EP3405452A1 - Method for preparing methionine analogues - Google Patents
Method for preparing methionine analoguesInfo
- Publication number
- EP3405452A1 EP3405452A1 EP17706536.4A EP17706536A EP3405452A1 EP 3405452 A1 EP3405452 A1 EP 3405452A1 EP 17706536 A EP17706536 A EP 17706536A EP 3405452 A1 EP3405452 A1 EP 3405452A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- alkyl group
- group
- alkyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 35
- 125000001360 methionine group Chemical class N[C@@H](CCSC)C(=O)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 56
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 125000002015 acyclic group Chemical group 0.000 claims abstract description 5
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 5
- 125000002252 acyl group Chemical group 0.000 claims abstract description 3
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 claims description 27
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 16
- 239000012429 reaction media Substances 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 229960004452 methionine Drugs 0.000 claims description 12
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 11
- 229930182817 methionine Natural products 0.000 claims description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- 229940107700 pyruvic acid Drugs 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- LRKYLKBLUJXTFL-UHFFFAOYSA-N 1-(piperidin-1-ylmethyl)piperidine Chemical compound C1CCCCN1CN1CCCCC1 LRKYLKBLUJXTFL-UHFFFAOYSA-N 0.000 claims description 4
- SXFSQZDSUWACKX-UHFFFAOYSA-N 4-methylthio-2-oxobutanoic acid Chemical compound CSCCC(=O)C(O)=O SXFSQZDSUWACKX-UHFFFAOYSA-N 0.000 claims description 4
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 4
- 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
- 229920002866 paraformaldehyde Polymers 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- WBGBLGWWFQCJAI-UHFFFAOYSA-N 1-(methylsulfanylmethyl)piperidine Chemical compound CSCN1CCCCC1 WBGBLGWWFQCJAI-UHFFFAOYSA-N 0.000 claims description 2
- UIPWANJHLKAGEO-UHFFFAOYSA-N 1-(methylsulfanylmethyl)pyrrolidine Chemical compound CSCN1CCCC1 UIPWANJHLKAGEO-UHFFFAOYSA-N 0.000 claims description 2
- KQISQNCCCASSDX-UHFFFAOYSA-N 1-(pyrrolidin-1-ylmethyl)pyrrolidine Chemical compound C1CCCN1CN1CCCC1 KQISQNCCCASSDX-UHFFFAOYSA-N 0.000 claims description 2
- PICCHNWCTUUCAQ-UHFFFAOYSA-N 2-hydroxypentanethioic s-acid Chemical compound CCCC(O)C(O)=S PICCHNWCTUUCAQ-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
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- 159000000003 magnesium salts Chemical class 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 239000013067 intermediate product Substances 0.000 abstract 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-O Piperidinium(1+) Chemical compound C1CC[NH2+]CC1 NQRYJNQNLNOLGT-UHFFFAOYSA-O 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- ONFOSYPQQXJWGS-UHFFFAOYSA-N 2-hydroxy-4-(methylthio)butanoic acid Chemical compound CSCCC(O)C(O)=O ONFOSYPQQXJWGS-UHFFFAOYSA-N 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229960004635 mesna Drugs 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- JCHJBEZBHANKGA-UHFFFAOYSA-N 1-methoxy-3,5-dimethylbenzene Chemical compound COC1=CC(C)=CC(C)=C1 JCHJBEZBHANKGA-UHFFFAOYSA-N 0.000 description 2
- 239000002028 Biomass Substances 0.000 description 2
- -1 KM B Chemical compound 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 235000019728 animal nutrition Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 150000003342 selenium Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- BOCQEKBKBUOBCR-UHFFFAOYSA-N 4-(2-methyliminohydrazinyl)benzoic acid Chemical compound CN=NNC1=CC=C(C(O)=O)C=C1 BOCQEKBKBUOBCR-UHFFFAOYSA-N 0.000 description 1
- DRGHCRKOWMAZAO-UHFFFAOYSA-N 4-(Methylthio)-2-butanone Chemical compound CSCCC(C)=O DRGHCRKOWMAZAO-UHFFFAOYSA-N 0.000 description 1
- ZJPZEDHXSNMXCE-UHFFFAOYSA-N CS.[Ca] Chemical compound CS.[Ca] ZJPZEDHXSNMXCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000002210 biocatalytic effect Effects 0.000 description 1
- 230000005587 bubbling Effects 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
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 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
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000000769 gas chromatography-flame ionisation detection Methods 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000004615 ingredient Substances 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
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 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
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
Definitions
- the present invention relates to a process for preparing analogs of methionine, as well as to the selenium derivatives of methionine analogs, from abundant and accessible compounds derived from biomass.
