CN117586293B - Novel organic selenium boron reagent and application thereof in synthesis of L-selenium-methyl selenocysteine - Google Patents
Novel organic selenium boron reagent and application thereof in synthesis of L-selenium-methyl selenocysteine Download PDFInfo
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- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 56
- FXQVXDWQPZPZNA-UHFFFAOYSA-N selanylideneboron Chemical compound [Se]=[B] FXQVXDWQPZPZNA-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 230000015572 biosynthetic process Effects 0.000 title abstract description 7
- 238000003786 synthesis reaction Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 13
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 13
- 239000011669 selenium Substances 0.000 claims description 23
- 229910052711 selenium Inorganic materials 0.000 claims description 22
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- VLXBWPOEOIIREY-UHFFFAOYSA-N dimethyl diselenide Chemical group C[Se][Se]C VLXBWPOEOIIREY-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 150000003958 selenols Chemical class 0.000 claims description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 4
- VRDKYJSLDJDLML-UHFFFAOYSA-N methylselenol Chemical group [Se]C VRDKYJSLDJDLML-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- 239000000758 substrate Substances 0.000 abstract description 10
- 230000003287 optical effect Effects 0.000 abstract description 7
- 238000006467 substitution reaction Methods 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 3
- 230000000269 nucleophilic effect Effects 0.000 abstract description 2
- 229940091258 selenium supplement Drugs 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 8
- 238000003821 enantio-separation Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012039 electrophile Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- MCAHWIHFGHIESP-UHFFFAOYSA-L selenite(2-) Chemical compound [O-][Se]([O-])=O MCAHWIHFGHIESP-UHFFFAOYSA-L 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000002024 ethyl acetate extract Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- UXAKWALRESEHOR-GSVOUGTGSA-N N[C@H](C[Se]C)C(=[Se])O Chemical compound N[C@H](C[Se]C)C(=[Se])O UXAKWALRESEHOR-GSVOUGTGSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- XDSSPSLGNGIIHP-VKHMYHEASA-N Se-methyl-L-selenocysteine Chemical compound C[Se]C[C@H]([NH3+])C([O-])=O XDSSPSLGNGIIHP-VKHMYHEASA-N 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 229940082569 selenite Drugs 0.000 description 2
- -1 sodium trimethoxyborohydride Chemical group 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- UJDFUUWGCSFGOJ-QWWZWVQMSA-N (3S,6S)-3,6-bis(chloromethyl)piperazine-2,5-dione Chemical compound ClC[C@@H]1C(N[C@@H](C(N1)=O)CCl)=O UJDFUUWGCSFGOJ-QWWZWVQMSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 241000234282 Allium Species 0.000 description 1
- 235000002732 Allium cepa var. cepa Nutrition 0.000 description 1
- 240000002234 Allium sativum Species 0.000 description 1
- 235000011299 Brassica oleracea var botrytis Nutrition 0.000 description 1
- 235000017647 Brassica oleracea var italica Nutrition 0.000 description 1
- 240000003259 Brassica oleracea var. botrytis Species 0.000 description 1
- UQBOJOOOTLPNST-UHFFFAOYSA-N Dehydroalanine Chemical class NC(=C)C(O)=O UQBOJOOOTLPNST-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- ZKZBPNGNEQAJSX-REOHCLBHSA-N L-selenocysteine Chemical compound [SeH]C[C@H](N)C(O)=O ZKZBPNGNEQAJSX-REOHCLBHSA-N 0.000 description 1
- 229930182853 L-selenocysteine Natural products 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- PPXAQNPNOPCBRG-UHFFFAOYSA-M [Se](=O)(=O)(OC)[O-].[Na+] Chemical compound [Se](=O)(=O)(OC)[O-].[Na+] PPXAQNPNOPCBRG-UHFFFAOYSA-M 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000002929 anti-fatigue Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940107666 astragalus root Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- RNGFNLJMTFPHBS-UHFFFAOYSA-L dipotassium;selenite Chemical compound [K+].[K+].[O-][Se]([O-])=O RNGFNLJMTFPHBS-UHFFFAOYSA-L 0.000 description 1
- BVTBRVFYZUCAKH-UHFFFAOYSA-L disodium selenite Chemical compound [Na+].[Na+].[O-][Se]([O-])=O BVTBRVFYZUCAKH-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 235000004611 garlic Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 125000003357 methylseleno group Chemical group [H]C([H])([H])[Se][*] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000003405 preventing effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 235000011649 selenium Nutrition 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229960001471 sodium selenite Drugs 0.000 description 1
- 235000015921 sodium selenite Nutrition 0.000 description 1
- 239000011781 sodium selenite Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C391/00—Compounds containing selenium
-
- 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
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
- Y02E60/10—Energy storage using batteries
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel organic selenium boron reagent and application thereof in synthesis of L-selenium-methyl selenocysteine, wherein the chemical name of the organic selenium boron reagent is monomethoxy-dimethyl seleno-sodium borohydride, and the organic selenium boron reagent can be used as a nucleophilic chemical reagent in a selenizing substitution reaction, and particularly in synthesis of L-selenium-methyl selenocysteine; the organic selenium boron reagent has mild property, does not influence the optical activity of a reaction substrate, can obtain the product with the same configuration as the substrate to the maximum extent in the selenization substitution reaction, and has the reaction yield of 70%.
