CN1038033C - Process for producing methanediphosphonate compound - Google Patents
Process for producing methanediphosphonate compound Download PDFInfo
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- CN1038033C CN1038033C CN94190078A CN94190078A CN1038033C CN 1038033 C CN1038033 C CN 1038033C CN 94190078 A CN94190078 A CN 94190078A CN 94190078 A CN94190078 A CN 94190078A CN 1038033 C CN1038033 C CN 1038033C
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- Prior art keywords
- compound
- phosphonic acid
- methyl
- ethylhexyl phosphonic
- reaction
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 25
- -1 methanediphosphonate compound Chemical class 0.000 title claims description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 229910044991 metal oxide Inorganic materials 0.000 claims abstract description 14
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- JJJOZVFVARQUJV-UHFFFAOYSA-N 2-ethylhexylphosphonic acid Chemical compound CCCCC(CC)CP(O)(O)=O JJJOZVFVARQUJV-UHFFFAOYSA-N 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 150000004706 metal oxides Chemical class 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 239000005864 Sulphur Substances 0.000 claims description 7
- 150000002500 ions Chemical class 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 150000001768 cations Chemical class 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 14
- 239000000395 magnesium oxide Substances 0.000 description 9
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 9
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 9
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 6
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 238000006482 condensation reaction Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 229960004643 cupric oxide Drugs 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000011787 zinc oxide Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 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 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 208000018083 Bone metabolism disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000002156 mixing Methods 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
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- LGAWFGCTQRLGQE-UHFFFAOYSA-N octan-3-ylphosphonic acid Chemical class CCCCCC(CC)P(O)(O)=O LGAWFGCTQRLGQE-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3865—Polyphosphonic acids containing sulfur substituents
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
- C07F9/4043—Esters of poly(thio)phosphonic acids containing sulfur substituents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Developing Agents For Electrophotography (AREA)
- Optical Record Carriers And Manufacture Thereof (AREA)
- Ink Jet Recording Methods And Recording Media Thereof (AREA)
Abstract
A process for producing a 1-alkylthio- or 1-arylthiomethanediphosphonate compound by conducting the coupling reaction represented by formula (I) in the presence of a metallic oxide, wherein R' groups represent each independently C1-C6 linear or branched alkyl; R1 groups represent each independently a pharmacologically acceptable cation, hydrogen or C1-C6 linear or branched alkyl; and R2 represents alkyl or aryl. This process is extremely useful from the economic and industrial points of view, because the yield is remarkably improved and accordingly the purification procedure is simplified as compared with the conventional ones.
Description
The present invention relates to the preparation method of methanediphosphonatecompound compound, these compounds can be used as metal chelator or medicine such as anti-inflammatory medicaments, resisting rheumatoid disease medicine, bone metabolism disease therapeuticing medicine etc.
Synthetic 1-alkylthio-or the method for 1-arylthio-methyl di 2 ethylhexyl phosphonic acid for example be described on Japanese patent laid-open publication gazette 4-29676 number (Japanese Examined PatentPublication (Kokoku) No.4-29676).In the described condensation reaction of this patent, methyl di 2 ethylhexyl phosphonic acid four alkane esters change into the corresponding metal derivative by introducing metal agent such as sodium hydride, then with various disulphide and this derivatives reaction to synthesize 1-alkylthio-or 1-arylthio-methyl di 2 ethylhexyl phosphonic acid four alkane esters.This condensation reaction generates desired compound with low-yield.Yet a large amount of disulphide and methyl di 2 ethylhexyl phosphonic acid four alkane esters and reaction are paid product mercaptan and are recovered in the thick product, must use the operation such as the silica gel column chromatography partition method of industrial costliness for purifying.Because desired compound methanediphosphonatecompound compound is extremely useful in fields such as pharmaceutical compositions, aforesaid method provides a large amount of compounds unsatisfactorily, thereby need seek simple and economic method.
