fourths are isolated by vacuum distillation
Alcohol.Such as it is evaporated under reduced pressure at 150 DEG C.
In a specific embodiment, in step 6), the second mother liquor addition alkali to pH is 7.5-8.5；Pass through
Air-distillation detaches the methanol, ethyl alcohol；The isopropanol, n-butanol are detached by being evaporated under reduced pressure；It is detached by being evaporated under reduced pressure
S- (+) -2- amino-n-butyl alcohol.
In a specific embodiment, in step 3), the water content of the surplus material is in below 3wt%.Wherein
Moisture can be obtained by the form added, can be from upstream product.But if it is from upstream product and described
Water content in upstream product is higher than if 3wt%, it should by removing water controlling measurement water content in below 3wt%.
In a specific embodiment, in step 3), the water content of the surplus material is in below 1.5wt%.
In a specific embodiment, the alkali is at least one of sodium hydroxide, potassium hydroxide and ammonia.
The advantageous effect that the application generates includes but not limited to：
1) residue on ignition of the ebutol obtained using the application method is lower, and granularity is controlled in 80 mesh extremely
Between 100 mesh, thus product quality is high.
2) the application uses amino butanol (+9.3 ° to+10.9 °) raw material of high specific rotation, is conducive to carrying for product purity
It is high.
2) entire reaction carries out in anhydrous conditions, thus is conducive to require moisture harsh and very expensive
S- (+) -2- amino-n-butyl alcohol raw materials recovery, that is, the moisture of S- (+) -2- amino-n-butyl alcohol recycled is low, without into one
The processing of step can directly cover the cost for for the production of next group product, reducing S- (+) -2- amino-n-butyl alcohol recycling, carry
The high rate of recovery, S- (+) -2- amino-n-butyl alcohol unit consumption decline apparent.And the method that the application provides can be in generation hydrochloric acid
After ethambutol and add in HCl alcoholic solution before and crystallize out in the mother liquor after ebutol and recycle amino butanol, example
Can be recycled from after obtaining finished product ethambutol a mother liquor (waste liquid) such as the application the secondary mother liquid after alcohols into
S- (+) -2- amino-n-butyl alcohol is recycled in row deep processing, therefrom extraction.
3) eliminate has the stronger neutralization procedure of corrosivity to reaction unit；At the same time, neutralization procedure is no longer generated
The generation of middle salt, thus reduce the generation of solid waste；And the step of compared to the alcoholic solution that HCl is added in the later stage, subtract significantly
The alcoholic solution usage amount of HCl is lacked.
4) the present processes simplify synthesis technology, shorten technological process, reduce the production cycle, reduce and be produced into
This, more profits are created in the unit interval；Manipulation strength is alleviated, improves production efficiency, is suitble to large-scale production, has
It is environmentally friendly, the advantages that remarkable benefit.
Description of the drawings
Fig. 1 is the process flow chart for preparing ebutol.
Specific embodiment
The application is described in detail, but the application is not limited to these embodiments with reference to embodiment.
S- (+) -2- amino-n-butyl alcohol is purchased from Hebei Kai Liang bio tech ltd.
1,2- dichloroethanes is purchased from Chemical Co., Ltd. of 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. of Yancheng City Soviet Union.
N-butanol is purchased from Kunshan Kun Hua Co., Ltds.
Embodiment 1
The there-necked flask of S- (+) -2- amino of 295g (3.3094mol)-n-butyl alcohol (+10.1 ° of specific rotation) input 500mL
In, stirring is warming up to 110 DEG C, in the case where being sufficiently stirred, is slowly added to 1, the 2- dichloroethanes (amino butanols of 35g (0.3536mol)
It is 9.36 with 1,2- dichloroethanes rate of charge:1), control temperature adds at 110 DEG C -140 DEG C in 2 hours, then in this temperature
In the range of insulation reaction 3 hours.Vacuum distillation recycling S- (+) -2- amino-n-butyl alcohol 221.5g is used at 150 DEG C
(2.4849mol), control vacuum pressure are -0.09MPa.70 DEG C are cooled to, adds in absolute ethyl alcohol 200g, stirring, slow cooling
To 30 DEG C or so, 37.3g acidic alcohols (HCl contents 30%) are added dropwise, stirring, pH is between 3 to 3.5 for control.Slow cooling is to 8
DEG C to 10 DEG C, isolated ebutol 79.3g (yield 80.98%, m.p.199 DEG C to 204 DEG C), purity are filtered
99.9%, ignition residue 0.01%, 90 to 110 mesh of granularity.