Description
Technical Field
The invention relates to the field of organic selenium chemistry, in particular to a novel organic selenium boron reagent and application thereof in synthesis of L-selenium-methyl selenocysteine.
Background
Selenium is a very important trace element in human body and is closely related to the health of people. Selenium-containing compounds have numerous biological activities such as antioxidant, antifatigue, immunological and preventing liver and stomach mucosal injury. Selenium obtained from daily diet is limited, the requirement of human body on selenium can not be met, the purpose of selenium supplement is realized by supplementing selenium nutrition enhancer, the common selenium nutrition enhancer is L-selenium methylselenocysteine, which is the methylation derivative of 21 st amino acid L-selenocysteine of human body, and is widely existed in plants such as astragalus root, garlic, onion and broccoli and selenium-enriched yeast, and the chemical structure of the selenium-enriched yeast is equivalent to that of thiol (-SH) or hydroxyl (-OH) of L-cysteine is replaced by methyl selenium group (CH 3 Se-) substitution.
For the synthesis of L-selenium-methylselenocysteine, a selenizing reagent is often used for introducing a methylseleno group, but in the current preparation process, a selenite (such as sodium selenite and potassium selenite) is used as the selenizing reagent.
Patent document CN101033208A discloses a method for preparing methylselenocysteine, which comprises the steps of carrying out addition reaction on methyl selenol or methyl selenolate aqueous solution and alpha-amino acrylic acid derivatives, carrying out alkaline hydrolysis, acidification, acidolysis and alkali neutralization to obtain DL-selenium-methylselenocysteine.
Patent document CN110683976a discloses a method for preparing (R) -selenomethylselenocysteine from L-serine as a starting material, which comprises the steps of firstly preparing (3 s,6 s) -3, 6-dichloromethyl-2, 5-diketopiperazine through esterification, cyclization and chlorination in sequence, preparing sodium methylselenate as a selenizing reagent, then carrying out nucleophilic substitution reaction, and finally hydrolyzing to generate (R) -selenomethylselenocysteine.
However, the physicochemical properties of the selenite salt used in the above prior art are very active and cannot exist stably; the current data and information about the chemical thermodynamics of the selenite salt are less, limiting its use; and there is no commercially available product of selenite in the market at present. Thus, it is necessary to find alternative novel selenizing agents. At present, no report on the use of sodium monomethoxy-dimethylseleno-borohydride as a selenizing reagent is known in the prior art, and the invention is specially proposed in view of the report.
Disclosure of Invention
The invention overcomes the defects existing in the prior art and provides an organic selenium boron reagent and a preparation method and application thereof.
In a first aspect, the present invention provides an organic selenium boron reagent having a structure as shown in formula i:
a formula I;
z is Na or K, preferably Na.
Further, the organic selenium boron reagent is monomethoxy-dimethyl seleno-sodium borohydride (Mono-methoxybis-methyl)lanylhydroborate sodium salt，NaBH(OMe)(SeCH 3 ) 2 ）；
In a second aspect, the present invention provides a method for preparing an organic selenium boron reagent according to the first aspect, the method comprising the steps of:
s1, mixing borohydride and selenol reagent, and reacting.
