CN115043816A - Chiral resolution method of selenooctanoic acid - Google Patents
Chiral resolution method of selenooctanoic acid Download PDFInfo
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- 239000002253 acid Substances 0.000 title claims abstract description 66
- 238000000034 method Methods 0.000 title claims abstract description 33
- 239000002904 solvent Substances 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 238000010438 heat treatment Methods 0.000 claims abstract description 15
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 238000005406 washing Methods 0.000 claims abstract description 10
- 239000012452 mother liquor Substances 0.000 claims abstract description 6
- 239000012044 organic layer Substances 0.000 claims abstract description 6
- 230000020477 pH reduction Effects 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 80
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 21
- 239000012046 mixed solvent Substances 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000000967 suction filtration Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- NJOYQMJRKZHFFW-UHFFFAOYSA-N [Se].C(CCCCCCC)(=O)O Chemical compound [Se].C(CCCCCCC)(=O)O NJOYQMJRKZHFFW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003929 acidic solution Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 235000015165 citric acid Nutrition 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000012670 alkaline solution Substances 0.000 claims description 6
- 239000010410 layer Substances 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 3
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 239000002244 precipitate Substances 0.000 abstract description 2
- 238000001953 recrystallisation Methods 0.000 abstract description 2
- CRDYSYOERSZTHZ-UHFFFAOYSA-M selenocyanate Chemical compound [Se-]C#N CRDYSYOERSZTHZ-UHFFFAOYSA-M 0.000 abstract description 2
- 238000010992 reflux Methods 0.000 description 6
- 229910052711 selenium Inorganic materials 0.000 description 5
- 239000011669 selenium Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 description 2
- 235000019136 lipoic acid Nutrition 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 229940065287 selenium compound Drugs 0.000 description 2
- 150000003343 selenium compounds Chemical class 0.000 description 2
- 229960002663 thioctic acid Drugs 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DLEIVKFXKPQFTG-UHFFFAOYSA-N CCCCCCCC(O)=O.CCCCCCCC(O)=O.[SeH2] Chemical compound CCCCCCCC(O)=O.CCCCCCCC(O)=O.[SeH2] DLEIVKFXKPQFTG-UHFFFAOYSA-N 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229950010033 ebselen Drugs 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000013332 literature search Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 150000002898 organic sulfur compounds Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 125000003748 selenium group Chemical group *[Se]* 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000032895 transmembrane transport Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D345/00—Heterocyclic compounds containing rings having selenium or tellurium atoms as the only ring hetero atoms
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a chiral resolution method of selenooctanoic acid, which takes chiral methylbenzylamine as a resolution reagent and precipitates and separates out corresponding enantiomer salt through salifying. After recrystallization, the corresponding single chiral selenooctanoic acid is obtained by acidification reaction. The method for preparing the chiral selenooctanoic acid from the racemic selenooctanoic acid has the advantages of mild reaction conditions, simple process, convenient operation and suitability for industrial application; the prepared single chiral selenocyanate has important pharmaceutical application. The method also comprises the steps of acidifying the mother liquor containing the other enantiomer selenooctanoic acid in the splitting process, washing with water, taking an organic layer, heating to react at normal pressure, concentrating the solvent, and recrystallizing to obtain the racemic selenooctanoic acid, so that the raw materials are fully utilized, and the production cost is reduced.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a chiral resolution method of selenooctanoic acid.
Background
The organic sulfur and selenium compounds have various biological activities such as anti-tumor, anti-oxidation, anti-fungus and the like. In recent years, scientists have made extensive studies on the synthesis and biological activities of Organic selenium compounds, and especially on five-membered heterocyclic compounds containing selenium, and the representative drugs entering clinical trials are ebselen, selenazolofuran, etc. (see Rafique J, Canto RFS, Saba S, et al. Current Organic Chemistry,2016,20(2): 166-188.). The literature reports that the five-membered heterocyclic compound containing double selenium bonds has larger ring tension, stronger acidity and alcohol-acid reducing property, is easier to be taken by cells, has better stability in cells, has the advantages of high bioavailability, strong bioactivity and the like than the compound containing double sulfur bonds, and the selenocytic acid is the best (refer to Chuard N, Poblador-Bahamode AI, Zong LL, et al. chemical Science,2018,9(7): 1860-1866.). Selenium caprylic acid has the advantages of small molecular volume, convenient synthesis, high stability, good solubility, low toxicity and the like, and further research finds that the selenium caprylic acid has very high-efficiency and strong transmembrane transport capacity, and can even carry substrates with two orders of magnitude larger volume than the selenium caprylic acid self into cells (see Bartolami E, Basagiannis D, Zong L, et al. chemistry-A European Journal,2019,25: 4047-.
