CN1055476C - 甲二膦酸化合物的制法 - Google Patents
甲二膦酸化合物的制法 Download PDFInfo
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- CN1055476C CN1055476C CN95191046A CN95191046A CN1055476C CN 1055476 C CN1055476 C CN 1055476C CN 95191046 A CN95191046 A CN 95191046A CN 95191046 A CN95191046 A CN 95191046A CN 1055476 C CN1055476 C CN 1055476C
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- China
- Prior art keywords
- phosphonic acid
- ethylhexyl phosphonic
- compound
- making
- reaction
- 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.)
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- 238000000034 method Methods 0.000 title claims abstract description 41
- -1 methanediphosphonic acid compound Chemical class 0.000 title claims description 41
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims abstract 3
- JJJOZVFVARQUJV-UHFFFAOYSA-N 2-ethylhexylphosphonic acid Chemical compound CCCCC(CC)CP(O)(O)=O JJJOZVFVARQUJV-UHFFFAOYSA-N 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 150000002148 esters Chemical class 0.000 claims description 29
- 239000003513 alkali Substances 0.000 claims description 18
- 229910044991 metal oxide Inorganic materials 0.000 claims description 15
- 150000004706 metal oxides Chemical class 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 10
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 10
- 150000002500 ions Chemical class 0.000 claims description 8
- 239000000395 magnesium oxide Substances 0.000 claims description 8
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 8
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 229960004643 cupric oxide Drugs 0.000 claims description 5
- 239000011787 zinc oxide Substances 0.000 claims description 5
- 229910052728 basic metal Inorganic materials 0.000 claims description 4
- 150000003818 basic metals Chemical class 0.000 claims description 4
- 150000004678 hydrides Chemical class 0.000 claims description 4
- 229910000272 alkali metal oxide Inorganic materials 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000007944 thiolates Chemical class 0.000 abstract description 16
- 239000006227 byproduct Substances 0.000 abstract description 11
- 125000003118 aryl group Chemical group 0.000 abstract description 7
- 238000006482 condensation reaction Methods 0.000 abstract description 6
- 239000000047 product Substances 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract 2
- 150000001768 cations Chemical class 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 50
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 15
- 229910052717 sulfur Inorganic materials 0.000 description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 13