The mechanism of the reaction is as follows:
。
further, the molar ratio of borohydride to selenium reagent is 1: (1-3), preferably 1: (1-2).
In one embodiment of the invention, the molar ratio of borohydride to selenium agent is 1:1.5.
In one embodiment of the invention, the borohydride is sodium trimethoxyborohydride.
Further, the selenium reagent is methyl selenol.
Further, the preparation method also comprises the steps of mixing borohydride, selenol reagent and inert reagent for reaction;
the inert solvent comprises tetrahydrofuran, dioxane, toluene, dimethyl ether or ethylene glycol monomethyl ether.
In one embodiment of the invention, the inert solvent is tetrahydrofuran.
Further, the reaction temperature in the step S1 is 0 to 50 ℃ (e.g., 0 ℃,5 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃), preferably 0 to 10 ℃.
Further, the reaction time in the step S1 is 50-120 min (such as 50min, 60min, 70min, 80min, 90min, 100min, 110min, 120 min), preferably 60-100 min.
In one embodiment of the invention, the reaction time of step S1 is 60 minutes.
Further, the method also comprises S2 washing and/or filtering.
In a third aspect, the present invention provides another method for preparing an organic selenium boron reagent according to the first aspect, the method comprising the steps of:
S A mixing borohydride and selenium reagent with alcohol, and reacting.
The mechanism of the reaction is as follows:
。
further, the molar ratio of the borohydride, the alcohol and the selenium reagent is 1 (1-5): (0.5 to 1.5), preferably 1 (1 to 3): (0.5-1), more preferably 1 (1.2-2.8): (0.6-0.9).
In one embodiment of the invention, the molar ratio of borohydride, alcohol and selenium reagent is 1:2.7:0.8.
In one embodiment of the invention, the molar ratio of borohydride, alcohol and selenium reagent is 1:1.3:0.8.
Further, the borohydride includes sodium borohydride or potassium borohydride.
In one embodiment of the invention, the borohydride is sodium borohydride.
In one embodiment of the invention, the borohydride is potassium borohydride.
Further, the alcohol is methanol or ethanol or isopropanol or tertiary butanol.
In one embodiment of the invention, the alcohol is methanol.
Further, the selenium reagent is dimethyl diselenide.
Further, step S A The reaction temperature of (a) is 0 to 50 ℃ (e.g. 0 ℃,5 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃), preferably 0 to 10 ℃.
Further, step S A The reaction time is 0.5-6 hours, the reaction time is related to the scale of the reaction kettle, the reaction time is 0.5-1 hour when the reaction kettle is 1L, the reaction time is 3-6 hours when the reaction kettle is 5L, and the reaction time is 6-12 hours when the reaction kettle is 10L.
Further, the method also comprises a step S B Washing and/or filtering.
In a fourth aspect the present invention provides the use of an organic selenium boron reagent as described in the first aspect or an organic selenium boron reagent prepared by a method of preparation as described in the second or third aspect as a selenizing reagent.
Further, the use is to prepare L-selenium-methyl selenocysteine by adopting the organic selenium boron reagent in the first aspect or the organic selenium boron reagent prepared by the preparation method in the second or third aspect.
Further, the application is that the organic selenium boron reagent as the first aspect is used as a selenizing reagent to carry out nucleophilic substitution reaction with an electrophile (i.e. substrate) so as to realize the introduction of a selenium methyl group.
Further, the selenizing reagent has no effect on the optical activity of the electrophile (i.e., substrate).
Further, the configuration of the product of the nucleophilic substitution reaction corresponds to the configuration of the electrophile (i.e., substrate).
In one embodiment of the invention, the nucleophilic substitution reaction product is L-selenium-methylselenocysteine.
In one embodiment of the invention, the nucleophilic substitution reaction product is DL-selenium-methylselenocysteine.
Further, the reaction equation of the nucleophilic substitution reaction is as follows:
the first step:
；
and a second step of:
，
wherein RX is an electrophile (i.e., substrate), R is an amino acid residue or a derivative of an amino acid residue;
x is an electron withdrawing group such as halogen (e.g., -F, -Cl, -Br, -I), -OTs (p-toluenesulfonate group), preferably X is halogen.