Selenooctanoic acid is a biological isostere of lipoic acid, and is a compound obtained by substituting sulfur atoms at the 6 and 8 positions with selenium atoms on the basis of the structure of lipoic acid. The molecular structure of the selenooctanoic acid contains a chiral center, and from the aspects of pharmaceutical application development and pharmacological research, the single chiral selenooctanoic acid is obtained as a key material basis, and a method for simply, conveniently and efficiently obtaining the chiral selenooctanoic acid is necessary to be established. Through literature search, no effective selenium caprylate resolution report is found, and no relevant patent disclosure is found.
Disclosure of Invention
The invention aims to provide a method for chiral resolution of selenooctanoic acid, which is mild in reaction condition, simple in process, convenient and fast to operate and suitable for industrial application, and aims to overcome the defects of the prior art.
The technical scheme adopted by the invention is as follows: a chiral resolution method of selenooctanoic acid comprises the following specific steps:
the method comprises the following steps: dissolving selenooctanoic acid in a first solvent, heating to 25-80 ℃, dropwise adding chiral methylbenzylamine, wherein the molar ratio of selenooctanoic acid to chiral methylbenzylamine is 1: 0.5-0.8, chiral methylbenzylamine is R-methylbenzylamine or S-methylbenzylamine, separating out a tan solid, cooling, and performing suction filtration to obtain a salt of R-selenooctanoic acid and chiral methylbenzylamine or a salt of S-selenooctanoic acid and chiral methylbenzylamine;
step two: recrystallizing the salt with a second solvent for 1 to 5 times, and purifying;
step three: dissolving the obtained salt in an organic solvent, heating to 25-80 ℃, dropwise adding an acidic solution, stirring for 0.5-1 hour, adding water, extracting, taking an organic solvent layer, washing with water, drying with anhydrous magnesium sulfate, and spin-drying to obtain R-selenooctanoic acid or S-selenooctanoic acid;
or dissolving the obtained salt in an alkaline solution, washing with an organic solvent, dropwise adding an acidic solution to adjust the pH value to 1-2, precipitating a large amount of tan solid, performing suction filtration, and drying to obtain R-selenooctanoic acid or S-selenooctanoic acid.
Further, in the first step, the first solvent is formed by mixing any one or two of acetonitrile, toluene, tetrahydrofuran and water according to any ratio, and the volume/mass ratio of the solvent to the selenooctanoic acid is 5-10 ml/g.
Further, in the second step, the second solvent is toluene, acetonitrile or acetone, or a toluene/methanol mixed solvent, a toluene/ethanol mixed solvent, a toluene/isopropanol mixed solvent, a toluene/water mixed solvent, an acetonitrile/methanol mixed solvent, an acetonitrile/ethanol mixed solvent, an acetonitrile/isopropanol mixed solvent, an acetonitrile/water mixed solvent; in the mixed solvent, the volume ratio of the front and the back of the "/" is 1: 0.2-5.
Further, in the third step, the organic solvent is toluene, dichloromethane, chloroform or ethyl acetate; the volume-mass ratio of the organic solvent to the obtained salt is 5-10 ml/g.
Further, in the third step, the acid of the acidic solution is hydrochloric acid, acetic acid, citric acid, oxalic acid or tartaric acid, and the molar ratio of the obtained salt to the acid is 1: 1-1.2; the solvent of the acidic solution is water, methanol or ethanol, and the volume mass ratio of the solvent to the acid is 1-5 ml/g.
Further, in the third step, the alkali of the alkaline solution is sodium hydroxide or potassium hydroxide, and the molar ratio of the obtained salt to the alkali is 1: 1-1.2; the solvent of the alkaline solution is water, methanol or ethanol, and the volume mass ratio of the solvent to the alkali is 1-5 ml/g.
Further, in the step one, the selenium caprylic acid is recovered from the mother liquor after suction filtration by the following method: acidifying the filtrate, washing with water, and collecting the organic layer; and heating the organic layer at normal pressure for reaction, concentrating the solvent, and recrystallizing to obtain the selenium caprylic acid.
Further, the acidification is to adjust the pH of the filtrate to 1-3 by using acid, wherein the acid is selected from hydrochloric acid, acetic acid, sulfuric acid, citric acid, oxalic acid and tartaric acid.