- 239000011593 sulfur Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 229940122361 Bisphosphonate Drugs 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 235000015424 sodium Nutrition 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-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
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 150000004663 bisphosphonates Chemical class 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 150000001457 metallic cations Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 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 2
- 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 description 2
- 239000011591 potassium Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000004097 bone metabolism Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000004122 cyclic 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
- 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
- 238000004821 distillation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002460 imidazoles Chemical class 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
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 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
- 229930192474 thiophene Natural products 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 239000008096 xylene Substances 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)]
-
- 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
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Abstract
本发明涉及甲二膦四烷基酯与二硫化物进行缩合反应,然后将副产的硫醇盐不溶物或不熔性盐除去,以制备通式(Ⅰ)表示的甲二膦酸化合物的方法。所述反应还可在碱或碱和金属氧化物的存在下进行。本发明方法比以往的方法简单,且可显著提高收率,在工业上极为经济有效。式(Ⅰ)中,R1为药理上可容许的阳离子、H或C1-C6的直链或支链烷基。R2为C3-C20的芳基。R4为H、C1-C6的直链或支链烷基。
Description
技术领域
本发明涉及金属螯合剂或消炎药、抗风湿药、骨代谢药等作为医药品用的甲二膦酸化合物的制法。
技术背景
过去的1-烷基硫代或1-芳基硫代甲二膦酸的合成法,例如已在特公平4-29676号公报中记载。其中所揭示的方法是采用氢氧化钠等将甲二膦酸四烷基酯转化成相应的金属衍生物后,再与各种二硫化物反应合成所要的1-烷基硫代或1-芳基硫代甲二膦酸四烷基酯。这种合成法收率低,在反应粗生成物中除目的产物外,还混入大量未反应的二硫化物和甲二膦酸四烷基酯以及反应副产物硫醇,在工业上要除去这些物质,必须用硅胶柱色谱等费用极高的精制操作。考虑到目的产物甲二膦酸化合物在医药领域极为有用,在大量供应这种化合物方面很难有满意的制法,因此希望有更简单、成本低的制法。
特公平4-29676号公报记载的合成法中,最大的问题是残留大量甲二膦酸四烷基酯原料。对该原料和目的物的分离精制十分费力。因此,如果能尽量减少反应混合物中残留的甲二膦酸四烷基酯,则成为1-烷基硫代或1-芳基硫代甲二膦酸化合物的出色制法。本发明人详细研究甲二膦酸四烷基酯与二硫化物缩合反应的结果,发现在缩合反应生成目的物1-烷基硫代甲二膦酸四烷基酯或1-芳基硫代甲二膦酸四烷基酯时,除去等摩尔副产的烷基硫醇盐或芳基硫醇盐,则能以极高的收率得到目的物。此外,发现在此缩合反应中添加氧化镁等金属氧化物,同样能以高收率得到目的产物1-烷基硫代甲二膦酸四烷基酯或1-芳基硫代甲二膦酸四烷基酯。
即本发明的目的是提供作为医药品极为有用的1-烷基硫代甲二膦酸化合物或1-芳基硫代甲二膦酸化合物的新制法。
发明的公开
本发明涉及通式(1)所示的甲二膦酸化合物的制法,式中R1是药理学上可容许的阳离子、H、或C1-C6的直链或支链烷基,可以相同也可以不同,R2表示C3-C20的芳基。R4表示H、C1-C6的直链或支链烷基。
其特征在于使甲二膦酸四烷基酯与二硫化物进行反应,然后,将烷基硫醇盐或芳基硫醇盐作为不溶性物或不溶性盐除去。所述甲二膦酸四烷基酯由下式表示:式中R’代表C1-C6的直链或支链烷基,可以相同也可以不同,R3代表H、Na、K或Li,R4定义同前。所述二硫化物由下式表示,R2S-SR2式中,R2定义同上。实施发明的最佳方式
(式中R1′代表C1-C6的直链或支链烷基,R2代表烷基或芳基,R1代表药理学上可容许的阳离子、H或C1-C6的直链或支链烷基)。
如反应式A中所示,本发明是在(a)碱存在下或(b)在碱与金属氧化物存在下进行甲二膦酸四烷基酯与二硫化物的反应,除去副产的硫醇盐不溶性盐制得甲二膦酸化合物的方法。
