CN115583867A - Resolution method of L-2-aminopropanol - Google Patents
Resolution method of L-2-aminopropanol Download PDFInfo
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- CN115583867A CN115583867A CN202211018676.4A CN202211018676A CN115583867A CN 115583867 A CN115583867 A CN 115583867A CN 202211018676 A CN202211018676 A CN 202211018676A CN 115583867 A CN115583867 A CN 115583867A
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- aminopropanol
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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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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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention discloses a method for splitting L-2-aminopropanol, which comprises the following steps: the first step is as follows: carrying out chemical reaction on racemic 2-aminopropanol and L-methyl mandelate to generate a racemic amide compound (a mixture of a compound 1 and a compound 2); the second step is that: obtaining a single chiral isomer (compound 1 or compound 2) by a crystallization method; the third step: recovering mandelic acid by acid hydrolysis; the fourth step: alkalizing the hydrolysis solution to obtain the D, L-2-aminopropanol with high chiral purity. The method has the characteristics of simple resolution method, low cost and high yield, the resolution reagent can be recovered, and the used solvent and the generated waste liquid can be recycled, so the method is green and environment-friendly and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of L-2-aminopropanol resolution, in particular to a method for resolving L-2-aminopropanol.
Background
Levofloxacin is quinolone antibacterial drugs, and has the advantages of broad spectrum, effective oral administration, less side effects and the like, L-2-aminopropanol is an important intermediate for synthesizing the antibacterial drugs levofloxacin, and the production technology for producing and preparing L-2-aminopropanol mainly comprises two methods, namely a chemical method and a biological method, wherein the production process for producing L-2-aminopropanol by the chemical method is mainly obtained by an amino acid ester reduction method, and the biological method is mainly produced by microorganisms or biological enzymes.
The chemical method is mainly used for reducing L-alanine or derivatives of L-alanine esters, the reducing reagent generally adopts lithium aluminum hydride, sodium borohydride, potassium borohydride, zinc borohydride or borohydride resin, the alanine esters are firstly generated into amino acid esters, and then the amino acid esters are reduced by using a strong reducing agent to prepare corresponding amino alcohols, so that the method is the current main route for chemically synthesizing L-2-aminopropanol in China.
The biocatalysis method is more and more concerned due to the characteristics of mild reaction conditions, high selectivity, environmental protection and the like, and documents report that the chirality reaches over 96 percent when L-2-aminopropanol is produced by transamination of microorganisms, and the two synthetic routes have the problems of high production cost, only L-2-aminopropanol can be produced and single product.
With the development of pharmaceutical industry, D-2-aminopropanol has larger market demand, in recent years, the process of producing racemic 2-aminopropanol by condensing sodium acetate and chloroacetone to generate 1-acetoxyacetone, hydrolyzing to obtain hydroxyacetone and then hydrogenating to produce racemic 2-aminopropanol is mature, but a method capable of resolving racemic 2-aminopropanol is not found so far.
Disclosure of Invention
The invention aims to provide a method for splitting L-2-aminopropanol, which aims to solve the problem of splitting the L-2-aminopropanol.
In order to achieve the purpose, the invention provides the following technical scheme: a resolution method of L-2-aminopropanol comprises the following steps:
the first step is as follows: carrying out chemical reaction on racemic 2-aminopropanol and L-methyl mandelate to generate a racemic amide compound (a mixture of a compound 1 and a compound 2);
the second step: obtaining a single chiral isomer (compound 1 or compound 2) by a crystallization method;
the third step: recovering mandelic acid by acid hydrolysis;
the fourth step: alkalizing the hydrolysis solution to obtain the D, L-2-aminopropanol with high chiral purity.
Preferably, the chemical reaction between the racemic 2-aminopropanol and the L-methyl mandelate in the first step adopts toluene as a solvent.
Preferably, gu can be added in the first step 2+ Reagent, preferably copper chloride and copper sulfate, to improve the resolution yield and purity of racemic 2-aminopropanol.
Preferably, the mixed solvent of dichloroethane and acetone is added to improve the resolution yield and purity, and the preferable ratio is that the dichloroethane: acetone = 1.
Preferably, the resolving agent L-mandelic acid methyl ester can be replaced by L-mandelic acid ethyl ester.
Preferably, the resolving solvent is dichloromethane, and one or more of dichloroethane, ethyl acetate, acetone, acetonitrile and methyl tert-butyl ether can be selected.
Preferably, after hydrolysis of the chiral amide compound with hydrochloric acid, mandelic acid can be recovered by extraction with methyl tert-butyl ether.