In one embodiment of the invention, X is-Cl.
In one embodiment of the invention, X is-OTs.
Further, RX is selected from one of Ac-beta-chloro-L-Ala-OMe, ac-beta-chloro-DL-Ala-OMe and Ac-beta-OTs-L-Ala-OMe.
The beneficial effects of the invention include:
1. the sodium monomethoxy-dimethyl seleno-borohydride is a novel organic selenium boron reagent, can be used as a nucleophilic chemical reagent to be applied to a selenization substitution reaction, and is particularly suitable for being applied to synthesis of L-selenium-methyl selenocysteine;
2. the sodium monomethoxy-dimethyl seleno-borohydride provided by the invention has stable and mild properties, does not influence the optical activity of a reaction substrate, can maximally obtain a product with the same structure as the substrate in the selenization substitution reaction, and has a reaction yield of 70%.
Drawings
FIG. 1 is a L-selenium-methylselenocysteine standard control chromatogram (wherein A is a beta-SeMe-L-Ala standard chromatogram; and B is a beta-SeMe-DL-Ala standard chromatogram).
FIG. 2 is a chiral chromatogram of the L-selenium-methylselenocysteine product corresponding to examples 1-3 (wherein C is the chiral chromatogram of the L-selenium-methylselenocysteine product corresponding to example 1; D is the chiral chromatogram of the L-selenium-methylselenocysteine product corresponding to example 2; E is the chiral chromatogram of the L-selenium-methylselenocysteine product corresponding to example 3).
Detailed Description
In order that the technical content of the present invention may be more clearly understood, the following detailed description of the embodiments is given only for better understanding of the content of the present invention and is not intended to limit the scope of the present invention.
"Ac" in the present invention refers to acetyl;
"Chloro" in the present invention means chloro;
"Ala" in the present invention means alanine;
in the present invention, "OMe" refers to methoxy;
"OTs" in the present invention refers to p-toluenesulfonyl;
"SeMe" in the present invention refers to seleno;
the physicochemical properties of the organic selenium boron reagent of the invention of the monomethoxy-dimethyl seleno-sodium borohydride are as follows:
1 H NMR：3.39ppm，0.99ppm。 13 C NMR：47ppm，12ppm。
elemental analysis: 14.20% of C, 3.97% of H, 4.26% of B, 9.06% of Na, 6.30% of O and 62.21% of Se.
Mass spectrometry data: 232.9155 (anion meter).
Molecular formula C 3 H 10 BNaOSe 2 。
The molecular weight is 253.83.
The melting point is 110-112 ℃ (dec.) (lit.).
The boiling point is 110.1 ℃ [ at 101.325 Pa ].
The density was 1.36[ at 20 ℃ C.).
The vapor pressure was 0Pa at 25 ℃.
The storage condition is that the storage is carried out under inert gas atmosphere or at low temperature.
The form is solid.
The color is white.
The water solubility is a reaction with water.
Sensitivity is wet sensitivity and high temperature sensitivity.
The solubility is a strong polar solvent such as tetrahydrofuran, dioxane, toluene, etc., and the solubility is poor in ether solvents such as diethyl ether.
Example 1
A mixture of dimethyl diselenide (282 g, 1.5 mol) and 50% hypophosphorous acid (270 g, 1.8 mol) is placed in a flask, the temperature is slowly raised to 80 ℃ and nitrogen is slowly introduced, the mixture in the flask is reacted under stirring, the generated methanol gas is directly introduced below the liquid level of 2000 ml of tetrahydrofuran solution containing trimethoxysodium borohydride (128 g, 1.0 mol) through nitrogen carrier gas, the reaction is carried out for 60 minutes at the temperature of <10 ℃ after the introduction, white solid separated out by washing with water is filtered to obtain 255g of monomethoxy-dimethyl seleno-sodium borohydride, the yield is 67%, and the product is stored in a sealed manner without drying treatment.