The first mother liquor obtained after suction filtration is concentrated, solid is precipitated and filters to obtain the second mother liquor and the hydrochloric acid second of 1.8g
Amine butanol；The second mother liquor after separation is added in into sodium hydroxide and is neutralized to pH after 8 or so, 100 DEG C of air-distillation ethyl alcohol add in
Toluene azeotropic water removing, 150 DEG C of vacuum distillation recycling S- (+) -2- amino-n-butyl alcohol 9.5g.
With reference to the reaction condition of embodiment 1, change S- (+) -2- amino-n-butyl alcohol and 1,2- dichloroethanes rate of charge,
His condition is constant, to determine the influence to product yield, is shown in Table one.
Table one：S- (+) -2- amino-n-butyl alcohol and influence of the 1,2- dichloroethanes rate of charge to product yield
Embodiment 2
With reference to the rate of charge and reaction condition of embodiment 1, individually change the ratio rotation of S- (+) -2- amino-n-butyl alcohol, other
Condition is constant, to determine the influence to product yield and quality, is shown in Table two.
Table two：S- (+) -2- amino-n-butyl alcohol is than revolving the influence to product yield and quality
Embodiment 3
With reference 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 three.
Embodiment 4
With reference to the reaction condition of embodiment 1, individually change the alcohol of dissolving distillation gains, other conditions are constant, to determine
Influence to product yield, is shown in Table four.
Embodiment 5
With reference to the reaction condition of embodiment 1, individually change the dosage of absolute ethyl alcohol, other conditions are constant, to determine to production
The influence of object yield, is shown in Table five.
Table three：The influence of setting-up point and reaction time on yield
Table four：Influence of the alcohol of dissolving distillation gains to product yield
Table five：Influence of the dosage of absolute ethyl alcohol to product yield
Embodiment 6
The there-necked flask of S- (+) -2- amino of 295g (3.3094mol)-n-butyl alcohol (+10.1 ° of specific rotation) input 500mL
In, stirring is warming up to 110 DEG C, in the case where being sufficiently stirred, is slowly added to 1, the 2- dichloroethanes (amino butanols of 35g (0.3536mol)
It is 9.36 with 1,2- dichloroethanes rate of charge:1), control temperature adds at 110 DEG C to 140 DEG C in 2 hours, then warm herein
Insulation reaction 3 hours in the range of degree.Vacuum distillation recycling S- (+) -2- amino-n-butyl alcohol 220.9g is used at 150 DEG C
(2.4781mol), control vacuum pressure are -0.09MPa, are cooled to 70 DEG C, add in absolute ethyl alcohol 200g, stirring, slow cooling
To 30 DEG C or so, 37.3g acidic alcohols (HCl contents 30%) are added dropwise, stirring, pH is between 3 to 3.5 for control.Slow cooling is to 8
DEG C to 10 DEG C, isolated ebutol 79.3g (yield 80.98%, m.p.199 DEG C to 204 DEG C), purity are filtered
99.8%, ignition residue 0.01%, 90 to 110 mesh of granularity.
Embodiment 7
In the there-necked flask of S- (+) -2- amino of 295g (3.3094mol)-n-butyl alcohol (+8.6 ° of specific rotation) input 500mL,
Stirring be warming up to 110 DEG C, in the case where being sufficiently stirred, be slowly added to 35g (0.3536mol) 1,2- dichloroethanes (amino butanol with
1,2- dichloroethanes rate of charge is 9.36:1), control temperature adds at 110 DEG C to 140 DEG C in 2 hours, then in this temperature
In the range of insulation reaction 3 hours.70 DEG C are cooled to, adds in absolute ethyl alcohol 200g, stirring, slow cooling is added in 30 DEG C or so
37.3g acidic alcohols (HCl contents 30%) are added dropwise in 20g purified waters, and stirring, pH is between 3 to 3.5 for control.Slow cooling is to 8
DEG C to 10 DEG C, isolated ebutol 69.6g (yield 71.09%, m.p.199 DEG C to 204 DEG C), purity are filtered
99.0%, ignition residue 0.01%, 20 to 40 mesh of granularity.
With reference to embodiment 6, the rate of charge and reaction condition of embodiment 7, we change S- (+) -2- amino-n-butyl alcohol ratio
Rotation changes the water for being added dropwise and being added in before acidic alcohol, to determine material quality with adding in water to product yield, quality and mesh number
Influence, be shown in Table six.
