JP2019503380A - メチオニン類似体の製造方法 - Google Patents
メチオニン類似体の製造方法 Download PDFInfo
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- JP2019503380A JP2019503380A JP2018537471A JP2018537471A JP2019503380A JP 2019503380 A JP2019503380 A JP 2019503380A JP 2018537471 A JP2018537471 A JP 2018537471A JP 2018537471 A JP2018537471 A JP 2018537471A JP 2019503380 A JP2019503380 A JP 2019503380A
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 11
- 125000001360 methionine group Chemical class N[C@@H](CCSC)C(=O)* 0.000 title 1
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 63
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 61
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 22
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 38
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000007810 chemical reaction solvent 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 11
- 229960004452 methionine Drugs 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 7
- 229930182817 methionine Natural products 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 229940107700 pyruvic acid Drugs 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
- 125000002015 acyclic 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
- 239000011734 sodium Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229920002866 paraformaldehyde Polymers 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
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- MGJURKDLIJVDEO-UHFFFAOYSA-N formaldehyde;hydrate Chemical compound O.O=C MGJURKDLIJVDEO-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
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052799 carbon Inorganic materials 0.000 abstract description 2
- 239000007806 chemical reaction intermediate Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 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
- ONFOSYPQQXJWGS-UHFFFAOYSA-N 2-hydroxy-4-(methylthio)butanoic acid Chemical compound CSCCC(O)C(O)=O ONFOSYPQQXJWGS-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-O Piperidinium(1+) Chemical compound C1CC[NH2+]CC1 NQRYJNQNLNOLGT-UHFFFAOYSA-O 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-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
- 150000002148 esters Chemical class 0.000 description 4
- JCHJBEZBHANKGA-UHFFFAOYSA-N 1-methoxy-3,5-dimethylbenzene Chemical compound COC1=CC(C)=CC(C)=C1 JCHJBEZBHANKGA-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 150000002741 methionine derivatives Chemical class 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000003748 selenium group Chemical class *[Se]* 0.000 description 3
- 239000002028 Biomass Substances 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 2
