CN108218723B - Process for preparing ethambutol hydrochloride - Google Patents
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- CN108218723B CN108218723B CN201611191696.6A CN201611191696A CN108218723B CN 108218723 B CN108218723 B CN 108218723B CN 201611191696 A CN201611191696 A CN 201611191696A CN 108218723 B CN108218723 B CN 108218723B
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Abstract
The application discloses a process for preparing ethambutol hydrochloride, which comprises the following steps: 1) mixing S- (+) -2-amino-1-butanol with 1, 2-dichloroethane, and reacting the two to form a reaction discharge; 2) separating S- (+) -2-amino-1-butanol from the reaction discharge in a separation system and returning the S- (+) -2-amino-1-butanol to the reactor; 3) adding HCl to the separation system; 4) crystallizing to obtain a first mother solution and precipitated ethambutol hydrochloride; 5) concentrating and recovering alcohol from the first mother liquor at normal pressure, crystallizing to obtain a second mother liquor and precipitated ethambutol hydrochloride, and returning the ethambutol hydrochloride to a separation system; 6) adding alkali into the second mother liquor to adjust the pH value, separating the alcohol from the second mother liquor, and returning the S- (+) -2-amino-1-butanol which is not completely separated in the step 2) to the reactor after removing water.
Description
Technical Field
The application relates to a method for synthesizing ethambutol hydrochloride.
Background
Ethambutol hydrochloride is widely used in combination with other antitubercular drugs for treating tuberculosis caused by tubercle bacillus, and can also be used for treating tubercular meningitis and atypical mycobacterial infections. The medicine accounts for over 13 percent of the market share of the antituberculosis drugs.
Ethambutol Hydrochloride (English name: Ethambutol Hydrochloride), its chemical name is [2R,2[ S- (R) ]*,R*)-R](+) -2, 2' - (1, 2-ethanediyldiimino) -bis-1-butanol dihydrochloride with the molecular formula C10H24N2O2HCl, molecular weight 277.23, CAS number 1070-11-7, formula:
the currently reported synthesis method includes a synthesis process using 1, 2-epoxy-3-butene, (S) -ethyl 2-aminobutyric acid, S- (+) -2-amino-1-butanol, etc. as starting materials.
The method for preparing ethambutol hydrochloride by using 1, 2-epoxy-3-butylene as a starting material has the following defects: because 1, 2-epoxy-3-butylene is gas, the complexity of equipment is increased, the feeding amount is difficult to control, and the synthesis process is excessive.
The disadvantages of the process starting from ethyl (S) -2-aminobutyrate are: the raw materials are difficult to obtain, the price is expensive, and the production cost is overhigh.
At present, the most widely applied method is that S- (+) -2-amino-1-butanol and 1, 2-dichloroethane are directly condensed to prepare ethambutol, HCl generated by the neutralization reaction needs NaOH after the condensation is finished, the yield is low, and the NaOH has large corrosion to equipment.
However, the method of firstly protecting and then condensing the amino group has the following defects: the raw materials are too many in variety, the operation is relatively complex, the product has many impurities, and the large-scale application is difficult.
The method for preparing the ethambutol hydrochloride from the ethambutol at present comprises the steps of introducing dry HCl gas into the ethambutol, and salifying to obtain the ethambutol hydrochloride. However, the time for introducing HCl gas is quite long, and 18-25 hours are needed to reach the required pH value. Therefore, the method has long equipment occupation time and great energy consumption, and limits the production progress during rolling feeding in large-scale production. Moreover, HCl gas is not easy to transport, and if the HCl gas is self-made, a large amount of strong acid waste liquid is generated, so that the waste liquid is difficult to treat. Thus, this method limits the application of large-scale production.