The greatest problem of the condensation reaction of describing in Japanese Examined Patent Publication (Kokoku) No.4-29676 is a still unreacted of a large amount of raw material methyl di 2 ethylhexyl phosphonic acid four alkanoic acids and disulphide, separates from raw material and the purifying desired product is required great effort very much.If can reduce the amount of unreacted methyl di 2 ethylhexyl phosphonic acid four alkane esters and disulphide, just can provide excellent 1-alkylthio-or the method for 1-arylthio-methyl di 2 ethylhexyl phosphonic acid for preparing.
Because to studying in great detail of condensation reaction, the inventor finds to add metal oxide such as magnesium oxide can obtain the product 1-alkylthio methyl di 2 ethylhexyl phosphonic acid four alkane esters of being wanted or 1-arylthio methyl di 2 ethylhexyl phosphonic acid four alkane esters with high yield in condensation reaction.In addition, find that the metal-salt of paying product mercaptan and the magnesium oxide in the reaction forms mixture, this mixture can be borrowed at an easy rate to filter and separate from want product.Therefore, the purpose of this invention is to provide a kind of 1-alkylthio methanediphosphonatecompound compound of medicine or preparation method of 1-arylthio methanediphosphonatecompound compound of being used as.
The invention provides the preparation method of a kind of formula (I) methanediphosphonatecompound compound:
R wherein
1Can be identical or different, be the positively charged ion that allows on the pharmacology, hydrogen atom or the straight or branched alkyl of 1 to 6 carbon atom is arranged; And R
2Be alkyl or aryl, the method is characterized in that in the presence of metal oxide, the metal derivative of the methyl di 2 ethylhexyl phosphonic acid four alkane esters of formula (II)
Wherein R ' can be identical or different for the straight or branched alkyl of 1 to 6 carbon atom is arranged, with dialkyl group two sulphur or diaryl two reaction of Salmon-Saxl of formula (III)
R
2S-SR
2R wherein
2Represent alkyl or aryl.
The present invention prepares 1-alkylthio methanediphosphonatecompound compound or 1-arylthio methanediphosphonatecompound compound is illustrated in the following reaction formula (A):
R wherein
1' representative has the straight or branched alkyl of 1 to 6 carbon atom, and R
2Represent alkyl or aryl.
Temperature of reaction and reaction times are depended on solvent for use, reaction reagent and raw material, and following described condition only is preferred condition.
Heating methyl di 2 ethylhexyl phosphonic acid four alkane esters in the presence of alkali and metal oxide, add disulphide then to react, filter reaction mixture is almost completely to remove the mercaptan as metal-salt, with the mixture of acid treatment filtrate with acquisition 1-alkylthio or 1-arylthio methyl di 2 ethylhexyl phosphonic acid four alkanoic acids and a small amount of disulphide.In this case, if do not use metal oxide to make reaction additives, desired product 1-alkylthio-or the productive rate of 1-arylthio methyl di 2 ethylhexyl phosphonic acid four alkane esters is very low, and simultaneously big content of starting materials methyl di 2 ethylhexyl phosphonic acid four alkane esters and disulphide are recovered.In addition, in this case, solvent for use preferably has high boiling point and low polar solvent such as toluene; Alkali does not preferably cause the alkali of transesterification reaction such as potassium tert.-butoxide etc.Though magnesium oxide, zinc oxide, cupric oxide etc. can both preferably use magnesium oxide as metal oxide as reaction additives.If potassium tert.-butoxide as alkali, can further improve productive rate by removing the product trimethyl carbinol of paying that forms between the reaction period.With respect to the amount of methyl di 2 ethylhexyl phosphonic acid four alkane esters, the molar weight of alkali, metal oxide and disulphide is 1 to 5 molar equivalent.Temperature of reaction is between room temperature and solvent for use boiling point, and the temperature that is higher than the temperature of pure boiling point under the uncle or is higher than the azeotropic temperature of the trimethyl carbinol is preferred.Reaction times is 1 to 5 hour.