Preferably, the L-2-aminopropanol or D-2-aminopropanol with higher purity is obtained after the compound 1 or the compound 2 is refined and hydrolyzed by one or more of butanone, isopropanol or toluene.
Compared with the prior art, the invention has the beneficial effects that:
1. the method realizes the resolution of racemic 2-aminopropanol to simultaneously obtain L-2-aminopropanol and D-2-aminopropanol, and greatly improves the resolution yield and the product purity of the racemic 2-aminopropanol by adding a catalyst and adjusting the type and the proportion of a resolution solvent.
2. The method has the characteristics of simple resolution method, low cost and high yield, the resolution reagent can be recovered, the used solvent and the generated waste liquid can be recycled, and the method is green, environment-friendly and suitable for industrial production.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Example I
A method for resolving L-2-aminopropanol comprises the following steps:
the first step is as follows: carrying out chemical reaction on racemic 2-aminopropanol and L-methyl mandelate to generate a racemic amide compound (a mixture of a compound 1 and a compound 2);
the second step: obtaining a single chiral isomer (compound 1 or compound 2) by a crystallization method;
the third step: recovering mandelic acid by acid hydrolysis;
the fourth step: alkalizing the hydrolysis solution to obtain the D, L-2-aminopropanol with high chiral purity.
In the first step, racemized 2-aminopropanol and L-methyl mandelate are subjected to chemical reaction by taking toluene as a solvent.
In the first step by adding Gu 2+ Reagent for improving resolution yield and purity of racemic 2-aminopropanol, preferably copper chloride and copper sulfate.
The resolution yield and purity are improved by adding a mixed solvent of dichloroethane and acetone, preferably, the ratio of dichloroethane: acetone = 1.
The resolving agent L-methyl mandelate can be replaced by L-ethyl mandelate.
The resolution solvent is dichloromethane, and one or more of dichloroethane, ethyl acetate, acetone, acetonitrile, and methyl tert-butyl ether can also be selected.
After hydrolysis of the chiral amide compound with hydrochloric acid, mandelic acid can be recovered by extraction with methyl tert-butyl ether.
The L-2-aminopropanol or D-2-aminopropanol with higher purity is obtained after refining and hydrolyzing the compound 1 or the compound 2 by one or more of butanone, isopropanol or toluene.
In use, the present embodiment: adding 600mL of toluene into a 1000mL triangular flask, pumping 166g of L-mandelic acid methyl ester and 75g of racemic 2-aminopropanol, heating and refluxing to separate out methanol generated by the reaction, concentrating to a small volume after the central control reaction is completed, adding 500mL of dichloromethane, stirring to separate out a large amount of solids, centrifuging, heating dichloromethane to reflux for 2h, cooling and crystallizing, centrifuging, combining the solids obtained in two times, and drying to obtain 86.48g of solids.
The dichloromethane mother liquor is combined, distilled under reduced pressure to a small volume, cooled and crystallized to obtain 84.72g of another diastereoisomer product.
Adding 200mL of 6M hydrochloric acid into 86.48g of the obtained solid, heating and refluxing for 6h, cooling, extracting and recovering mandelic acid by using 100mL of methyl tert-butyl ether to obtain 61.5g of mandelic acid, concentrating and drying the water phase to obtain 46.0g of L-2-aminopropanol hydrochloride, washing the L-2-aminopropanol hydrochloride to be neutral by using a saturated sodium carbonate solution, centrifuging and drying to obtain 30.85g of L-2-aminopropanol (the same preparation method of D-aminopropanol).
Example II
A method for resolving L-2-aminopropanol comprises the following steps:
the first step is as follows: carrying out chemical reaction on racemic 2-aminopropanol and L-methyl mandelate to generate a racemic amide compound (a mixture of a compound 1 and a compound 2);
the second step: obtaining a single chiral isomer (compound 1 or compound 2) by a crystallization method;
the third step: recovering mandelic acid by acid hydrolysis;
the fourth step: alkalizing the hydrolysis solution to obtain the D, L-2-aminopropanol with high chiral purity.
In the first step, racemized 2-aminopropanol and L-methyl mandelate are subjected to chemical reaction by taking toluene as a solvent.
In the first step by adding Gu 2+ Reagent for improving resolution yield and purity of racemic 2-aminopropanol, preferably copper chloride and copper sulfate.
The separation yield and purity are improved by adding a mixed solvent of dichloroethane and acetone, preferably, the proportion of dichloroethane: acetone =1, 0.1-5.
The resolving agent L-methyl mandelate can be replaced by L-ethyl mandelate.
The resolution solvent is dichloromethane, and one or more of dichloroethane, ethyl acetate, acetone, acetonitrile, and methyl tert-butyl ether can also be selected.