Disclosure of Invention
In order to overcome the problems in the prior art, the invention provides a process for preparing ethambutol hydrochloride, which comprises the following steps: 1) mixing S- (+) -2-amino-1-butanol and 1, 2-dichloroethane in a reactor, and reacting the two to form a reaction discharge;
2) separating S- (+) -2-amino-1-butanol from the reaction discharge obtained in the step 1) in a separation system to obtain a residual material, and returning the separated S- (+) -2-amino-1-butanol to the reactor;
3) after completion of step 2), transferring the remaining material to another reactor, to which HCl is added;
4) crystallizing to obtain ethambutol hydrochloride separated out from a first mother liquor, and separating the first mother liquor and the ethambutol hydrochloride;
5) concentrating and recovering alcohol from the first mother liquor at normal pressure, crystallizing to obtain ethambutol hydrochloride and a second mother liquor, and returning the ethambutol hydrochloride to the separation system in the step 2);
6) adding alkali into the second mother liquor to adjust the pH value, separating the alcohol from the second mother liquor, and returning the S- (+) -2-amino-1-butanol which is not completely separated in the step 2) to the reactor in the step 1) after removing water from the S- (+) -2-amino-1-butanol separated in the step.
In one embodiment, in step 1), the reaction occurs at a temperature of 100 ℃ to 140 ℃ for a reaction time of 2 hours to 5 hours.
In one embodiment, it is preferred that in step 1), the reaction takes place at a temperature of 120 ℃ to 140 ℃ for a reaction time of 2 hours to 4 hours.
In one embodiment, the specific rotation of the S- (+) -2-amino-1-butanol is from +9.3 ° to +10.9 °.
In one embodiment, the S- (+) -2-amino-1-butanol preferably has a specific rotation ranging from +10.0 to + 10.9.
In a specific embodiment, the molar ratio of the S- (+) -2-amino-1-butanol and the 1, 2-dichloroethane is from 8:1 to 12: 1.
In one embodiment, preferably, the molar ratio of S- (+) -2-amino-1-butanol and 1, 2-dichloroethane is from 9:1 to 10: 1.
In a specific embodiment, the alcohol in step 3) includes at least one of methanol, ethanol, isopropanol, and n-butanol.
In one embodiment, preferably, wherein the alcohol in step 3) is ethanol.
In one embodiment, the molar ratio of the 1, 2-dichloroethane to the alcohol is from 1:12 to 1: 19.
The molar ratio of the 1, 2-dichloroethane to the alcohol is from 1:12 to 1: 15.
In one embodiment, in step 3), pure HCl gas or an alcoholic HCl solution may be added to the reactor.
In one embodiment, an alcoholic solution of HCl is preferably added, and the alcoholic solution has an HCl content of 28 wt% to 37 wt%.
In one embodiment, in step 3), the alcohol is added to the reactor first, followed by HCl, to form a first alcohol solution comprising HCl; or mixing the alcohol and the HCl to obtain a second alcohol solution, and adding the second alcohol solution into the reactor to form a first alcohol solution containing HCl; and the pH of the first alcohol solution in the reactor is 2 to 4.
In one embodiment, the second glycol solution has an HCl content of 28 wt% to 37 wt%.
In one embodiment, the conditions in step 2) are: the temperature is 100 ℃ to 150 ℃ and the time is 1 hour to 5 hours.
In one embodiment, it is preferred that the temperature in step 2) is 120 ℃ to 150 ℃ for 3 hours to 5 hours.
In one embodiment, the conditions in step 3) are: the temperature is 10 ℃ to 50 ℃ and the time is 1 hour to 4 hours.
In one embodiment, it is preferable that the temperature condition in the step 3) is 30 ℃ to 50 ℃ for 1 hour to 2 hours.
In one embodiment, in step 4), the temperature for crystallization separation of ethambutol hydrochloride is 0 ℃ to 30 ℃ for 1 hour to 8 hours.
In one embodiment, it is preferred that in step 4), the temperature for crystallization separation of ethambutol hydrochloride is 5 ℃ to 15 ℃ for 2 hours to 4 hours.
In a particular embodiment, in step 2), the S- (+) -2-amino-1-butanol is isolated by distillation under reduced pressure. For example, distillation under reduced pressure at 150 ℃.
In one embodiment, in step 6), the second mother liquor is added with a base to a pH of 7.5-8.5; separating the methanol and ethanol by atmospheric distillation; separating the isopropanol and n-butanol by distillation under reduced pressure; s- (+) -2-amino-1-butanol was separated by distillation under reduced pressure.