Further, the heating reaction temperature is 60-120 ℃, and the heating reaction time is 6-24 hours.
Further, the product after concentration of the solvent was recrystallized from cyclohexane.
The invention has the beneficial effects that:
1. the method takes chiral methylbenzylamine as a resolving reagent, and precipitates and separates out corresponding enantiomer salt through salification. After recrystallization, the corresponding single chiral selenooctanoic acid is obtained by acidification reaction. The method for preparing the chiral selenooctanoic acid from the racemic selenooctanoic acid has the advantages of mild reaction conditions, simple process, convenient operation and suitability for industrial application; the prepared single chiral selenocyanate has important pharmaceutical application.
2. And acidifying and washing mother liquor containing the other enantiomer selenooctanoic acid in the resolution process, taking an organic layer, heating to react under normal pressure, concentrating a solvent, and recrystallizing to obtain the racemic selenooctanoic acid, so that the raw materials are fully utilized, and the production cost is reduced.
Detailed Description
The corresponding reaction of the invention is as follows:
the present invention is further illustrated by the following specific examples.
EXAMPLE 1 preparation of R-selenooctanoic acid
Selenium octanoic acid (39.0 g, 0.13 mol) was dissolved in toluene (270 ml), heated to 40 ℃, R-methylbenzylamine (10.1 g, 0.083 mol) was added dropwise to precipitate a large amount of tan solid, cooled, and filtered to obtain 24.3 g of R-selenium octanoic acid-R-methylbenzylamine salt. The salt was repeatedly recrystallized 5 times from a mixed solution of toluene and methanol, the amount of toluene was successively decreased and the amount of methanol was appropriately increased, to obtain 20.9 g of the salt. The resulting salt was dissolved in toluene (100 ml), heated to 35 ℃, a solution of citric acid (9.6g, 0.05 mol) in methanol (20 ml) was added dropwise, stirred for 1 hour, water (60ml) was added, extracted, the toluene layer was taken and washed with water (10ml)Washing for three times, drying by anhydrous magnesium sulfate, and spin-drying to obtain R-selenooctanoic acid: tan solid, 13.3 g, total yield: 68.2% (calculated as theoretical 19.5g of R-selenooctanoic acid); purity: 96.2% (liquid area normalization method); melting point mp: 81.2-82.8 ℃; optically active
Infrared IR v max (KBr)/cm -1 : 3025,1701,1427,1245,1204,942,731, respectively; hydrogen spectrum 1 H NMR(600MHz,CDCl 3 ),δ：3.91(m,1H,Se-CH-),3.32(t,2H,J＝6.0Hz,Se-C 2 H-),3.00-2.95(m,1H,Se-CH 2 -CHH-),2.52(m,1H,Se-CH 2 -CHH-),2.38(t,2H,J＝7.2Hz,C 2 H-CO-),1.87-1.81(m,1H,CHH-CH 2 -CH 2 -CH 2 -CO-),1.78-1.72(m,1H,CHH-CH 2 -CH 2 -CH 2 -CO-),1.73-1.63(m,2H,C 2 H-CH 2 -CO-),1.53-1.43(m,2H,-C 2 H-CH 2 -CH 2 -CO-); carbon spectrum 13 C NMR(150MHz,CDCl 3 ) δ: 179.1,52.5,45.7,35.3,33.7,29.6,29.4, 24.4; mass spectrum ESI-MS: 300.9([ M-H)] - )。
EXAMPLE 2 preparation of R-selenooctanoic acid
Selenium octanoic acid (39.0 g, 0.13 mol) was dissolved in toluene (270 ml), heated to 40 ℃, R-methylbenzylamine (10.1 g, 0.083 mol) was added dropwise to precipitate a large amount of tan solid, cooled, and filtered to obtain 24.3 g of R-selenium octanoic acid-R-methylbenzylamine salt. Adding a small amount of acetone into the salt, heating to 50 ℃ to dissolve, gradually cooling to 0 ℃, precipitating a large amount of solid, performing suction filtration, and repeating the operation on the filter cake for 1 time. Dissolving the obtained solid sodium hydroxide solution, washing with dichloromethane, adjusting the pH value to 1-2 with dilute hydrochloric acid, separating out a large amount of tan solid, performing suction filtration, and performing vacuum drying to obtain R-selenium caprylic acid: tan solid, 6.1 g, total yield: 31.2% (calculated as 19.5g of theoretical R-selenooctanoic acid); purity: 97.9% (liquid area normalization method).