After hydrolysis of the chiral amide compound with hydrochloric acid, mandelic acid can be recovered by extraction with methyl tert-butyl ether.
The L-2-aminopropanol or D-2-aminopropanol with higher purity is obtained after refining and hydrolyzing the compound 1 or the compound 2 by one or more of butanone, isopropanol or toluene.
This embodiment is used: adding 600mL of toluene into a 1000mL enamel kettle, pumping 166g of methyl mandelate, 75g of racemic 2-aminopropanol and 20g of copper chloride, heating and refluxing to separate out methanol generated by the reaction, concentrating to a small volume after the completion of the control reaction, adding 500mL of mixed solvent (dichloromethane: acetone = 1:1) and stirring to separate out a large amount of solid, centrifuging, heating the mixed solvent to reflux for 2h, cooling and crystallizing, centrifuging, combining the solids obtained in the two steps, and drying to obtain 88.61g of solid.
The mother liquids of the mixed solvents are combined, distilled under reduced pressure to a small volume, cooled and crystallized to obtain 86.44g of another diastereoisomer product.
Adding 200mL of 6M hydrochloric acid into 88.61g of the obtained solid, heating and refluxing for 6h, cooling, extracting and recovering mandelic acid by using 100mL of methyl tert-butyl ether to obtain 62.3g of mandelic acid, concentrating and drying the water phase to obtain 46.5g of L-2-aminopropanol hydrochloride, washing the L-2-aminopropanol hydrochloride to be neutral by using a saturated sodium carbonate solution, centrifuging and drying to obtain 31.32g of L-2-aminopropanol (the D-aminopropanol is prepared by the same method).
Example III
A method for resolving L-2-aminopropanol comprises the following steps:
the first step is as follows: carrying out chemical reaction on racemic 2-aminopropanol and L-methyl mandelate to generate a racemic amide compound (a mixture of a compound 1 and a compound 2);
the second step is that: obtaining a single chiral isomer (compound 1 or compound 2) by a crystallization method;
the third step: recovering mandelic acid by acid hydrolysis;
the fourth step: alkalizing the hydrolysis solution to obtain the D, L-2-aminopropanol with high chiral purity.
In the first step, racemized 2-aminopropanol and L-methyl mandelate are subjected to chemical reaction by taking toluene as a solvent.
In the first step by adding Gu 2+ Reagent for improving resolution yield and purity of racemic 2-aminopropanol, preferably copper chloride and copper sulfate.
The separation yield and purity are improved by adding a mixed solvent of dichloroethane and acetone, preferably, the proportion of dichloroethane: acetone = 1.
The resolving agent L-methyl mandelate can be replaced by L-ethyl mandelate.
The resolution solvent is dichloromethane, or one or more of dichloroethane, ethyl acetate, acetone, acetonitrile, and methyl tert-butyl ether.
After hydrolysis of the chiral amide compound with hydrochloric acid, mandelic acid can be recovered by extraction with methyl tert-butyl ether.
The L-2-aminopropanol or D-2-aminopropanol with higher purity is obtained after refining and hydrolyzing the compound 1 or the compound 2 by one or more of butanone, isopropanol or toluene.
Example IV
This embodiment further illustrates, in relation to other examples, a method for resolving L-2-aminopropanol, which comprises:
the first step is as follows: carrying out chemical reaction on racemic 2-aminopropanol and L-methyl mandelate to generate a racemic amide compound (a mixture of a compound 1 and a compound 2);
the second step: obtaining a single chiral isomer (compound 1 or compound 2) by a crystallization method;
the third step: recovering mandelic acid by acid hydrolysis;
the fourth step: alkalizing the hydrolysis solution to obtain the D, L-2-aminopropanol with high chiral purity.
In the first step, racemic 2-aminopropanol and L-methyl mandelate react chemically with toluene as solvent.
In the first step by adding Gu 2+ Reagent for improving resolution yield and purity of racemic 2-aminopropanol, preferably copper chloride and copper sulfate.
The separation yield and purity are improved by adding a mixed solvent of dichloroethane and acetone, preferably, the proportion of dichloroethane: acetone = 1.
The resolving agent L-methyl mandelate can be replaced by L-ethyl mandelate.
The resolution solvent is dichloromethane, and one or more of dichloroethane, ethyl acetate, acetone, acetonitrile, and methyl tert-butyl ether can also be selected.
After hydrolysis of the chiral amide compound with hydrochloric acid, mandelic acid can be recovered by extraction with methyl tert-butyl ether.
The L-2-aminopropanol or D-2-aminopropanol with higher purity is obtained after refining and hydrolyzing the compound 1 or the compound 2 by one or more of butanone, isopropanol or toluene.