In a particular embodiment, in step 3), the water content of the remaining material is below 3 wt%. The water content can be obtained in a supplementary form or from an upstream product. But if it comes from an upstream product and the water content in said upstream product is higher than 3 wt%, the water content should be controlled below 3 wt% by water removal measures.
In one embodiment, in step 3), the water content of the remaining material is below 1.5 wt%.
In one embodiment, the base is at least one of sodium hydroxide, potassium hydroxide, and ammonia.
The benefits produced by the present application include, but are not limited to:
1) the ignition residue of the ethambutol hydrochloride obtained by the method is lower, the granularity of the ethambutol hydrochloride is controlled between 80 meshes and 100 meshes, and the product quality is high.
2) The method adopts the aminobutanol (+9.3 degrees to +10.9 degrees) raw material with high specific rotation degree, and is favorable for improving the product purity.
2) The whole reaction is carried out under anhydrous condition, thus being beneficial to the recovery of the raw material of the S- (+) -2-amino-1-butanol which has strict requirement on the moisture content and is very expensive, namely the recovered S- (+) -2-amino-1-butanol has low moisture and can be directly used for the production of the next batch of products without further treatment, the recovery cost of the S- (+) -2-amino-1-butanol is reduced, the recovery rate is improved, and the unit consumption of the S- (+) -2-amino-1-butanol is obviously reduced. The method provided by the application can recover the aminobutanol from the mother liquor after the formation of the ethambutol hydrochloride and before the addition of the alcoholic solution of HCl, for example, the method can recover the secondary mother liquor after the recovery of alcohols from the primary mother liquor (waste liquor) after the ethambutol hydrochloride is obtained, and then extract and recover the S- (+) -2-amino-1-butanol from the secondary mother liquor.
3) A neutralization step with strong corrosivity on a reaction device is omitted; meanwhile, the generation of salt in the neutralization step is not generated, so that the generation of solid waste is reduced; compared with the later step of adding HCl alcoholic solution, the use amount of HCl alcoholic solution is greatly reduced.
4) The method simplifies the synthesis process, shortens the process flow, reduces the production period, reduces the production cost and creates more profits in unit time; the operation intensity is reduced, the production efficiency is improved, and the method is suitable for large-scale production and has the advantages of environmental friendliness, remarkable benefit and the like.
Drawings
FIG. 1 is a process flow diagram for the preparation of ethambutol hydrochloride.
Detailed Description
The present application will be described in detail with reference to examples, but the present application is not limited to these examples.
S- (+) -2-amino-1-butanol was purchased from Kelieon Biotech, Inc. of Hebei.
1, 2-dichloroethane was purchased from Populus chemical Co., Ltd.
Ethanol hydrochloride was purchased from Pentium chemical Co., Ltd.
Ethanol was purchased from Chongqing Chundong chemical (group) Co., Ltd.
Methanol was purchased from environmental protection technologies, ltd, juyang, city.
Isopropanol was purchased from shopul chemical technology ltd, salt city.
N-butanol was purchased from Kunshan Kunzhi, Inc.
Example 1
295g (3.3094mol) of S- (+) -2-amino-1-butanol (specific rotation degree +10.1 ℃) is put into a 500mL three-necked bottle, stirred and heated to 110 ℃, under full stirring, 35g (0.3536mol) of 1, 2-dichloroethane (the feeding ratio of the aminobutanol to the 1, 2-dichloroethane is 9.36:1) is slowly added, the temperature is controlled to be 110-140 ℃ and is added within 2 hours, and then the temperature range is kept for reaction for 3 hours. 221.5g (2.4849mol) of S- (+) -2-amino-1-butanol was recovered by distillation under reduced pressure at 150 ℃ under a vacuum pressure of-0.09 MPa. Cooling to 70 ℃, adding 200g of absolute ethyl alcohol, stirring, slowly cooling to about 30 ℃, dropwise adding 37.3g of hydrochloric acid ethanol (HCl content is 30%), stirring, and controlling the pH value to be between 3 and 3.5. Slowly cooling to 8-10 deg.C, filtering and separating to obtain 79.3g of ethambutol hydrochloride (yield 80.98%, m.p. 199-204 deg.C), purity 99.9%, ignition residue 0.01%, and granularity 90-110 mesh.
