CN108779064A - 制备蛋氨酸类似物的方法 - Google Patents
制备蛋氨酸类似物的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 125000001360 methionine group Chemical class N[C@@H](CCSC)C(=O)* 0.000 title 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 61
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 10
- 239000012429 reaction media Substances 0.000 claims description 15
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 14
- -1 dipyrromethene alkane Chemical class 0.000 claims description 14
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 claims description 14
- 229960004452 methionine Drugs 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 9
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 229930182817 methionine Natural products 0.000 claims description 7
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 7
- 150000003053 piperidines Chemical class 0.000 claims description 7
- 229940107700 pyruvic acid Drugs 0.000 claims description 7
- 125000005936 piperidyl group Chemical group 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 4
- FFEARJCKVFRZRR-UHFFFAOYSA-N methionine Chemical compound CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- UIPWANJHLKAGEO-UHFFFAOYSA-N 1-(methylsulfanylmethyl)pyrrolidine Chemical class CSCN1CCCC1 UIPWANJHLKAGEO-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229930195722 L-methionine Natural products 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- UZBQIPPOMKBLAS-UHFFFAOYSA-N diethylazanide Chemical compound CC[N-]CC UZBQIPPOMKBLAS-UHFFFAOYSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 2
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- MGJURKDLIJVDEO-UHFFFAOYSA-N formaldehyde;hydrate Chemical compound O.O=C MGJURKDLIJVDEO-UHFFFAOYSA-N 0.000 claims 1
- 159000000003 magnesium salts Chemical class 0.000 claims 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 1
- 230000004913 activation Effects 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002741 methionine derivatives Chemical class 0.000 description 3
- 150000003342 selenium Chemical class 0.000 description 3