Though being used for the alkyl and the aryl in diaryl two sulphur of dialkyl group two sulphur of the present invention can be selected without restriction, preferred alkyl is straight or branched alkyl or (mixing) cycloalkyl, for example methyl that 1 to 20 carbon atom is arranged, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, amyl group, cyclobutyl, cyclopentyl, cyclohexyl, ring octyl group etc.Alkyl comprises the group of the two keys of band, and comprises the substituent alkyl that has such as halogen, alkoxyl group, CN, nitro, amino, ester group, phenyl ring.Aryl comprises phenyl, naphthyl, quinolyl, isoquinolyl, thienyl, pyridyl, pyrryl, benzothiazolyl, benzoxazolyl etc.Aryl comprises the aryl that does not replace and replace.Substituting group comprises halogen, alkyl, alkoxyl group, siloxy-, alkylthio, nitro, amino etc.
The hydrolysis of 1-alkylthio methyl di 2 ethylhexyl phosphonic acid four alkane esters or 1-arylthio methyl di 2 ethylhexyl phosphonic acid four alkane esters provides corresponding di 2 ethylhexyl phosphonic acid.Hydrolysis can be undertaken by known general method.For example hydrolysis can be carried out with salt acid treatment ester between room temperature to 100 ℃.Even ester is and the mixture of the disulphide that is used for synthetic ester that after the hydrolysis, disulphide is easy to extraction or filters and remove.The di 2 ethylhexyl phosphonic acid compound of Huo Deing can change into its salt by currently known methods like this.
Positively charged ion representation metal ion of Yun Xuing or ammonium ion NR in the present invention
4Wherein R is a hydrogen atom, or the straight or branched alkyl of 1 to 7 carbon atom, particularly preferred metal ion are arranged is the positively charged ion of basic metal such as lithium, sodium, potassium and alkaline-earth metal such as magnesium, calcium positively charged ion.But positively charged ions such as other metal such as aluminium, zinc, iron are also included among the present invention.Ammonium ion comprises the ammonium ion and the quaternary ammonium ion of ammonia, primary amine, secondary amine and tertiary amine.Ammonium ion comprises the ammonium ion and the tetramethylammonium ion of ammonia, methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, propylamine, dipropyl amine, Isopropylamine, Diisopropylamine, butylamine, dibutylamine, isobutylamine, TERTIARY BUTYL AMINE, Monoethanolamine MEA BASF, diethanolamine, trolamine, Tetrylammonium ion etc. like this.Wherein sodium and potassium cationic, the ammonium ion of nitrogen or alkylamine is preferred.
With add above-mentioned metal oxide be feature prepare the 1-alkylthio-or the method for 1-arylthio-methanediphosphonatecompound compound compare with the method for routine and improved productive rate greatly, simplified purifying process simultaneously, from economy and industrial point of view, this is of great use.
Embodiment
The following example is intended to explain rather than restriction the present invention.Embodiment 1 4-methylthio phenyl sulfenyl methyl di 2 ethylhexyl phosphonic acid (R in the general formula (I)
1=H; R
2=4-MeSPh)
(making the method for metal oxide with magnesium oxide)
Under the argon atmosphere, will heat by the suspension returning that 0.99g potassium tert.-butoxide, 0.48g magnesium oxide and 10ml toluene are formed, 1.32ml methyl di 2 ethylhexyl phosphonic acid four isopropyl esters are added in this suspension.At this moment, remove trimethyl carbinol azeotropic mixture, keep reaction mixture at initial concentration to replenish the solvent of removing thereby add fresh toluene to this reaction mixture with distillation plant.After this operation is carried out 30 minutes, add the solution of forming by 2.48g 4,4 '-diformazan sulfenyl phenylbenzene two sulphur and 10ml toluene, heating is 4 hours under refluxing, and removes the trimethyl carbinol with distillation simultaneously.With the reaction mixture cool to room temperature, remove by filter insoluble solid.Under vigorous stirring, add 50ml 1.5N hydrochloric acid.Separate organic layer, with 10ml toluene extraction waterbearing stratum.Re-extract 3 times.Merge organic layer and use dried over mgso, steam solvent and obtain four isopropyl esters of desired compound di 2 ethylhexyl phosphonic acid and the mixture of disulphide.With thick product reflux 5 hours in the 20ml concentrated hydrochloric acid, reaction mixture is diluted to 2 times of original volume with 1.5N hydrochloric acid.Removing the disulphide that still exists, the aqueous solution is concentrated into dried white solid with 8ml toluene wash water solution 3 times.White solid gets 1.23g with acetone/methylene dichloride recrystallization and wants compound (productive rate 93% fusing point 215 to 216 ℃ (decomposition)).After the drying, white solid and yellow soda ash are reacted in water,, after activated carbon treatment disodium salt solution, filtration and concentrating this solution, get the disodium salt (productive rate 93% of corresponding di 2 ethylhexyl phosphonic acid with this salt of ethanol/water recrystallization to change into disodium salt; Fusing point is higher than 300 ℃).