Concentrating the first mother liquor obtained after suction filtration, separating out solids, and performing suction filtration to obtain a second mother liquor and 1.8g of ethambutol hydrochloride; and (3) adding sodium hydroxide into the separated second mother liquor to neutralize until the pH value is about 8, then distilling ethanol at the normal pressure of 100 ℃, adding toluene for azeotropic dehydration, and distilling at the reduced pressure of 150 ℃ to recover 9.5g of S- (+) -2-amino-1-butanol.
The charge ratio of S- (+) -2-amino-1-butanol to 1, 2-dichloroethane was varied with reference to the reaction conditions of example 1, and other conditions were unchanged to determine the effect on the product yield, as shown in Table one.
Table one: influence of S- (+) -2-amino-1-butanol and 1, 2-dichloroethane feed ratio on product yield
Example 2
The effect on the yield and quality of the product was determined by varying the ratio of S- (+) -2-amino-1-butanol alone and the other conditions with reference to the charge ratio and reaction conditions of example 1, see Table II.
Table two: effect of S- (+) -2-amino-1-butanol Bicyclol on product yield and quality
Example 3
The reaction conditions of example 1 were referenced, and the condensation reaction temperature and condensation reaction time were varied, while the other conditions were not varied, to determine the effect on the product yield, see table three.
Example 4
Referring to the reaction conditions of example 1, the alcohol dissolving the distillation product was changed alone, and the other conditions were not changed, to confirm the effect on the product yield, as shown in Table four.
Example 5
The effect on product yield was determined by varying the amount of absolute ethanol alone and the other conditions with reference to the reaction conditions of example 1, see table five.
Table three: effect of condensation reaction temperature and reaction time on yield
Table four: effect of alcohol dissolving distillation product on product yield
Table five: effect of Anhydrous ethanol dosage on product yield
Example 6
295g (3.3094mol) of S- (+) -2-amino-1-butanol (specific rotation degree +10.1 ℃) is put into a 500mL three-necked bottle, stirred and heated to 110 ℃, under full stirring, 35g (0.3536mol) of 1, 2-dichloroethane (the charging ratio of aminobutanol to 1, 2-dichloroethane is 9.36:1) is slowly added, the temperature is controlled to be 110 ℃ to 140 ℃ and is added within 2 hours, and then the temperature range is kept for reaction for 3 hours. And (2) recovering 220.9g (2.4781mol) of S- (+) -2-amino-1-butanol by reduced pressure distillation at 150 ℃, controlling the vacuum pressure to be-0.09 MPa, cooling to 70 ℃, adding 200g of absolute ethyl alcohol, stirring, slowly cooling to about 30 ℃, dropwise adding 37.3g of hydrochloric acid ethanol (the HCl content is 30%), stirring, and controlling the pH to be 3-3.5. Slowly cooling to 8-10 deg.C, filtering and separating to obtain 79.3g of ethambutol hydrochloride (yield 80.98%, m.p. 199-204 deg.C), purity 99.8%, ignition residue 0.01%, and granularity 90-110 mesh.
Example 7
295g (3.3094mol) of S- (+) -2-amino-1-butanol (specific rotation degree +8.6 ℃) is put into a 500mL three-necked bottle, stirred and heated to 110 ℃, under full stirring, 35g (0.3536mol) of 1, 2-dichloroethane (the charging ratio of aminobutanol to 1, 2-dichloroethane is 9.36:1) is slowly added, the temperature is controlled to be 110 ℃ to 140 ℃ and is added within 2 hours, and then the temperature range is kept for reaction for 3 hours. Cooling to 70 ℃, adding 200g of absolute ethyl alcohol, stirring, slowly cooling to about 30 ℃, adding 20g of purified water, dropwise adding 37.3g of hydrochloric acid ethanol (HCl content is 30%), stirring, and controlling the pH value to be between 3 and 3.5. Slowly cooling to 8-10 deg.C, filtering to obtain 69.6g of ethambutol hydrochloride (yield 71.09%, m.p. 199-204 deg.C), purity 99.0%, ignition residue 0.01%, and granularity 20-40 mesh.