- JCHJBEZBHANKGA-UHFFFAOYSA-N 1-methoxy-3,5-dimethylbenzene Chemical class COC1=CC(C)=CC(C)=C1 JCHJBEZBHANKGA-UHFFFAOYSA-N 0.000 description 2
- 239000002028 Biomass Substances 0.000 description 2
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229960004635 mesna Drugs 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 150000004719 oxaloacetic acids Chemical class 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- WBGBLGWWFQCJAI-UHFFFAOYSA-N 1-(methylsulfanylmethyl)piperidine Chemical class CSCN1CCCCC1 WBGBLGWWFQCJAI-UHFFFAOYSA-N 0.000 description 1
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- HDGAOLFVXXYZQD-UHFFFAOYSA-N [S].CCCC(O)=O Chemical compound [S].CCCC(O)=O HDGAOLFVXXYZQD-UHFFFAOYSA-N 0.000 description 1
- 235000019728 animal nutrition Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000000769 gas chromatography-flame ionisation detection Methods 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XHXXWWGGXFUMAJ-UHFFFAOYSA-N methanethiol;sodium Chemical compound [Na].SC XHXXWWGGXFUMAJ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
- C07C321/02—Thiols having mercapto groups bound to acyclic carbon atoms
- C07C321/04—Thiols having mercapto groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/185—Saturated compounds having only one carboxyl group and containing keto groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- 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
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/04—Sodium compounds
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及一种由式(II)的化合物或者其盐来制备式(I)的化合物或者其盐的方法,和所述方法的应用,所述的化合物的式(I)为:R1OOC‑C(=X)‑CHR2R3(I),其中X选自O;N‑R’,其中R’表示H或者C1‑C6烷基;和N‑OR”,其中R”表示H,C1‑C6烷基,或者烷基芳基;R1表示H或者C1‑C6烷基;R2表示H,C1‑C6烷基或者烷基芳基;和R3表示CH2SR4或者CH2SeR4,并且R4表示H或者C1‑C6烷基;其中式(II)的化合物为:R1OOC‑C(=X)‑CHR2R5(II)和R5表示H或者COOR6,并且R6表示H或者C1‑C6烷基,所述的方法是在式(III)的化合物存在下进行的:CH2(Y)(Z)。其中Y表示H;OR7,并且R7表示H、C1‑C6烷基或者式CO‑R4的酰基;SR4或者SeR4,并且R4满足前述定义;或者NR8R9,并且R8和R9相同或者不同,其每个或者一起表示C1‑C6烷基,或者烷基芳基;Z与Y相同或不同,表示OR10,并且R10表示H、C1‑C6烷基,或者CO‑R4;成环或者成环的N(COR4)(COR4)基团;或者NR11R12,并且R11和R12相同或者不同,每个或者一起表示C1‑C6烷基,或者烷基芳基;其中Y和Z一起表示=O;所述的方法包括中间体(IV)R1OOC‑C(=X)‑CHR2‑CH2Z。