- Methionine and its analogs such as 2-hydroxy-4-methylthiobutanoic acid (HMTBA) and 2-oxo-4-methylthiobutane acid (KMB), as well as salts, chelates, especially metal chelates (from Zn, Ca, M n, Mg, Cu, Na ...) and esters of these acids, such as isopropyl and tert-butyl esters of H MTBA, are widely used in animal nutrition.
- the selenium derivatives of methionine and its hydroxyanalogues are also constituents of major interests in animal nutrition.
- this process makes it possible to prepare a compound or one of its salts, said compound corresponding to formula I,
- R 1 represents H or a C1-C6 alkyl group
- R 2 represents H, a C 1 -C 6 alkyl group, or an alkylaryl group
- R 3 is CH 2 SR 4 or CH 2 SeR 4 with R 4 is H or an alkyl group
- R 1 , R 2 and X are as defined above;
- R 5 represents H or COOR 6 with R 6 represents H or a C 1 -C 6 alkyl group.
- R 7 with R 7 represents H, a C 1 -C 6 alkyl group or an acyl group of formula CO-R 4 with R 4 as defined above; SR 4 or SeR 4 with R 4 as defined above; or NR 8 R 9 , with R 8 and R 9 , which may be identical or different, represent, each or together, a C 1 -C 6 alkyl group, or an alkylaryl group;
- Z which is the same or different from Y, represents OR 10 with R 10 represents H; a C 1 -C 6 alkyl group, or CO-R 4 with R 4 as defined above; a group N (COR 4 ) (COR 4 ), cyclic or acyclic, with R 4 as defined above; or a group NR 1: L R 12 , with R 11 and R 12 , which are identical or different, represent, each or together, a C 1 -C 6 alkyl group or an alkylaryl group;
- reaction of the compound (IV) with R 4 SH or one of its salts, or R 4 SeH or one of its salts, with R 4 according to the preceding definition, already present in the reaction medium or added during the process may lead to a compound having the structure (V) F ⁇ OOC-AMBKHF ⁇ -CHZZ (V)
- A represents OH; HN-R 'where R' is H or a C1-C6 alkyl group; or HN-OR "where R” is H, a C1-C6 alkyl group, or an alkylaryl group; and
- B represents SR 4 or SeR 4 with R 4 as defined above.
- alkyl denotes a monovalent hydrocarbon radical linear or branched having 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, such as methyl ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, ⁇ -hexyl or a monovalent cyclic hydrocarbon radical containing from 3 to 20 carbon atoms, advantageously from 3 to 6 carbon atoms, such as cyclopropyl, cyclohexyl.
- alkylaryl group is meant an aryl group comprising from 6 to 20 carbon atoms, said aryl group being substituted by at least one alkyl group as defined above.
- a first route preferably consists in reacting a compound (II) with formaldehyde or paraformaldehyde, in hydrated form or otherwise, in a basic medium and in the presence of MeSH or of one of its salts, such as sodium salts. , potassium or calcium methylmercaptan.
- a second route comprises reacting a compound (II) with a compound (III), said compound (III) being chosen from 1 - [(methylsulfanyl) methyl] - piperidine, 1 - [(methylsulfanyl) methyl] pyrrolidine and 1 - [(methylsulfanyl) methyl] diethylamine.
- This second route leads to an intermediate compound that can be isolated or not, which is an object of the present invention.