EXAMPLE 3 preparation of S-selenooctanoic acid
Selenooctanoic acid (39.0 g, 0.13 mol) was dissolved in toluene (270 ml) and heated toS-methylbenzylamine (10.1 g, 0.083 mol) is dripped at 40 ℃, a large amount of tan solid is separated out, and the S-selenooctanoic acid-S-methylbenzylamine salt 23.3 g is obtained after cooling and suction filtration. The salt was repeatedly recrystallized from a mixed solution of toluene and methanol 3 times to obtain 19.8 g of salt. The resulting salt was dissolved in toluene (100 ml), heated to 35 ℃, and a solution of citric acid (9.0 g, 0.047 mol) in ethanol (20 ml) was added dropwise, stirred for 1 hour, water (60ml) was added, extracted, the toluene layer was taken and washed three times with water (10ml), dried over anhydrous magnesium sulfate, and spin-dried to give S-selenooctanoic acid: tan solid, 14.2 g, total yield: 72.8% (calculated as 19.5g of theoretical S-selenooctanoic acid); purity: 98% (liquid area normalization); melting point mp: 84.9-86.8 ℃; optically active
Infrared IR v max (kbr)/cm-1: 3026,2928,2898,1702,1427,1245,1205,944,732, respectively; hydrogen spectrum 1H NMR (600MHz, CDCl3), δ: 3.92(m,1H, Se-CH-),3.33(t,2H, J ═ 5.4Hz, Se-CH2-),3.00-2.95(m,1H, Se-CH2-CHH-),2.53(m,1H, Se-CH2-CHH-),2.39(t,2H, J ═ 7.2Hz, CH2-CO-),1.87-1.81(m,1H, CHH-CH2-CH2-CH2-CO-),1.78-1.72(m,1H, CHH-CH2-CH2-CH2-CO-),1.72-1.63(m,2H, CH2-CH2-CO-),1.53-1.43(m,2H, -CH2-CH 73742-CH 73784); carbon spectrum 13C NMR (150MHz, CDCl3), δ: 179.3,52.5,45.7,35.3,33.7,29.6,29.4, 24.4; mass spectrum ESI-MS: 300.9([ M-H)]-)。
The method disclosed by the invention can be used for preparing the single chiral selenocytic acid with higher total yield and purity, and is mild in reaction conditions, simple in process, convenient and fast to operate and suitable for industrial application.
[ example 4]
Will [ example 1]And (3) dropwise adding 1N hydrochloric acid into the mother liquor (containing S-selenooctanoic acid and S-selenooctanoic acid-R-methylbenzylamine salt) obtained by suction filtration to adjust the pH value to 1-2. Water (60mL) was added, extracted, and the toluene layer was taken and washed three times with water (10 mL). Heating and refluxing the toluene solution at the reflux temperature of 112 ℃, refluxing for 24h, and concentrating the solvent. Recrystallizing with cyclohexane to obtain racemic selenooctanoic acid 16.4g,
[ example 5]
Will [ example 3]]The resulting mother liquor (containing R-selenooctanoic acid and R-selenooctanoic acid-S-methylbenzylamine salt) was cooled and filtered, and acidified by adding citric acid (9.6g, dissolved in 20mL of water) dropwise. Water (60mL) was added, extracted, and the toluene layer was taken and washed three times with water (10 mL). Heating and refluxing the toluene solution at the reflux temperature of 112 ℃, refluxing for 20h, and concentrating the solvent. Recrystallizing with cyclohexane to obtain racemic selenooctanoic acid, 17.3g,
as can be seen from the above examples, the method of the present invention can recover and obtain racemic selenooctanoic acid, so that the raw materials are fully utilized, and the production cost is reduced.