Description
本发明涉及一种由来源于生物质的丰富的和可利用的化合物,来制备蛋氨酸类似物以及蛋氨酸类似物的硒衍生物的方法。
蛋氨酸及其类似物例如2-羟基-4-甲基硫丁酸(HMTBA)和2-氧杂-4-甲基硫丁酸(KMB),以及这些酸的盐,螯合物,特别是金属螯合物(Zn,CaMn,Mg,Cu,Na…)和酯,例如HMTBA的异丙酯和叔丁酯,被广泛用于动物营养。蛋氨酸及其羟基类似物的硒衍生物也是动物营养学中主要关注的成分。
依照这些成分目前世界范围消耗的持续增长体量,必需开发以可再生的、能量有效和非污染源作为原料的制造方法。
作者因此开发了一种由有机酸,其盐或者衍生物制备这些化合物的方法,其可以获自生物质,特别是通过生物转化例如发酵方法获得。
根据本发明,这种方法允许一种由式(II)的化合物或者其盐来制备式(I)的化合物或者其盐,所述的化合物的式(I)为:
R1OOC-C(=X)-CHR2R3 (I)
其中X选自O;N-R’,其中R’表示H或者C1-C6烷基;和N-OR”,其中R”表示H、C1-C6烷基或者烷基芳基;
R1表示H或者C1-C6烷基;
R2表示H、C1-C6烷基或者烷基芳基;和
R3表示CH2SR4或者CH2SeR4,并且R4表示H或者C1-C6烷基;
其中式(II)的化合物为:
R1OOC-C(=X)-CH2R2R5 (II)
其中R1、R2和X具有上述定义;和
R5表示H或者COOR6,并且R6表示H或者C1-C6烷基,
这种方法允许由酸例如草酰乙酸和丙酮酸以对于工业开发来说关注的产率来制造蛋氨酸类似物例如KMB,而不释放过量的副产物,并且包括了适度的反应条件和可利用的试剂。此外,这些化合物具体构成了蛋氨酸处于它的不同酸形式D,L;D和L和HMTBA处于它的不同的对映体形式D,L;D和L的关注的前体。它们可以通过简单的还原来真正转化成所述的蛋氨酸或者所述的HMTBA,例如使用NaBH4类型的氢化物,或者使用催化或者生物催化氢化,或者通过外消旋或者对映选择性生化转化,或者通过本领域技术人员已知的任何其他方法来进行。
更具体地,本发明的方法是在式(III)的化合物存在下进行的:
CH2(Y)(Z) (III)
其中Y表示H;OR7,并且R7表示H、C1-C6烷基或者式CO-R4的酰基,并且R4满足前述定义;SR4或者SeR4并且R4满足前述定义;或者NR8R9,并且R8和R9相同或者不同,其每个或者一起表示C1-C6烷基,或者烷基芳基;
Z与Y相同或不同,表示OR10,并且R10表示H、C1-C6烷基,或者CO-R4,并且R4满足前述定义;成环或者成环的N(COR4)(COR4)基团,并且R4满足前述定义;或者NR11R12,并且R11和R12相同或者不同,每个或者一起表示C1-C6烷基,或者烷基芳基;
或者Y和Z一起表示=O;
并且所述的方法包含下面的步骤:
化合物(II)与化合物(III)反应来产生具有结构(IV)的中间体:
R1OOC-C(=X)-CHR2-CH2Z (IV)
其中R1、R2、X和Z具有上述定义,
因此获得的化合物(IV)与已经存在于反应介质中或者已经在所述方法过程中加入的R4SH或者其盐,或者R4SeH或者其盐反应,并且R4满足前述定义,
然后,通过完成所述反应,分离化合物(I)或者其盐。
如下文将描述的,根据所述方法的一个变体,化合物(IV)与已经存在于反应介质中或者已经在所述方法过程中加入的R4SH或者其盐,或者R4SeH或者其盐反应产生了具有结构(V)的化合物,并且R4满足前述定义,
R1OOC-C(A)(B)-CHR2-CH2Z (V)
其中R1、R2和Z具有上述定义
A表示OH;HN-R’,其中R’表示H、C1-C6烷基,或者HN-OR”,其中R”表示H、C1-C6烷基、或者烷基芳基;和
B表示SR4或者SeR4,并且R4满足前述定义。
在更详细地呈现本发明之前,上下文所用的一些术语规定如下。
在定义所获得或者所包括的化合物和试剂的式中,术语《烷基》表示具有1-20个碳原子的线性或者支化的单价烃基,有利地1-6个碳原子,例如甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基,新戊基,正己基,或者具有3-20个碳原子的成环单价烃基,有利地3-6个碳原子,例如环丙基,环己基。
烷基芳基表示包含6-20个碳原子的芳基,所述的芳基是通过满足上述定义的至少一个烷基取代的。
本发明在下文详述,并且显示它的有利变体。
上面公开的方法可以根据几个方案来执行。
第一路线优选组成为化合物(II)与处于水合或者非水合形式的甲醛或者多聚甲醛在碱性介质和在MeSH或者其盐存在下反应,例如甲基硫醇的钠,钾或者钙盐。
第二路线包括化合物(II)与化合物(III)反应,所述的化合物(III)选自1-[(甲基硫烷基)甲基]-哌啶,1-[(甲基硫烷基)甲基]-吡咯烷和1-[(甲基硫烷基)甲基]-二乙基胺。这种第二路线导致了中间体化合物,其可以是分离的或者不是分离的,其是本发明的目标。这种化合物满足下式(V):