Table six：Material quality is with adding in influence of the water to product yield, quality and mesh number
Comparative example 1
In the there-necked flask of S- (+) -2- amino-n-butyl alcohol (than+10.1 ° of rotation) input 500mL of 295g (3.3094mol),
Stirring be warming up to 110 DEG C, in the case where being sufficiently stirred, be slowly added to 35g (0.3536mol) 1,2- dichloroethanes (amino butanol with
1,2- dichloroethanes rate of charge is 9.36:1), control temperature adds at 110 DEG C to 140 DEG C in 2 hours, then in this temperature
In the range of insulation reaction 3 hours.Then 60 DEG C to 80 DEG C are cooled to and adds in sodium hydroxide 24.6g (0.615mol), and at 85 DEG C
Half an hour is stirred to 95 DEG C.Using vacuum distillation recycling S- (+) -2- amino-n-butyl alcohol 235.5g at 150 DEG C, control is very
Pneumatics power is -0.09MPa.70 DEG C are cooled to, adds in absolute ethyl alcohol 200g, and stirred half an hour at 75 DEG C to 80 DEG C, while hot
Filter, filtrate slow cooling to 30 DEG C or so, be added dropwise acidic alcohol (HCl contents 30%), stirring, control pH 3 to 3.5 it
Between, spend 87.3g acidic alcohols.Slow cooling filters separation, obtains ebutol 78.5g (yields to 8 DEG C to 10 DEG C
80.16%, m.p.199 DEG C to 204 DEG C), purity 99.8%.Ignition residue 0.08%, 90 to 110 mesh of granularity.
The first mother liquor obtained after suction filtration is concentrated, solid is precipitated and filters isolated second mother liquor and the salt of 1.9g
Acid diethylamide butanol；The second mother liquor after separation is added in into sodium hydroxide and is neutralized to pH after 8 or so, 100 DEG C of air-distillation alcohol add
Enter 95 DEG C of azeotropic water removings of toluene, 150 DEG C of vacuum distillation recycling S- (+) -2- amino-n-butyl alcohol 10g.And front is evaporated under reduced pressure to
The amino butanol 235.5g arrived carries out toluene azeotropic water removing recycling, obtains the amino butanol 217.6g for meeting raw material standard.
Embodiment 8
With reference to the rate of charge and reaction condition of comparative example 1, we change the amount for adding in sodium hydroxide, and other conditions are constant,
To determine influence of the amount of sodium hydroxide to product yield and quality, it is shown in Table seven.
Table seven：Influence of the sodium hydroxide inventory to product yield and ignition residue
Embodiment 9
With reference to the rate of charge and reaction condition of comparative example 1, change and add alkali type, other conditions are constant, to determine alkali to production
The influence of object yield and residue on ignition.It is shown in Table eight.
Table eight：Influence of the different alkali to product yield and ignition residue
Embodiment 10
In the proportioning and reaction condition for not changing comparative example 1, change the amount of sodium hydroxide, with regard to the unit consumption and product of its raw material
Yield guality compare (amino butanol can lose the amino butanol of part when being distilled to recover water removal).It is shown in Table nine.
Table nine：Influence of the sodium hydroxide inventory to each raw material consumption
The above is only several embodiments of the application, any type of limitation is not done 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, make a little variation using the technology contents of the disclosure above or modification is equal to
Case study on implementation is imitated, is belonged in the range of technical solution.
Claims (10)
1. a kind of technique for preparing ebutol, which is characterized in that the technique includes the following steps：
1) S- (+) -2- amino-n-butyl alcohol and 1,2- dichloroethanes mix in the reactor, and the two reacts to form reaction
Discharging；
2) the reaction discharging obtained in step 1) obtains residue after S- (+) -2- amino-n-butyl alcohol is isolated in piece-rate system
Material, and S- (+) -2- amino-n-butyl alcohol isolated is returned in the reactor；
3) after completing step 2), the surplus material is transferred in another reactor, HCl is added in into the reactor；
4) the first mother liquor and the ebutol being precipitated are obtained by crystallization, detaches first mother liquor and ethylamine hydrochloride fourth
Alcohol；
5) from first mother liquor after normal pressure concentration and recovery alcohol, the second mother liquor and the ethylamine hydrochloride fourth being precipitated are obtained by crystallization
Alcohol detaches second mother liquor and ebutol, by the ebutol return to step 2) in piece-rate system in；
6) alkali is added in into second mother liquor and adjusts pH value, then therefrom detached and be not kept completely separate out in the alcohol and step 2)
S- (+) -2- amino-n-butyl alcohol, and step will be returned to after the water removal of S- (+) -2- amino isolated in the step-n-butyl alcohol
1) in the reactor.
2. technique according to claim 1, which is characterized in that in step 1), the temperature that reacts for 100 DEG C extremely
140 DEG C, the reaction time is 2 hours to 5 hours；
It is preferred that 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.