Disodium salt
1HNMR (D
2O, ppm)
2.49(s，3H)，3.23(t，J＝20H2，1H)，
7.25-7.32(m，2H)，7.51-7.58(m，2H)。
The IR of disodium salt (KBr, cm
-1)
1479，1197，1158，1110，1071，928
The MASS of disodium salt (FAB) m/2 375 (M+H)-1
To C
8H
10O
6S
2P
2Na
2Ultimate analysis
Calculated value: C25.68% H2.70%
Analytical value: C25.71% H2.73% embodiment 2 4-methylthio phenyl sulfenyl methyl di 2 ethylhexyl phosphonic acids (R in the general formula (I)
1=H; R
2=4-MeSPh) (make the method for metal oxide with zinc oxide)
Repeat the method for embodiment 1, difference is to replace magnesium oxide with 0.98g zinc oxide, and the productive rate of the compound of is 90%.Embodiment 3 4-methylthio phenyl sulfenyl methyl di 2 ethylhexyl phosphonic acid (R in general formula (I)
1=H; R
2=4-MeSPh) (make metal oxide) with cupric oxide
Repeat the method for embodiment 1, part is not to replace oxide compound with the 0.95g cupric oxide, and the productive rate of the compound of is 85%.Embodiment 4 4-chlorobenzene sulfenyl methyl di 2 ethylhexyl phosphonic acid (R in general formula (I)
1=H; R
2=4-Cl-Ph)
Repeating the method for embodiment 1, difference is 4,4 '-dichloro phenylbenzene two sulphur are as raw material disulphide, the productive rate 92% of the compound of.
To C
7H
7O
6ClSP
2Na
2Ultimate analysis
Calculated value: C23.19% H1.95%
Analytical value: C23.22% H1.93% Comparative Examples 4-methylthio phenyl sulfenyl methyl di 2 ethylhexyl phosphonic acid (R in general formula (I)
1=H; R
2=4-MeSPh) (make the method for reaction additives without magnesium oxide)
Repeat the method for embodiment 1, difference is without magnesium oxide, by raw material methyl di 2 ethylhexyl phosphonic acid four isopropyl esters obtain the compound of wanting and by condensed products (IV) not:
For the thick product methyl di 2 ethylhexyl phosphonic acid of obtain, disodium salt is not carried out recrystallization as embodiment 1 is described, measure the compound of wanting and the ratio of condensed products not.This ratio is by crude product mixture
1HNMR spectrogram (compound of wanting: 3.23ppm, t, J=20Hz, H; Condensed products: 2.12ppm not, t, J=20Hz, 2H) in phosphonate group a proton integrated value calculate.The result want compound and not condensed products through being 2: 5 (mol ratio), show that when not having metal oxide the productive rate of the compound of wanting is about 30%.
Industrial applicability
To add above-mentioned metal oxide as the preparation 1-alkylthio group of feature-or 1-virtue sulphur The method of base-methanediphosphonatecompound compound is compared with the method for routine and has greatly been improved productive rate, Simplified simultaneously purifying process, from economy and industrial point of view, this is of great use.