- This compound has the following formula (V):
- R 1 represents H or a C 1 -C 6 alkyl group
- R 2 represents H, a C 1 -C 6 alkyl group, or an alkylaryl group
- A represents OH; HN-R 'where R' is H or a C1-C6 alkyl group; or HN-OR “or R” represents H or a C1-C6 alkyl group or an alkylaryl group;
- B is SR 4 or SeR 4 with R 4 is H or C 1 -C 6 alkyl
- Z is OR with R is H; a C1-C6 alkyl group; a CO-R 4 group with R 4 represents H or a C 1 -C 6 alkyl group; a group N (COR 4 ) (COR 4 ), cyclic or acyclic, with R 4 as defined above; or NR 1: L R 12 , with R 11 and R 12 , identical or different, represent, each or together, a C 1 -C 6 alkyl group, or an alkylaryl group.
- the second route advantageously involves oxaloacetic acid or an ester thereof, that is to say a compound of formula (II) in which X represents 0, R 2 represents H and R 5 represents C0 2 R 6 with R 6 is H or C1-C6 alkyl, with a compound of formula (III) type CH 2 (Y) (Z) wherein Y and Z respectively represent the group SCH 3 and the group NR 1: L R 12 as defined above; preferably the NR 1 group : L R 12 represents the piperidinyl group.
- the invention therefore also relates to the compound of formula (V) in which A represents OH, B represents SCH 3 , R 2 represents H and Z represents the piperidinyl group.
- X is selected from 0; N-R 'where R' is H or a C1-C6 alkyl group; and N-OR "wherein R" represents H, a C1-C6 alkyl group, or an aryl group;
- R 1 represents H or a C1-C6 alkyl group
- R 2 represents H, a C 1 -C 6 alkyl group, or an alkylaryl group
- Z is NR 8 R 9 , with R 8 and R 9 , which are the same or different, each represent together or together a C 1 -C 6 alkyl group or an alkylaryl group.
- a compound of formula (III) in which Y and Z respectively represent the group NR 8 R 9 and the group NR 1: L R 12 as defined previously.
- at least one of NR 8 R 9 and NR 1: L R 12 but more preferably both, represent the same piperidinyl group.
- the invention relates to the intermediate compound of formula (IV) in which X represents O, R 2 represents H and Z represents the piperidinyl group, R 1 being as defined above, namely H when the compound (II) is oxaloacetic acid or a C1-C6 alkyl group when the compound (II) is the corresponding ester of oxaloacetic acid.
- the compound (II) is advantageously chosen from oxaloacetic acid and pyruvic acid.
- the process of the invention makes it possible to obtain different analogs of methionine.
- 2-oxo-4-methylthiobutanoic acid (KMB) or one of its salts, such as its calcium, magnesium, manganese, copper, zinc, sodium or ammonium salts and its corresponding selenium or one of its salts are products of the process of the invention under economically interesting conditions and yields.
- Another subject of the invention is a process of D, L-methionine, D- or L-methionine, D, L-2-hydroxy-4-methylthiobutanoic acid (HMTBA), or D- or L- -HMTBA, starting from 2-oxo-4-methylthiobutanoic acid (KMB), said process comprising the preparation of KMB according to the process of the invention as defined above and then converting the KMB thus obtained into methionine or HMTBA, chemically or biologically, by techniques known to those skilled in the art.
- HMTBA 2-oxo-4-methylthiobutanoic acid
- reaction medium is cooled to 10 ° C. and then the MeSH is added by bubbling into the reaction medium at 10 ° C. until the required amount (1 eq). The addition is completed in 4 hours then the set temperature is raised to 20 ° C. The reaction medium is stirred for 3h this temperature.
- a GC-FID control (column Equity-1) indicates that the conversion of piperidine is complete and the RRdose in species "thiomethyl activated" is 97%.
- reaction medium is withdrawn and then concentrated under reduced pressure (1mbar, 20 ° C., 6 h).
- KM B piperidinium is obtained as a yellow oil without further purification.