3. technique according to claim 1 or 2, which is characterized in that the specific rotation of S- (+) -2- amino-n-butyl alcohol is
+ 9.3 ° to+10.9 °；Preferably, the specific rotation of S- (+) -2- amino-n-butyl alcohol is+10.0 ° to+10.9 °.
4. according to the technique described in any one in claim 1-3, which is characterized in that S- (+) -2- amino-n-butyl alcohol
Molar ratio with the 1,2- dichloroethanes is 8:1 to 12:1；Preferably, S- (+) -2- amino-n-butyl alcohol and 1,2- bis-
The molar ratio of chloroethanes is 9:1 to 10:1.
5. according to the technique described in any one in claim 1-4, which is characterized in that further included in step 3) to described point
From adding in alcohol in system；It is preferred that the alcohol includes at least one of methanol, ethyl alcohol, isopropanol and n-butanol；Preferably, it is described
Alcohol is ethyl alcohol；
It is preferred that the molar ratio of the 1,2- dichloroethanes and the alcohol is 1:12 to 1:19；Preferably, 1, the 2- dichloroethanes
Molar ratio with the alcohol is 1:12 to 1:15；
It is preferred that in step 3), the alcohol is first added in the reactor, adds HCl, it is molten to form the first alcohol containing HCl
Liquid；Or the second alcoholic solution is obtained, then second alcoholic solution is added in step 3) after first mixing the alcohol and HCl
In the reactor, to form the first alcoholic solution containing HCl；
And the pH value of first alcoholic solution in piece-rate system is 2 to 4；
The HCl contents of more preferable second alcoholic solution are 28wt% to 37wt%.
6. according to the technique described in any one in claim 1-5, which is characterized in that the condition in step 2) is：Temperature 100
DEG C to 150 DEG C, 1 hour to 5 hours time；Preferred steps 2) in temperature put forward condition as 120 DEG C to 150 DEG C, 3 hours time is extremely
5 hours.
7. according to the method described in any one in claim 1-6, which is characterized in that the condition in step 3) is：Temperature 10
DEG C to 50 DEG C, 1 hour to 4 hours time；Preferred steps 3) in temperature condition for 30 DEG C to 50 DEG C, the time is 1 hour to 2 small
When.
8. according to the technique described in any one in claim 1-7, which is characterized in that in step 4), Crystallization Separation hydrochloric acid
The temperature of ethambutol is 0 DEG C to 30 DEG C, and the time is 1 hour to 8 hours；It is preferred that in step 4), Crystallization Separation ethylamine hydrochloride
The temperature of butanol is 5 DEG C to 15 DEG C, and the time is 2 hours to 4 hours.
9. according to the technique described in any one in claim 1-8, which is characterized in that in step 2), pass through vacuum distillation
Isolate S- (+) -2- amino-n-butyl alcohol；
In step 6), addition alkali to pH is 7.5-8.5；The methanol, ethyl alcohol are detached by air-distillation；Pass through vacuum distillation
Detach the isopropanol, n-butanol；S- (+) -2- amino-n-butyl alcohol is detached by vacuum distillation.
10. according to the technique described in any one in claim 1-9, which is characterized in that in step 3), the surplus material
Water content in below 3wt%；It is preferred that in step 3), the water content of the surplus material is in below 1.5wt%.
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| CN119246737A (en) * | 2024-12-04 | 2025-01-03 | 浙江省食品药品检验研究院 | A method for simultaneous determination of (+)-2-aminobutanol and ethambutol hydrochloride based on RP-HPLC-NQAD |
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| US3769347A (en) * | 1971-02-11 | 1973-10-30 | American Cyanamid Co | Production of d,d'-2,2'-(ethylenediimino) di-1-butanol hydrochloride |
| 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 |
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2016
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3769347A (en) * | 1971-02-11 | 1973-10-30 | American Cyanamid Co | Production of d,d'-2,2'-(ethylenediimino) di-1-butanol hydrochloride |
| 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 |
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Cited By (1)
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| CN119246737A (en) * | 2024-12-04 | 2025-01-03 | 浙江省食品药品检验研究院 | A method for simultaneous determination of (+)-2-aminobutanol and ethambutol hydrochloride based on RP-HPLC-NQAD |
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Inventor after: Zhao Taotao Inventor after: Pi Jinhong Inventor after: Zhang Wei Inventor after: Guo Dongpo Inventor after: Ran Xue Inventor after: Zhang Qi Inventor after: Xie Guofan Inventor before: Pi Jinhong Inventor before: Zhao Taotao Inventor before: Zhang Wei Inventor before: Guo Dongpo Inventor before: Ran Xue Inventor before: Zhang Qi Inventor before: Xie Guofan |