255g of novel organic selenium boron methyl selenizing reagent monomethoxy-dimethyl seleno-sodium borohydride prepared in the steps is uniformly mixed with 2500mL of tetrahydrofuran, then 90g of Ac-beta-chloro-L-Ala-OMe is added, stirring is carried out for 12 hours at room temperature, the pH value is regulated to 1-4, 1000mL of ethyl acetate is added for extraction for 3 times, the ethyl acetate extract is respectively washed with 500mL of saturated saline water for 3 times, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure, so as to obtain 77g of pale yellow solid Ac-beta-SeMe-L-Ala-OMe, and the yield is 65%. Chiral ee (%) was analyzed by HPLC chiral chromatography as 98% L-configuration and 2% D-configuration.
77g of Ac-beta-SeMe-L-Ala-OMe pale yellow solid prepared by the steps is transferred to a rotary evaporation bottle of a rotary evaporator, 750mL of concentrated hydrochloric acid is added, 750mL of water is added, the temperature of a water bath kettle is set to 45 ℃, the water bath kettle is kept stand for more than 12 hours, then a vacuum pump is started, the acid solvent is removed by rotary evaporation, the solid product is decolorized by active carbon, the pH value is regulated to 6-7, ethanol is added for crystallization, and the product is filtered and dried, thus obtaining 45g of L-selenium-methylselenocysteine white solid (yield 76%). Melting point 165-166 ℃; optical rotation [ alpha ]] D 20 =-13.8 (c=10mg/mL, H 2 O)。
The L-configuration purity (HPLC chiral chromatography) was 98.2%.
The structure was analyzed by nuclear magnetic resonance hydrogen and carbon (NMR) spectroscopy and the results were as follows: 1 H-NMR (D 2 O) δ (ppm) 4.13 (t, 1H) , 3.07 (dd, 2H), 2.05 (s, 3H); 13 C-NMR (D 2 o) δ (ppm) 173.45, 54.56, 25.65, 6.03. The product is consistent with the standard reference substance.
Example 2
A mixture of dimethyl diselenide (282 g, 1.5 mol) and sodium borohydride (68 g, 1.8 mol) was placed in a flask, nitrogen was slowly introduced into the flask at a temperature of less than 10 ℃, 600 ml of methanol was slowly added dropwise to the flask while stirring the mixture in the flask, hydrogen was evolved by vigorous reaction, and after the hydrogen evolved, the white solid precipitated by water addition was filtered to obtain 258g of monomethoxy-dimethyl seleno-sodium borohydride, the yield was 68%, and the product was stored in a sealed condition without drying.
258g of novel organic selenium boron methyl selenizing reagent monomethoxy-dimethyl seleno-sodium borohydride prepared in the steps is uniformly mixed with 2500mL of tetrahydrofuran, 90g of Ac-beta-chloro-DL-Ala-OMe (D/L80/20) is added, stirring is carried out for 12 hours at room temperature, the pH value is regulated to 1-4 by concentrated hydrochloric acid, 1000mL of ethyl acetate is added for extraction for 3 times, the ethyl acetate extract is respectively washed by 500mL of saturated saline water for 3 times, dried by anhydrous sodium sulfate, and the ethyl acetate is evaporated under reduced pressure to obtain 83g of pale yellow solid Ac-beta-SeMe-DL-Ala-OMe, and the yield is 70%. Chiral ee (%) was analyzed by HPLC chiral chromatography as 82% D-configuration and 18% L-configuration.
83g Ac-beta-SeMe-DL-Ala-OMe pale yellow solid prepared in the above steps is transferred into a rotary evaporation bottle of a rotary evaporator, 1500mL 8M dilute hydrochloric acid is added, the temperature of a water bath kettle is set to be 95 ℃, the water bath kettle is kept for more than 3 hours, then a vacuum pump is started, an acid solvent is removed by rotary evaporation, the solid product is decolorized by active carbon, the pH value is regulated to 6-7, ethanol is added for crystallization, and the product is filtered and dried, thus obtaining 55g of L-selenium-methylselenocysteine white solid (yield 87%).
Melting point 165-166 ℃; optical rotation [ alpha ]] D 20 =+7.8 (c=10mg/mL, H 2 O)。
The L-configuration purity (HPLC chiral chromatography) was 18.2%, and the D-configuration purity (HPLC chiral chromatography) was 81.8%. The retention time of the nuclear magnetic spectrum and the liquid phase peak of the product is consistent with that of a standard reference substance.