Referring to the feed ratio and reaction conditions of example 6 and example 7, we changed S- (+) -2-amino-1-butanol ratio and the amount of water added before dropping ethanol hydrochloride to determine the influence of the quality of raw materials and the amount of added water on the yield, quality and mesh number of the product, as shown in Table six.
Table six: influence of raw material quality and water addition quantity on product yield, quality and mesh number
Comparative example 1
295g (3.3094mol) of S- (+) -2-amino-1-butanol (beta-rotation +10.1 ℃) is put into a 500mL three-necked bottle, stirred and heated to 110 ℃, under full stirring, 35g (0.3536mol) of 1, 2-dichloroethane (the charging ratio of the aminobutanol to the 1, 2-dichloroethane is 9.36:1) is slowly added, the temperature is controlled to be 110 ℃ to 140 ℃ and the addition is finished within 2 hours, and then the temperature range is kept for reaction for 3 hours. Then the temperature is reduced to 60 ℃ to 80 ℃, 24.6g (0.615mol) of sodium hydroxide is added, and the mixture is stirred for half an hour at 85 ℃ to 95 ℃. 235.5g of S- (+) -2-amino-1-butanol was recovered by distillation under reduced pressure at 150 ℃ under a vacuum pressure of-0.09 MPa. Cooling to 70 ℃, adding 200g of absolute ethyl alcohol, stirring at 75-80 ℃ for half an hour, carrying out suction filtration while the solution is hot, slowly cooling the filtrate to about 30 ℃, dropwise adding hydrochloric acid ethanol (the content of HCl is 30%), stirring, controlling the pH value to be 3-3.5, and using 87.3g of hydrochloric acid ethanol. Slowly cooling to 8-10 deg.C, filtering, and separating to obtain 78.5g of ethambutol hydrochloride (yield 80.16%, m.p. 199-204 deg.C), and purity 99.8%. 0.08% of ignition residue and 90-110 mesh granularity.
Concentrating the first mother liquor obtained after suction filtration, separating out solids, and performing suction filtration and separation to obtain a second mother liquor and 1.9g of ethambutol hydrochloride; and (3) adding sodium hydroxide into the separated second mother liquor to neutralize until the pH value is about 8, distilling alcohol at 100 ℃ under normal pressure, adding toluene to remove water by azeotropy at 95 ℃, and distilling at 150 ℃ under reduced pressure to recover 10g of S- (+) -2-amino-1-butanol. And 235.5g of aminobutanol obtained by the previous reduced pressure distillation is subjected to azeotropic dehydration and recovery of toluene to obtain 217.6g of aminobutanol which meets the raw material standard.
Example 8
Referring to the charge ratio and reaction conditions of comparative example 1, we varied the amount of sodium hydroxide added, and the other conditions were not changed, to determine the effect of the amount of sodium hydroxide on the yield and quality of the product, see table seven.
TABLE VII: influence of sodium hydroxide dosage on product yield and ignition residue
Example 9
The influence of the alkali on the product yield and the ignition residue was determined by changing the kind of the alkali added and the other conditions with reference to the charge ratio and the reaction conditions of comparative example 1. See table eight.
Table eight: effect of different bases on product yield and ignition residue
Example 10
The ratio of the raw materials and the reaction conditions of comparative example 1 were not changed, and the amount of sodium hydroxide was changed to compare the unit consumption of the raw materials with the yield and quality of the product (part of the aminobutanol is lost when the aminobutanol is distilled to recover water). See table nine.
Table nine: influence of sodium hydroxide feeding amount on unit consumption of raw materials
Although the present application has been described with reference to a few embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.