Claims (2)
1. the method for preparation formula (I) methanediphosphonatecompound compound,
R wherein
1Can be identical or different, be the positively charged ion that allows on the pharmacology, hydrogen atom or the straight or branched alkyl of 1 to 6 carbon atom is arranged; And R
2Be alkyl or aryl, the method is characterized in that in the presence of metal oxide, the metal derivative of the methyl di 2 ethylhexyl phosphonic acid four alkane esters of formula (II)
Wherein R ' can be identical or different for the straight or branched alkyl of 1 to 6 carbon atom is arranged, with dialkyl group two sulphur or diaryl two reaction of Salmon-Saxl of formula (III)
R
2S-SR
2R wherein
2Represent alkyl or aryl.
2. formula (I) methanediphosphonatecompound compound
R wherein
1Can be identical or different, be the positively charged ion that allows on the pharmacology, hydrogen atom or the straight or branched alkyl of 1 to 6 carbon atom is arranged; And R
2It is the aryl that alkylthio replaces.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP36832/93 | 1993-02-25 | ||
| JP3683293 | 1993-02-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1102750A CN1102750A (en) | 1995-05-17 |
| CN1038033C true CN1038033C (en) | 1998-04-15 |
Family
ID=12480724
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94190078A Expired - Fee Related CN1038033C (en) | 1993-02-25 | 1994-02-23 | Process for producing methanediphosphonate compound |
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| Country | Link |
|---|---|
| JP (1) | JP2546067B2 (en) |
| KR (1) | KR950701338A (en) |
| CN (1) | CN1038033C (en) |
| AU (1) | AU674059B2 (en) |
| FI (1) | FI944998A (en) |
| TW (1) | TW346489B (en) |
| WO (1) | WO1994019359A1 (en) |
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|---|---|---|---|---|
| CN1055476C (en) * | 1994-08-24 | 2000-08-16 | 东丽株式会社 | Process for producing methanediphosphonic acid compound |
| EP2340841B1 (en) | 2008-09-03 | 2016-11-09 | Tohoku University | Osteogenesis promoter comprising [4-(methylthio)phenylthio]methanebisphosphonic acid or pharmaceutically acceptable salt thereof as active ingredient |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5942395A (en) * | 1982-07-29 | 1984-03-08 | サノフイ | Antiinflammatory product derived from methylene-diphosphonic acid |
| JPH0377894A (en) * | 1989-08-18 | 1991-04-03 | Toray Ind Inc | Methylene diphosphonic acid compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH675422A5 (en) * | 1988-03-31 | 1990-09-28 | Symphar Sa |
-
1994
- 1994-02-23 WO PCT/JP1994/000283 patent/WO1994019359A1/en active Application Filing
- 1994-02-23 KR KR1019940703838A patent/KR950701338A/en not_active IP Right Cessation
- 1994-02-23 AU AU61150/94A patent/AU674059B2/en not_active Ceased
- 1994-02-23 CN CN94190078A patent/CN1038033C/en not_active Expired - Fee Related
- 1994-02-23 JP JP6518824A patent/JP2546067B2/en not_active Expired - Fee Related
- 1994-02-24 TW TW083101579A patent/TW346489B/en active
- 1994-10-24 FI FI944998A patent/FI944998A/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5942395A (en) * | 1982-07-29 | 1984-03-08 | サノフイ | Antiinflammatory product derived from methylene-diphosphonic acid |
| JPH0377894A (en) * | 1989-08-18 | 1991-04-03 | Toray Ind Inc | Methylene diphosphonic acid compound |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2546067B2 (en) | 1996-10-23 |
| KR950701338A (en) | 1995-03-23 |
| WO1994019359A1 (en) | 1994-09-01 |
| AU6115094A (en) | 1994-09-14 |
| AU674059B2 (en) | 1996-12-05 |
| TW346489B (en) | 1998-12-01 |
| FI944998A0 (en) | 1994-10-24 |
| FI944998A (en) | 1994-10-24 |
| CN1102750A (en) | 1995-05-17 |
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