R1OOC-C(A)(B)-CHR2-CH2Z (V)
其中R1表示H或者C1-C6烷基;
R2表示H,C1-C6烷基或者烷基芳基;
A表示OH,HN-R’,其中R’表示H或者C1-C6烷基,或者HN-OR”,其中R”表示H或者C1-C6烷基或者烷基芳基;
B表示SR4或者SeR4,并且R4表示H或者C1-C6烷基;
Z表示OR10,并且R10表示H;C1-C6烷基;CO-R4,并且R4表示H或者C1-C6烷基,成环或者成环的N(COR4)(COR4)基团,并且R4满足前述定义;或者NR11R12,并且R11和R12相同或者不同,每个或者一起表示C1-C6烷基,或者烷基芳基。
第二路线有利地是将草酰乙酸或者其酯,也就是说式(II)的化合物,其中X表示O,R2表示H和R5表示CO2R6,并且R6表示H或者C1-C6烷基,与类型CH2(Y)(Z)的式(III)化合物接触,其中Y和Z分别表示前述定义的基团SCH3和基团NR11R12;优选基团NR11R12表示哌啶基。所以,本发明还涉及式(V)的化合物,其中A表示OH,B表示SCH3,R2表示H和Z表示哌啶基。
根据第三路线,化合物(II)可能与选自下面的化合物(III)反应:亚甲基二哌啶,亚甲基二吡咯烷和亚甲基二(二乙基胺)。这种第三路线的中间体化合物(其可以是分离或者未分离的)也是本发明的目标。它满足下式(IV):
R1OOC-C(=X)-CHR2-CH2Z (IV)
其中X选自O;N-R’,其中R’表示H或者C1-C6烷基;和N-OR”,其中R”表示H、C1-C6烷基或者芳基,
R1表示H或者C1-C6烷基;
R2表示H、C1-C6烷基或者烷基芳基;和
Z表示NR8R9,并且R8和R9相同或者不同,每个或者一起表示C1-C6烷基,或者烷基芳基;
如实施例将显示的,第三路线有利地将草酰乙酸或者其酯,也就是说式(II)的化合物,其中X表示O,R2表示H和R5表示CO2R6,并且R6=H,与式(III)化合物接触,其中Y和Z分别表示前述定义的基团NR8R9和基团NR11R12。优选NR8R9和NR11R12中的至少一种,但是甚至更好是二者,表示相同的哌啶基。因此,本发明涉及式(IV)的中间体化合物,其中X表示O,R2表示H和Z表示哌啶基,R1是前述定义的,即当化合物(II)是草酰乙酸时为H,或者当化合物(II)是草酰乙酸相应的酯时是C1-C6烷基。
不管所保持的路线如何,化合物(II)有利地选自草酰乙酸和丙酮酸。
如前所述,本发明的方法允许获得不同的蛋氨酸类似物。具体地,2-氧杂-4-甲基硫丁酸(KMB)或者其盐,例如其钙,镁,锰,铜,锌,钠或者鎓盐及其硒类似物或者其盐是本发明的方法在有经济吸引力条件和产率下的产物。
本发明的另一目标是一种由2-氧杂-4-甲基硫丁酸(KMB)制造D,L-蛋氨酸,D-或者L-蛋氨酸,D,L-2-羟基-4-甲基硫丁酸(HMTBA),D-或者L-HMTBA的方法,所述方法包含根据前述定义的本发明的方法制备KMB,然后将因此获得的KMB通过本领域技术人员已知的技术来化学或者生物转化成蛋氨酸或者HMTBA。
本发明通过下面的实施例来更详细地描述,其显示了根据不同的合成路线(全部落入本发明范围内),由草酰乙酸和丙酮酸来合成KMB。
实施例1:通过第一路线,在NaOH,HCHO和MeSNa存在下制备KMB
该合成的一般方案如下:
在反应器中放置100mg草酰乙酸,并且加入NaOH 1M溶液(2当量)。将该反应器置于30℃,并且草酰乙酸立即溶解。2分钟后加入37%w/w甲醛溶液(1当量)。该搅拌在30℃保持2分钟,然后一次性加入MeSNa(2当量,108mg),并且将该反应介质在30℃搅拌。
在接触10分钟后,通过HPLC-UV(C18Hydro-RP柱)监控反应,然后每20分钟监控。最佳性能是在30℃接触30分钟后测量的,具有下面的结果:
■转化率草酰乙酸=100%
■在KMB中的剂量产率=75%
■在KMB中的选择性=75%
实施例2:通过第二路线,使用活化的硫代甲基衍生物和草酰乙酸来制备KMB
该合成的一般方案如下:
第1步骤:合成活化的硫代甲基衍生物[化合物(III)]
在1L反应器中在氩气下,在搅拌下在20℃连续引入:
-90.0g哌啶
-180ml的THF
-34.4g多聚甲醛
将该反应介质冷却到10℃,然后通过鼓泡到10℃的反应介质中来加入MeSH,直到所需量(1当量)。该添加在4小时完成,然后将设定温度升高到20℃。将该反应介质在这个温度搅拌3h。GC-FID对照(Equity-1柱)显示哌啶完全转化,并且“活化的硫代甲基”物质中RR剂量是97%。
将180ml的甲基叔丁基醚(MTBE),然后是180ml的NaCl饱和水溶液加入该反应介质中,将这两相搅拌5min,然后分离。将有机相用180ml的NaCl饱和水溶液清洗两次,然后在Na2SO4上干燥和减压(10mbar,30℃)下浓缩。该“活化的硫代甲基”衍生物是以无色液体形式获得的,没有另外净化(150.4g)。获得了下面的性能:
■哌啶完全转化
■活化的硫代甲基衍生物的分离的产率=95%
■浓度测定=94%(通过NMR1H相对于3,5-二甲基苯甲醚的剂量)
第2步骤:合成KMB哌啶
在具有调温控制浴的100mL反应器中在氩气下,引入3g(1当量)的草酰乙酸和30ml的乙醇。在20℃溶解(大约1分钟)后,然后加入活化的硫代甲基衍生物(1当量),将该介质在30分钟中加热高到60℃,然后保温1h。
在接触10分钟后,通过HPLC-UV(C18Hydro-RP柱)监控反应,然后每20分钟监控。最佳性能是在60℃接触1小时后测量的:
■草酰乙酸完全转化
■在KMB中的剂量产率=78%
■在KMB中的选择性=78%
将该反应介质抽出,然后减压(10mbar,20℃,6h)下浓缩。获得了黄色油形式的KMB哌啶,没有另外的净化。
■在KMB哌啶中的分离的产率=60%
■浓度测定=60%(通过HPLC相对于标准物的剂量)
实施例3:通过第二路线,使用活化的硫代甲基衍生物和丙酮酸制备KMB
该合成的一般方案如下:
第1步骤:合成活化的硫代甲基衍生物
它是实施例2的第1步所述。
第2步骤:用丙酮酸缩合
在小瓶中引入300mg(1当量)的丙酮酸和3mL乙醇。在20℃溶解后,加入活化的硫代甲基衍生物(TMA)(1当量),然后将该小瓶置于事先加热到60℃的平板中。将反应介质在这个温度搅拌1小时。
在接触15分钟后,通过HPLC-UV(C18Hydro-RP柱)监控反应,然后每15分钟监控。最佳性能是在60℃接触15min后测量的:
●丙酮酸的转化率=57%
●在KMB中的剂量产率=42%
●在KMB中的选择性=74%
实施例4:通过第三路线以顺序方式经由亚甲基二哌啶物质来制备KMB
该合成的一般方案如下:
第1步骤:合成中间体(IV)
在装备有温度探针的10mL反应器中在氩气下,在0℃连续引入。
-500mg的草酰乙酸
-5mL的EtOH
-209mg乙酸
在所述酸溶解后(搅拌大约5分钟),在50分钟内经由注射器泵加入二哌啶并甲烷(0.95当量)。添加结束后,将该介质在1小时内加热到60℃,然后在这个温度搅拌10分钟。通过HPLC-MS(ESI+)对照证实形成了中间体IV。
将该反应介质冷却到20℃,然后将溶剂减压下蒸发(10mbar,20℃,1h)来产生淡黄色油形式的(IV)(1.2g)。
■完全TT草酰乙酸
■活化的硫代甲基衍生物的RR分离=60%
■滴定浓度=35%(通过NMR1H相对于3,5-二甲基苯甲醚的剂量)
第2步骤:合成KMB哌啶
在装备有温度探针的10mL反应器中在氩气下,在0℃搅拌下连续引入:
-300mg中间体(IV)
-5mL的EtOH
一旦反应介质处于低于5℃的温度,则将MeSH气体在1小时内引入(经由注射器泵)。该反应介质然后在1小时内加热到60℃,然后将这个温度保持30分钟。
HPLC对照显示中间体完全转化,并且主要形成了KMB哌啶。
抽出该反应介质,然后减压(10mbar,20℃,1h)下浓缩。获得了黄色油形式的KMB哌啶,没有另外净化(260mg)
■完全TT中间体IV
■KMB哌啶的RR分离=90%
■浓度测定=45%(通过HPLC相对于标准物的剂量。
Claims (13)
1.一种由式(II)的化合物或者其盐来制备式(I)的化合物或者其盐的方法,所述的化合物的式(I)为:
R1OOC-C(=X)-CHR2R3 (I)
其中X选自O;N-R’,其中R’表示H或者C1-C6烷基;和N-OR”,其中R”表示H,C1-C6烷基,或者烷基芳基;
R1表示H或者C1-C6烷基;
R2表示H,C1-C6烷基或者烷基芳基;和
R3表示CH2SR4或者CH2SeR4,并且R4表示H或者C1-C6烷基;
其中式(II)的化合物为:
R1OOC-C(=X)-CHR2R5 (II)
其中R1、R2和X具有上述定义;和
R5表示H或者COOR6,并且R6表示H或者C1-C6烷基,
所述的方法是在式(III)的化合物存在下进行的:
CH2(Y)(Z) (III)
其中Y表示H;OR7,并且R7表示H、C1-C6烷基或者式CO-R4的酰基,并且R4满足前述定义;SR4或者SeR4并且R4满足前述定义;或者NR8R9,并且R8和R9相同或者不同,其每个或者一起表示C1-C6烷基,或者烷基芳基;
Z与Y相同或不同,表示OR10,并且R10表示H、C1-C6烷基,或者CO-R4,并且R4满足前述定义;成环或者成环的N(COR4)(COR4)基团,并且R4满足前述定义;或者NR11R12,并且R11和R12相同或者不同,每个或者一起表示C1-C6烷基,或者烷基芳基;
或者Y和Z一起表示=O;
所述的方法特征在于:
化合物(II)与化合物(III)反应来产生具有结构(IV)的中间体:
R1OOC-C(=X)-CHR2-CH2Z (IV)
其中R1、R2、X和Z具有上述定义,
因此获得的化合物(IV)与已经存在于反应介质中或者已经在所述方法过程中加入的R4SH或者其盐,或者R4SeH或者其盐反应,并且R4满足前述定义,
然后,通过完成所述反应,分离化合物(I)或者其盐。
2.根据权利要求1的方法,特征在于化合物(IV)与已经存在于反应介质中或者已经在所述方法过程中加入的R4SH或者其盐,或者R4SeH或者其盐反应产生了具有结构(V)的化合物,并且R4满足前述定义,
R1OOC-C(A)(B)-CHR2-CH2Z (V)
其中R1、R2和Z具有上述定义
A表示OH、HN-R’,其中R’表示H、C1-C6烷基,或者HN-OR”,其中R”表示H,C1-C6烷基,或者烷基芳基;和
B表示SR4或者SeR4,并且R4满足前述定义。
3.根据权利要求1的方法,特征在于化合物(II)是与水合或者非水合甲醛或者多聚甲醛在碱性介质中和在MeSH或者其盐存在下反应的。
4.根据权利要求1的方法,特征在于式(II)的化合物是与选自下面的化合物(III)反应的:1-[(甲基硫烷基)甲基]-哌啶、1-[(甲基硫烷基)甲基]-吡咯烷和1-[(甲基硫烷基)甲基]-二乙基胺。
5.根据权利要求1的方法,特征在于式(II)的化合物是与选自下面的化合物(III)反应的:亚甲基二哌啶、亚甲基二吡咯烷和亚甲基二(二乙基胺)。
6.根据前述任一项权利要求的方法,特征在于化合物(II)选自草酰乙酸和丙酮酸。
7.根据前述任一项权利要求的方法,特征在于按照所述方法,获得了2-氧杂-4-甲基硫丁酸(KMB)或者其盐,优选是选自其的钙、钠、铵、锰、铜、锌和镁盐。
8.一种下式(IV)的化合物,
R1OOC-C(=X)-CHR2-CH2Z (IV)
其中X选自O;N-R’,其中R’表示H或者C1-C6烷基;和N-OR”,其中R”表示H,C1-C6烷基,或者芳基,
R1表示H或者C1-C6烷基;
R2表示H、C1-C6烷基或者烷基芳基;和
Z表示OR10,并且R10表示H;C1-C6烷基或者CO-R4,并且R4表示H或者C1-C6烷基,成环或者成环的N(COR4)(COR4)基团,并且R4表示H或者C1-C6烷基;或者NR11R12,并且R11和R12相同或者不同,每个或者一起表示C1-C6烷基,或者烷基芳基。
9.根据权利要求8的化合物,特征在于X表示O,R2表示H和Z表示哌啶基。
10.下式(V)的化合物:
R1OOC-C(A)(B)-CHR2-CH2Z (V)
其中R1表示H或者C1-C6烷基;
R2表示H、C1-C6烷基或者烷基芳基;
A表示OH;HN-R’,其中R’表示H或者C1-C6烷基;或者HN-OR”,其中R”表示H,C1-C6烷基,或者烷基芳基;
B表示SR4或者SeR4,并且R4表示H或者C1-C6烷基;和
Z表示OR10,并且R10表示H或者C1-C6烷基,或者COR4,并且R4表示H或者C1-C6烷基;或者NR11R12,并且R11和R12相同或者不同,每个或者一起表示C1-C6烷基,或者烷基芳基。
11.根据权利要求10的化合物,特征在于A表示OH,B表示SCH3,R2表示H和Z表示哌啶基。
12.根据权利要求9的式(IV)的化合物或者根据权利要求11的式(V)的化合物,其中R1表示H。
13.一种由2-氧杂-4-甲基硫丁酸(KMB)制造D,L-蛋氨酸,D-或者L-蛋氨酸,D,L-2-羟基-4-甲基硫丁酸(HMTBA),D-或者L-HMTBA的方法,特征在于KMB是根据权利要求1-7任一项所定义的方法制备的,然后KMB是化学或者生物转化成蛋氨酸或者HMTBA。
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PCT/FR2017/050096 WO2017125673A1 (fr) | 2016-01-18 | 2017-01-17 | Procédé de préparation d'analogues de la méthionine |
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JP2012067073A (ja) * | 2010-08-27 | 2012-04-05 | Sumitomo Chemical Co Ltd | 含硫黄2−ケトカルボン酸化合物の製造方法 |
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US20200283387A1 (en) | 2020-09-10 |
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BR112018014391A2 (pt) | 2018-12-11 |
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