Claims (15)
1. A process for preparing ethambutol hydrochloride, comprising the steps of:
1) mixing S- (+) -2-amino-1-butanol and 1, 2-dichloroethane in a reactor, and reacting the two to form a reaction discharge;
2) separating S- (+) -2-amino-1-butanol from the reaction discharge material obtained in the step 1) in a separation system to obtain a residual material, and returning the separated S- (+) -2-amino-1-butanol to the reactor, wherein the water content of the residual material is below 3 wt%;
3) after step 2) is completed, transferring the remaining material to another reactor, and adding ethanol and HCl into the reactor, wherein the molar ratio of the 1, 2-dichloroethane to the ethanol is 1:12 to 1: 19;
4) crystallizing to obtain a first mother liquor and precipitated ethambutol hydrochloride, and separating the first mother liquor and ethambutol hydrochloride;
5) concentrating and recovering alcohol from the first mother liquor at normal pressure, crystallizing to obtain a second mother liquor and precipitated ethambutol hydrochloride, separating the second mother liquor from the ethambutol hydrochloride, and returning the ethambutol hydrochloride to the separation system in the step 2);
6) adding alkali into the second mother liquor to adjust the pH value, separating the alcohol from the second mother liquor, and returning the S- (+) -2-amino-1-butanol which is not completely separated in the step 2) to the reactor in the step 1) after removing water;
the molar ratio of the S- (+) -2-amino-1-butanol to the 1, 2-dichloroethane is from 8:1 to 12: 1;
the specific rotation of the S- (+) -2-amino-1-butanol is from +9.3 degrees to +10.9 degrees;
in step 1), the reaction takes place at a temperature of from 100 ℃ to 140 ℃ for a reaction time of from 2 hours to 5 hours.
2. The process according to claim 1, wherein in step 1), the reaction is carried out at a temperature of 120 ℃ to 140 ℃ for a reaction time of 2 hours to 4 hours.
3. The process of claim 1, wherein the specific rotation of S- (+) -2-amino-1-butanol is from +10.0 ° to +10.9 °.
4. The process according to claim 1, characterized in that the molar ratio of S- (+) -2-amino-1-butanol and 1, 2-dichloroethane is from 9:1 to 10: 1.
5. The process according to claim 1, characterized in that the molar ratio of the 1, 2-dichloroethane to the ethanol is from 1:12 to 1: 15.
6. The process of claim 5, wherein in step 3), the ethanol is added to the reactor first, followed by HCl to form a first alcohol solution comprising HCl; or mixing the ethanol and the HCl to obtain a second alcohol solution, and adding the second alcohol solution into the reactor in the step 3) to form a first alcohol solution containing HCl; and the first alcohol solution has a pH of 2 to 4.
7. The process of claim 6, wherein the second glycol solution has an HCl content of 28 wt% to 37 wt%.
8. The process according to claim 1, wherein the conditions in step 2) are: the temperature is 100 ℃ to 150 ℃ and the time is 1 hour to 5 hours.
9. The process according to claim 8, wherein the temperature in step 2) is preferably 120 ℃ to 150 ℃ for 3 hours to 5 hours.
10. The process according to claim 1, characterized in that the conditions in step 3) are: the temperature is 10 ℃ to 50 ℃ and the time is 1 hour to 4 hours.
11. The process according to claim 10, wherein the temperature conditions in step 3) are 30 ℃ to 50 ℃ for 1 hour to 2 hours.
12. The process according to claim 1, wherein in step 4), the temperature for crystallization separation of ethambutol hydrochloride is 0 ℃ to 30 ℃ for 1 hour to 8 hours.
13. The process according to claim 12, wherein in step 4), the temperature for crystallization separation of ethambutol hydrochloride is 5 ℃ to 15 ℃ for 2 hours to 4 hours.
14. The process according to claim 1, characterized in that in step 2), S- (+) -2-amino-1-butanol is separated by distillation under reduced pressure;
in step 6), adding a base to a pH of 7.5-8.5; separating the ethanol by atmospheric distillation; s- (+) -2-amino-1-butanol was separated by distillation under reduced pressure.
15. The process of claim 1, wherein in step 3) the water content of the remaining material is below 1.5 wt%.
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Citations (2)
| 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 |
| 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 |
-
2016
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Patent Citations (2)
| 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 |
| 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 (3)
| Title |
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| An Environmentally Friendly, Scalable and Highly Efficient Synthesis of (S,S)-Ethambutol, a First Line Drug against Tuberculosis;Goncalves, Raoni S. B.等;《Letters in Organic Chemistry》;20150801;第12卷(第7期);第478-481页 * |
| 乙醇丁胺的合成研究;邢鹏;《硕士学位论文》;20041021;第37页倒数第2段 * |
| 盐酸乙胺丁醇的合成工艺改进;孙福强 等;《广州化工》;20140331;第42卷(第6期);第90-91页 * |
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