- 235000019728 animal nutrition Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002955 isolation Methods 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
- 238000005259 measurement Methods 0.000 description 2
- 229960004635 mesna Drugs 0.000 description 2
- 229940076788 pyruvate Drugs 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-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
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 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
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000013626 chemical specie 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 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
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002483 hydrogen compounds Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 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
- 239000007788 liquid Substances 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- XHXXWWGGXFUMAJ-UHFFFAOYSA-N methanethiol;sodium Chemical compound [Na].SC XHXXWWGGXFUMAJ-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 230000006340 racemization Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 241000894007 species Species 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
- 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
- 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
-
- 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
- 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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- 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
<NaOH、HCHOおよびMeSNaの存在下で、第1ルートによるKMBの製造>
合成の全体的スキームは、以下である。
KMBの投入収率(Dosed yield in KMB)=75%
KMBの選択率(Selectivity in KMB)=75%
(実施例2)
<活性チオメチル誘導体およびオキサロ酢酸を用いた、第2のルートによるKMBの製造>
合成の全体的スキームは、以下である。
− 180mlのTHF
− 34.4gのパラホルムアルデヒド
− 活性チオメチル誘導体の単離された収率=95%
− 滴定量(titer)=94%(1H NMRと3,5−ジメチルアニソールによって分析された(dosed by NMR 1H vs 3,5−dimethylanisole))。
− KMBの投入収率=78%
− KMBの選択率=78%
− 滴定量(Titer)=60%(HPLCと標準で分析(dosed by HPLC vs standard))
(実施例3)
<活性チオメチル誘導体およびピルビン酸を用いた、第2のルートによるKMBの製造>
合成の全体的スキームは、以下である。
これについては、実施例2の第1工程に記載されている。
− KMBの投入収率=42%
− KMBの選択率=74%
(実施例4)
<メチレンジピペリジンの化学種を用いた一連の方法の第3のルートによるKMBの製造>
合成の全体的スキームは以下である。
− エタノール5mL
− 酢酸209mg
− 活性チオメチル誘導体のRR単離(RRisolated)=60%
− 滴定量=35%(1H NMRと3,5−ジメチルアニソールによる分析)
−第2工程:KMBピペリジニウムの合成−
− エタノール5mL
− KMBピペリジニウムのRR単離(RRisolated)=90%
− 滴定量=45%(HPLCと標準で分析(dosed by HPLC vs standard))
Claims (13)
- 化合物またはその塩を製造する方法であって、上記化合物は式(I)で表され、
R1OOC−C(=X)−CHR2R3 (I)
XはO、N−R’(R’はHまたは炭素数1〜6のアルキル基)、およびN−OR”(R”はH、炭素数1〜6のアルキル基、またはアルキルアリール基)から選択され、
R1はHまたは炭素数1〜6のアルキル基であり、
R2はH、炭素数1〜6のアルキル基、またはアルキルアリール基であり、
R3はCH2SR4またはCH2SeR4(R4はHまたは炭素数1〜6のアルキル基)であり、
上記化合物は式(II)で表される化合物またはその塩に由来するものであり、
R1OOC−C(=X)−CHR2R5 (II)
R1、R2、およびXは上記と同じ定義のものであり、
R5は、HまたはCOOR6(R6はHまたは炭素数1〜6のアルキル基)であり、