Claims (10)
1. A method for chiral resolution of selenooctanoic acid is characterized by comprising the following specific steps:
the method comprises the following steps: dissolving selenooctanoic acid in a first solvent, heating to 25-80 ℃, dropwise adding chiral methylbenzylamine, wherein the molar ratio of selenooctanoic acid to chiral methylbenzylamine is 1: 0.5-0.8, chiral methylbenzylamine is R-methylbenzylamine or S-methylbenzylamine, separating out a tan solid, cooling, and performing suction filtration to obtain a salt of R-selenooctanoic acid and chiral methylbenzylamine or a salt of S-selenooctanoic acid and chiral methylbenzylamine;
step two: recrystallizing the salt with a second solvent for 1 to 5 times, and purifying;
step three: dissolving the obtained salt in an organic solvent, heating to 25-80 ℃, dropwise adding an acidic solution, stirring for 0.5-1 hour, adding water, extracting, taking an organic solvent layer, washing with water, drying with anhydrous magnesium sulfate, and spin-drying to obtain R-selenooctanoic acid or S-selenooctanoic acid;
or dissolving the obtained salt in an alkaline solution, washing with an organic solvent, dropwise adding an acidic solution to adjust the pH value to 1-2, precipitating a large amount of tan solid, performing suction filtration, and drying to obtain R-selenooctanoic acid or S-selenooctanoic acid.
2. The method according to claim 1, wherein in the first step, the first solvent is formed by mixing any one or two of acetonitrile, toluene, tetrahydrofuran and water according to any ratio, and the volume/mass ratio of the solvent to the selenooctanoic acid is 5-10 ml/g.
3. The method according to claim 1, wherein in the second step, the second solvent is toluene, acetonitrile or acetone, or a toluene/methanol mixed solvent, a toluene/ethanol mixed solvent, a toluene/isopropanol mixed solvent, a toluene/water mixed solvent, an acetonitrile/methanol mixed solvent, an acetonitrile/ethanol mixed solvent, an acetonitrile/isopropanol mixed solvent, an acetonitrile/water mixed solvent; in the mixed solvent, the volume ratio of the front and the back of the "/" is 1: 0.2-5.
4. The method according to claim 1, wherein in step three, the organic solvent is toluene, dichloromethane, chloroform or ethyl acetate; the volume-mass ratio of the organic solvent to the obtained salt is 5-10 ml/g.
5. The method according to claim 1, wherein in the third step, the acid of the acidic solution is hydrochloric acid, acetic acid, citric acid, oxalic acid or tartaric acid, and the molar ratio of the obtained salt to the acid is 1: 1-1.2; the solvent of the acidic solution is water, methanol or ethanol, and the volume mass ratio of the solvent to the acid is 1-5 ml/g.
6. The method according to claim 1, wherein in the third step, the alkali of the alkaline solution is sodium hydroxide or potassium hydroxide, and the molar ratio of the obtained salt to the alkali is 1: 1-1.2; the solvent of the alkaline solution is water, methanol or ethanol, and the volume mass ratio of the solvent to the alkali is 1-5 ml/g.
7. The method of claim 1, wherein in step one, the suction filtered mother liquor is used for recovering the selenooctanoic acid by the following method: acidifying the filtrate, washing with water, and collecting the organic layer; and heating the organic layer at normal pressure for reaction, concentrating the solvent, and recrystallizing to obtain the selenium caprylic acid.
8. The method according to claim 7, wherein the acidification is to adjust the pH of the filtrate to 1-3 with an acid selected from hydrochloric acid, acetic acid, sulfuric acid, citric acid, oxalic acid, tartaric acid.
9. The method according to claim 7, wherein the heating reaction temperature is 60 to 120 ℃ and the heating reaction time is 6 to 24 hours.
10. The process of claim 7, wherein the product after concentration of the solvent is recrystallized from cyclohexane.
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Citations (3)
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|---|---|---|---|---|
| CN102442994A (en) * | 2011-10-31 | 2012-05-09 | 江苏同禾药业有限公司 | Racemization method of S-lipoic acid and preparing method of R-lipoic acid |
| CN102993167A (en) * | 2012-11-07 | 2013-03-27 | 台州职业技术学院 | Preparation method of selenium caprylate |
| WO2013141417A1 (en) * | 2012-03-20 | 2013-09-26 | 에스지글로벌주조 주식회사 | Functional makgeolli with improved radioactive strontium discharge and antioxidant activity, containing selenium solution, and preparation method thereof |
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| CN102442994A (en) * | 2011-10-31 | 2012-05-09 | 江苏同禾药业有限公司 | Racemization method of S-lipoic acid and preparing method of R-lipoic acid |
| WO2013141417A1 (en) * | 2012-03-20 | 2013-09-26 | 에스지글로벌주조 주식회사 | Functional makgeolli with improved radioactive strontium discharge and antioxidant activity, containing selenium solution, and preparation method thereof |
| CN102993167A (en) * | 2012-11-07 | 2013-03-27 | 台州职业技术学院 | Preparation method of selenium caprylate |
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