- Step 2 Condensation with pyruvic acid 0 2 C .piperidinium
- reaction medium is cooled to 20 ° C. and the solvent is then evaporated under reduced pressure (10 °, 20 ° C., 1 h) to give (IV) as a pale yellow oil (1.2 g).
- the MeSH gas is introduced in Iesel (via a syringe pump).
- the reaction medium is then heated to 60 ° C in 1 hour and then this temperature is maintained for 30 minutes.
- HPLC control indicates a complete transformation of the intermediate and the majority formation of KM B piperidinium.
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- Chemical & Material Sciences (AREA)
- 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
Description
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Application Number | Priority Date | Filing Date | Title |
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FR1650366A FR3046791B1 (en) | 2016-01-18 | 2016-01-18 | PROCESS FOR THE PREPARATION OF METHIONINE ANALOGS |
PCT/FR2017/050096 WO2017125673A1 (en) | 2016-01-18 | 2017-01-17 | Method for preparing methionine analogues |
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EP3405452A1 true EP3405452A1 (en) | 2018-11-28 |
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EP17706536.4A Withdrawn EP3405452A1 (en) | 2016-01-18 | 2017-01-17 | Method for preparing methionine analogues |
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US (1) | US20200283387A1 (en) |
EP (1) | EP3405452A1 (en) |
JP (1) | JP2019503380A (en) |
KR (1) | KR20180101481A (en) |
CN (1) | CN108779064A (en) |
AR (1) | AR107581A1 (en) |
BR (1) | BR112018014391A2 (en) |
FR (1) | FR3046791B1 (en) |
RU (1) | RU2736212C2 (en) |
SG (1) | SG11201806119VA (en) |
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WO (1) | WO2017125673A1 (en) |
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US5731299A (en) * | 1992-05-29 | 1998-03-24 | The Procter & Gamble Company | Phosphonosulfonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism |
CN101921203A (en) * | 2009-06-09 | 2010-12-22 | 长江大学 | N-phenoxy phenyl substituted alpha-amino acid, as well as derivatives and application thereof as weedicide |
JP2012067073A (en) * | 2010-08-27 | 2012-04-05 | Sumitomo Chemical Co Ltd | Process for preparing sulfur-containing 2-ketocarboxylate compound |
JP2013075885A (en) * | 2011-09-16 | 2013-04-25 | Sumitomo Chemical Co Ltd | Method for producing methionine |
TWI633089B (en) * | 2013-03-28 | 2018-08-21 | 拜耳製藥股份有限公司 | Substituted oxopyridine derivatives |
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2016
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2017
- 2017-01-17 US US16/070,762 patent/US20200283387A1/en not_active Abandoned
- 2017-01-17 RU RU2018126611A patent/RU2736212C2/en active
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- 2017-01-17 CN CN201780007108.5A patent/CN108779064A/en active Pending
- 2017-01-17 KR KR1020187022821A patent/KR20180101481A/en unknown
- 2017-01-17 EP EP17706536.4A patent/EP3405452A1/en not_active Withdrawn
- 2017-01-17 JP JP2018537471A patent/JP2019503380A/en not_active Ceased
- 2017-01-17 BR BR112018014391-0A patent/BR112018014391A2/en not_active IP Right Cessation
- 2017-01-17 SG SG11201806119VA patent/SG11201806119VA/en unknown
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FR3046791A1 (en) | 2017-07-21 |
RU2736212C2 (en) | 2020-11-12 |
SG11201806119VA (en) | 2018-08-30 |
RU2018126611A (en) | 2020-02-20 |
CN108779064A (en) | 2018-11-09 |
RU2018126611A3 (en) | 2020-02-28 |
WO2017125673A1 (en) | 2017-07-27 |
JP2019503380A (en) | 2019-02-07 |
TW201726613A (en) | 2017-08-01 |
KR20180101481A (en) | 2018-09-12 |
AR107581A1 (en) | 2018-05-16 |
BR112018014391A2 (en) | 2018-12-11 |
US20200283387A1 (en) | 2020-09-10 |
FR3046791B1 (en) | 2020-01-10 |
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