上記方法は、式(III)で表される化合物の存在下で行われ、
CH2(Y)(Z) (III)
YはH、OR7(R7はH、炭素数1〜6のアルキル基、またはCO−R4のアシル基であってR4が上記で定義したもの)、SR4もしくはSeR4(R4は上記で定義したもの)、またはNR8R9(R8とR9は同じであるかまたは相異なっており、それぞれまたはいずれも炭素数1〜6のアルキル基、またはアルキルアリール基)であり、
Zは、Yと同じであるかまたは異なっており、OR10(R10はH、炭素数1〜6のアルキル基、またはCO−R4のアシル基であってR4が上記で定義したもの)、環式もしくは非環式のN(COR4)(COR4)基(R4は上記で定義したもの)、またはNR11R12基(R11とR12は同じであるかまたは相異なっており、それぞれまたはいずれも炭素数1〜6のアルキル基、またはアルキルアリール基)であり、
或いは、YおよびZはいずれも=Oであり、
上記方法は、
式(II)の化合物が、式(III)の化合物と反応し、式(IV)の中間体となり、
R1OOC−C(=X)−CHR2−CH2Z (IV)
R1、R2、XおよびZは、上記で定義したものと同じであり、
そのようにして得られる式(IV)の化合物を、R4SHもしくはその塩、またはR4SeHもしくはその塩(R4は、上記で定義したもの)であって、反応溶媒中に既に存在しているものかまたは本方法を行っている最中に添加されるもの、と反応させ、
次いで、反応が完了したら、式(I)の化合物またはその塩を単離する、
ことを特徴とする方法。 - 請求項1に記載した方法であって、
式(IV)の化合物を、R4SHもしくはその塩またはR4SeHもしくはその塩(R4は、上記で定義したもの)であって、反応溶媒中に既に存在しているものかまたは本方法を行っている最中に添加されるものと、反応させることによって、式(V)の化合物を生成させ、
R1OOC−C(A)(B)−CHR2−CH2Z (V)
R1、R2およびZは上記で定義したものと同じであり、
AはOH、HN−R’(R’は、Hまたは炭素数1〜6のアルキル基)またはHN−OR”(R”は、H、炭素数1〜6のアルキル基、またはアルキルアリール基)であり、
BはSR4またはSeR4(R4は、上記で定義したもの)である
ことを特徴とする方法。 - 請求項1に記載した方法であって、
式(II)の化合物を、水和のまたは非水和のホルムアルデヒドまたはパラホルムアルデヒドと、塩基性溶媒中、MeSHまたはその塩の存在下で、反応させる
ことを特徴とする方法。 - 請求項1に記載した方法であって、
式(II)の化合物を、1−[(メチルスルファニル)メチル]−ピペリジン、1−[(メチルスルファニル)メチル]−ピロリジンおよび1−[(メチルスルファニル)メチル]−ジエチルアミンから選択される式(III)の化合物と反応させる
ことを特徴とする方法。 - 請求項1に記載した方法であって、
式(II)の化合物を、メチレンジピペリジン、メチレンジピロリジンおよびメチレンジ(ジエチルアミン)から選択される式(III)の化合物と反応させる
ことを特徴とする方法。 - 請求項1〜5のいずれか1項に記載した方法であって、
式(II)の化合物はオキサロ酢酸およびピルビン酸から選択される
ことを特徴とする方法。 - 請求項1〜6のいずれか1項に記載した方法であって、
上記方法に従って、2−オキソ−4−メチルチオブタン酸(KMB)またはその塩が製造され、
上記塩は、好ましくは、カルシウム、ナトリウム、アンモニウム、マンガン、銅、亜鉛およびマグネシウムの塩から選択される
ことを特徴とする方法。 - 以下の式(IV)の化合物であって、
R1OOC−C(=X)−CHR2−CH2Z (IV)
XはO、N−R’(R’はHまたは炭素数1〜6のアルキル基)、およびN−OR”(R”はH、炭素数1〜6のアルキル基、またはアリール基)から選択され、
R1はHまたは炭素数1〜6のアルキル基を表し、
R2はH、炭素数1〜6のアルキル基、またはアルキルアリール基を表し、
ZはOR10(R10はH、炭素数1〜6のアルキル基、CO−R4基(R4はHまたは炭素数1〜6のアルキル基))、環式もしくは非環式のN(COR4)(COR4)基(R4はHまたは炭素数1〜6のアルキル基)、またはNR11R12(R11とR12は同じであるかまたは相異なっており、それぞれまたはいずれも、炭素数1〜6のアルキル基、またはアルキルアリール基)である
ことを特徴とする化合物。 - 請求項8に記載した化合物であって、
XがOを表し、R2がHを表し、Zがピペリジニル基を表す
ことを特徴とする化合物。 - 以下の式(V)で表される化合物であって、
R1OOC−C(A)(B)−CHR2−CH2Z (V)
R1がHまたは炭素数1〜6のアルキル基を表し、
R2がH、炭素数1〜6のアルキル基、またはアルキルアリール基を表し、
AがOH、HN−R’(R’はHまたは炭素数1〜6のアルキル基)、またはHN−R”(R”はH、炭素数1〜6のアルキル基、またはアルキルアリール基)を表し、
BがSR4またはSeR4(R4はHまたは炭素数1〜6のアルキル基)を表し、
ZがOR10(R10はH、炭素数1〜6のアルキル基、CO−R4(R4はHまたは炭素数1〜6のアルキル基))、またはNR11R12(R11とR12は同じであるかまたは相異なっており、それぞれまたはいずれも炭素数1〜6のアルキル基、またはアルキルアリール基)である
ことを特徴とする化合物。 - 請求項10に記載した化合物であって、
AがOHを表し、BがSCH3を表し、R2がHを表し、Zがピペリジニル基
ことを特徴とする化合物。 - 請求項9に記載した式(IV)の化合物または請求項11に記載した式(V)の化合物であって、R1がHを表す
ことを特徴とする化合物。 - 2−オキソ−4−メチルチオブタン酸(KMB)からD,L−メチオニン、D−もしくはL−メチオニン、D,L−2−ヒドロキシ−4−メチルチオブタン酸(HMTBA)、またはD−もしくはL−HMTBAを製造する方法であって、
KMBを請求項1〜7のいずれか1項に記載した方法によって製造し、次いでKMBを、化学的または生物学的に、メチオニンまたはHMTBAへ変換する
ことを特徴とする方法。
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