The yields after purification of compound 1 and compound 2 using butanone, isopropanol or toluene are shown in the table:
it should be noted that, in this document, relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
1. A method for resolving L-2-aminopropanol is characterized by comprising the following steps: the resolution method of the L-2-aminopropanol comprises the following steps:
the first step is as follows: carrying out chemical reaction on racemic 2-aminopropanol and L-methyl mandelate to generate a racemic amide compound (a mixture of a compound 1 and a compound 2);
the second step is that: obtaining a single chiral isomer (compound 1 or compound 2) by a crystallization method;
the third step: recovering mandelic acid by acid hydrolysis;
the fourth step: alkalizing the hydrolysis solution to obtain the D, L-2-aminopropanol with high chiral purity.
2. The method for resolving L-2-aminopropanol according to claim 1, wherein: in the first step, racemic 2-aminopropanol and L-methyl mandelate react chemically with toluene as solvent.
3. The method for resolving L-2-aminopropanol according to claim 1, wherein: in the first step, gu can be added 2+ Reagent for improving resolution yield and purity of racemic 2-aminopropanol, preferably copper chloride and copper sulfate.
4. The method for resolving L-2-aminopropanol according to claim 1, wherein: the mixed solvent of dichloroethane and acetone is added to improve the resolution yield and purity, and the preferred proportion is that dichloroethane: acetone = 1.
5. The method for resolving L-2-aminopropanol according to claim 1, wherein: the resolving agent L-methyl mandelate can be replaced by L-ethyl mandelate.
6. The method for resolving L-2-aminopropanol according to claim 1, wherein: the resolution solvent is dichloromethane, and one or more of dichloroethane, ethyl acetate, acetone, acetonitrile and methyl tert-butyl ether can be selected.
7. The method for resolving L-2-aminopropanol according to claim 1, wherein: after hydrolysis of the chiral amide compound with hydrochloric acid, mandelic acid can be recovered by extraction with methyl tert-butyl ether.
8. The method for resolving L-2-aminopropanol according to claim 1, wherein: the L-2-aminopropanol or D-2-aminopropanol with higher purity is obtained after the compound 1 or the compound 2 is refined and hydrolyzed by one or more of butanone, isopropanol or toluene.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4239912A (en) * | 1978-12-08 | 1980-12-16 | American Cyanamid Company | Process for resolving DL-Mandelic acid with novel 2-benzylamino-1-butanols |
| US4259521A (en) * | 1979-10-09 | 1981-03-31 | American Cyanamid Company | Process for resolving DL-mandelic acid |
| CN104152526A (en) * | 2014-08-13 | 2014-11-19 | 陈永军 | Resolution method for preparing optically pure R-1-phenylethylamine |
| CN104178548A (en) * | 2014-08-14 | 2014-12-03 | 陈永军 | Method for preparing optically-pure S-2-naphthylethylamine through resolution |
| CN104388517A (en) * | 2014-10-08 | 2015-03-04 | 王同俊 | R-mandelic acid and R-mandelic acid acylate compound |
| CN108586272A (en) * | 2018-06-28 | 2018-09-28 | 浙江昌明药业有限公司 | A kind of preparation method of 3- aminopropanols or 3- alanine derivatives |
| CN110668958A (en) * | 2019-09-12 | 2020-01-10 | 江苏宝利化学有限公司 | Method for preparing (R) -3-aminobutanol |
-
2022
- 2022-08-24 CN CN202211018676.4A patent/CN115583867A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4239912A (en) * | 1978-12-08 | 1980-12-16 | American Cyanamid Company | Process for resolving DL-Mandelic acid with novel 2-benzylamino-1-butanols |
| US4259521A (en) * | 1979-10-09 | 1981-03-31 | American Cyanamid Company | Process for resolving DL-mandelic acid |
| CN104152526A (en) * | 2014-08-13 | 2014-11-19 | 陈永军 | Resolution method for preparing optically pure R-1-phenylethylamine |
| CN104178548A (en) * | 2014-08-14 | 2014-12-03 | 陈永军 | Method for preparing optically-pure S-2-naphthylethylamine through resolution |
| CN104388517A (en) * | 2014-10-08 | 2015-03-04 | 王同俊 | R-mandelic acid and R-mandelic acid acylate compound |
| CN108586272A (en) * | 2018-06-28 | 2018-09-28 | 浙江昌明药业有限公司 | A kind of preparation method of 3- aminopropanols or 3- alanine derivatives |
| CN110668958A (en) * | 2019-09-12 | 2020-01-10 | 江苏宝利化学有限公司 | Method for preparing (R) -3-aminobutanol |
Non-Patent Citations (1)
| Title |
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