Example 3
A mixture of dimethyl diselenide (282 g, 1.5 mol) and potassium borohydride (97 g, 1.8 mol) was placed in a flask, nitrogen was slowly introduced into the flask at a temperature of less than 10 ℃, 300 ml of methanol was slowly added dropwise to the vessel while stirring the mixture in the flask, after a vigorous reaction to release hydrogen, water was added to wash the separated white solid, and after filtration, 252g of monomethoxy-dimethyl seleno-potassium borohydride was obtained, the yield was 62%, and the product was stored in a sealed condition without drying.
252g of novel organic selenium boron methyl selenizing reagent monomethoxy-dimethyl seleno-potassium borohydride prepared in the steps are uniformly mixed with 2500mL of water, then 176g of Ac-beta-OTs-L-Ala-OMe is added, stirring is carried out for 12 hours at room temperature, the pH value is regulated to 1-4 by concentrated hydrochloric acid, 1000mL of ethyl acetate is added for extraction for 3 times, the ethyl acetate extract is respectively washed by 500mL of saturated saline water for 3 times, dried by anhydrous sodium sulfate, and the ethyl acetate is evaporated to dryness under reduced pressure, thus 65g of pale yellow solid Ac-beta-SeMe-L-Ala-OMe is obtained, and the yield is 49%. Chiral ee (%) was analyzed by HPLC chiral chromatography as 4% D-configuration and 96% L-configuration.
Transferring 65g of Ac-beta-SeMe-DL-Ala-OMe pale yellow solid prepared in the above steps into a rotary evaporation bottle of a rotary evaporator, adding 1200mL of 6M dilute hydrochloric acid, setting the temperature of a water bath kettle to be 85 ℃, standing for more than 5 hours, then starting a vacuum pump, performing rotary evaporation to remove an acid solvent, decoloring a solid product by using active carbon, adjusting the pH value to 6-7, adding ethanol for crystallization, filtering and drying to obtain 45g of L-selenium-methylselenocysteine white solid (yield 91%).
Melting point 166-167 ℃; optical rotation [ alpha ]] D 20 =-10.0 (c=10mg/mL, H 2 O)。
Chiral ee (%) was analyzed by HPLC chiral chromatography as 4% D-configuration and 96% L-configuration. The retention time of the nuclear magnetic spectrum and the liquid phase peak of the product is consistent with that of a standard reference substance.
The results of the nucleophilic substitution reaction of examples 1, 2 and 3 are summarized in Table 1.
TABLE 1 NaBH (OMe) (SeCH 3 ) 2 Nucleophilic substitution reaction with different substrates
The above results indicate that the selenizing reagent of the present invention, naBH (OMe) (SeCH 3 ) 2 Has better optical selectivity, has little influence on the configuration of the substrate, and can furthest retain the chiral configuration of the raw material.
Claims (5)
1. The organic selenium boron reagent is characterized in that the organic selenium boron reagent is monomethoxy-dimethyl seleno-sodium borohydride and has a structure shown in a formula I:
z is Na.
2. A method for preparing the organic selenium boron reagent of claim 1, wherein the method comprises the following steps:
s1, mixing borohydride and selenol reagent for reaction;
the borohydride is trimethoxy sodium borohydride;
the selenol reagent is methyl selenol;
the molar ratio of the borohydride to the selenol reagent is 1: (1-3);
the preparation method also comprises the step of adding an inert reagent;
the inert reagent is tetrahydrofuran, dioxane, toluene, dimethyl ether or ethylene glycol monomethyl ether.
3. A method for preparing the organic selenium boron reagent of claim 1, wherein the method comprises the following steps:
S A mixing borohydride and selenium reagent with alcohol, and reacting;
the borohydride is sodium borohydride;
the alcohol is methanol;
the selenium reagent is dimethyl diselenide;
the molar ratio of the borohydride to the alcohol to the selenium reagent is 1:1: (0.5-2).
4. A process according to claim 2 or 3, wherein the process further comprises the step of washing and/or filtering the reaction product;
the reaction temperature of the preparation method is 0-50 ℃.
5. Use of an organic selenium boron reagent according to claim 1 or prepared by a method according to any of claims 2-4 for the preparation of a selenizing reagent.
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