即本发明的一种方法是在碱存在下,甲二膦酸四烷基酯与二硫化物反应后,除去副产的硫醇盐不溶性物质或不溶性盐而制得1-烷基硫代或1-芳基硫代甲二膦酸四烷基酯。不除去硫醇盐时,1-烷基硫代或1-芳基硫代甲二膦酸四烷基酯的收率明显下降,结果必须大量回收原料甲二膦酸四烷基酯和二硫化物。除去反应混合物或反应体系中的硫醇盐不溶性物或不溶性盐是很重要的。硫醇盐的不溶性(溶解度)受硫醇盐副产时的溶剂和副产硫醇盐本身的性质以及硫醇盐与盐形成的阳离子的种类控制。
硫醇盐的阳离子,碱金属类较好的例子有Na、K、Li等离子性强的元素,这些元素来自于用于缩合反应的碱或者后来或预先添加的碱。
溶剂较好的是对这种硫醇盐为非极性或低极性非质子溶剂,这类溶剂有苯、甲苯、二甲苯、环己烷、己烷、戊烷等烃类溶剂,其中最好的是甲苯、二甲苯这类高沸点低极性溶剂。
在这样的反应体系中副产的硫醇盐呈不溶性盐析出,采用过滤等方法基本上可完全除去反应体系(反应混合物)中副产的硫醇盐。然后进行通常的抽提或蒸馏等后处理则可高收率地制得目的物。
另外,本发明所用的碱较好的是从碱金属或碱土金属的氢化物、氢化物、烷基或烷氧基金属化物中选出的至少一种,其中最好用钠、锂、钾的氢化物、氨化物、烷基或烷氧基金属化物。烷氧基化物例如有甲醇盐、乙醇盐、丙醇盐、丁醇盐,这时最好预先从反应体系中除去副产的醇。最好的醇盐是不产生叔丁醇钾这种酯交换反应的碱。更具体地讲,所用的碱例如有氢化钠、氨基化钠、氨基锂、甲基锂、丁基锂、叔丁醇钾、二异丙基氨基锂等。
相对于甲二膦酸四烷基酯,碱的用量最好是2-5当量,相对于甲二膦酸四烷基酯二硫化物的用量最好为1-5当量。反应温度最好由-20℃到所用溶剂的沸点,反应时间最好是1-5小时。
本发明中用R1、R1′、R4表示的C1-C6的直链或支链烷基没有特殊的限制,例如可以是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、环戊基、甲基环戊基、环己基等。含有双键的基团也包括含有卤素、烷氧基、硝基、氨基、酯基、苯环等作为取代基的基团。
本发明所用的二烷基二硫化物或二芳基二硫化物的烷基部分、芳基部分没有特殊的限制,虽然可适当地选择,但烷基可以是C1-C20的直链或支链或(杂)环状基团,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、环丁基、环戊基、环己基、环庚基、环辛基等。这些烷基中含有双键的也包括含有卤素、烷氧基、硝基、氨基、酯基、苯环等作为取代基的那些烷基。芳基是C3-C20的芳基,也可以有1-3个N、O、S等杂原子、由C3、C4、C5组成的芳基表示含有1-3个杂原子,例如吡咯、呋喃、噻吩、吡啶、噻唑、噁唑、异噁唑、咪唑、吡唑、嘧啶、吡嗪等。由C3-C20组成的芳基表示只由碳构成或碳与杂原子构成,例如苯基、萘基、喹啉、异喹啉、苯并呋喃、吲杂、苯并咪唑、苯并噁唑、苯并噻唑等。另外,这些芳基可以是无取代基、有取代基的。取代基有卤素、烷基、烷氧基、甲硅烷氧基、烷硫基、硝基、氨基等。
碱与溶剂的最佳组合有叔丁醇钾、氢化钠、或正丁基锂与苯、甲苯、己烷或环己烷等的组合。
本发明的另一种制法如反应式A(b)所示,在碱和金属氧化物存在下,甲二膦酸四烷基酯与二硫化物反应后,除去金属氧化物硫醇盐和/或硫醇盐不溶性物,得到1-烷基硫代或1-芳基硫代甲二膦酸四烷基酯。不除去硫醇盐不溶性盐时,目的物的收率明显下降。
这里所用的金属氧化物较好的是氧化镁、氧化锌、氧化铜、也可以采用二种以上的金属氧化物。其中用氧化镁较好。相对于甲二膦酸四烷基酯,金属氧化物的用量为1-5当量。
而上述反应式A(b)中所用的甲二膦酸四烷基酯、二烷基二硫化物或二芳基二硫化物、溶剂、碱和反应条件最好用上述反应式A(a)制法中所用的条件。
有关碱、金属氧化物和溶剂的最佳组合,碱的例子有叔丁醇钾、氢化钠或正丁基锂,金属氧化物的例子有氧化镁、氧化锌或氧化铜,溶剂的例子有苯、甲苯、己烷或环己烷的组合。
上述A(a)、A(b)的二种方法中,用A(a)的方法更好。
可以用这样得到的1-烷基硫代甲二膦酸四烷基酯或1-芳基硫代甲二膦酸四烷基酯加水水解制得相应的二膦酸。这可采用一般公知的方法,例如用盐酸在室温-100℃处理二膦酸酯。此时,也可用二膦酸酯与上述反应得到的二硫化物的混合物加水水解后,经抽提或过滤,则容易分离二膦酸。另外,也用公知的方法将这样得到的二膦酸转化成其一种盐。
此外,作为本发明的R1,所容许的阳离子代表金属阳离子、N(R3)4季铵(式中R3是H或C1-C7的直链或支链烷基)。特别好的金属阳离子,有碱金属类,例如有Li、Na、K等,和碱土金属类,例如有Mg、Ca等阳离子,但本发明也包括其它金属,例如Al、Zn、Fe等阳离子。所用的铵是氨、伯胺、仲胺、叔胺等的胺和季胺。胺的例子有氨、甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、丙胺、二丙胺、异丙胺、二异丙胺、丁胺、二丁胺、异丁胺、叔丁胺、一乙醇胺、二乙醇胺、三乙醇胺等的胺及四甲胺、四乙胺等。其中钠、钾、氨、烷基胺的阳离子最好。
如上所述,除去副产的烷基硫醇盐或芳基硫醇盐不溶性盐为特征的1-烷基硫代或1-芳基硫代甲二膦酸化合物的制法,与过去的方法相比,是收率明显提高,结果其精制方法更简单、在经济上和工业上极为有利。
[实施例]
列举以下实施例说明本发明,但本发明不受这些实例的限制。
实施例1
(4-甲硫苯基)硫代甲二膦酸(通式(1)中,R1=H,R2=4-MeSPh,R4=H)
在氩气流保护下,将1.00g叔丁醇钾的甲苯(10ml)悬浮液加热回流,再加入1.32ml的甲二膦酸四异丙酯,用分留装置除去此时共沸的叔丁醇,按减少的溶剂量加入新甲苯,使反应浓度保持恒定。操作30分钟后,加入2.48g二(4-甲硫苯基)二硫化物的甲苯(10ml)溶液,继续除去共沸叔丁醇,加热回流4小时。此后,将反应液冷却到室温、过滤不溶物,在滤液中加入1.5当量盐酸50ml,激烈搅拌。分离有机层,用10ml甲苯抽提水层三次,将有机层合并,用硫酸镁干燥后,馏去溶剂,得到标题的二膦酸四异丙酯与二硫化物的混合物。在20ml的浓盐酸中将这种粗生成物加热回流5小时后,用1.5当量盐酸将反应水溶液稀释到2倍,用8ml甲苯将水溶液洗涤三次。除去残留的二硫化物,将水溶液浓缩干燥后得到白色固体。再用丙酮-二氯甲烷将白色固体进行重结晶,得到1.24g标题化合物(收率94%,m.p=215-216℃分解)。再将所得白色固体溶于水,用碳酸钠进行二钠化,经活性炭处理、过滤、浓缩后,用乙醇-水重结晶,可制得相应的二膦酸的二钠盐(收率93%,m.p=300℃以上):
二钠盐的1HNMR(D2O,ppm)结果;
2.49(S.3H)、3.23(t.J=20Hz、1H)、7.25-7.32(m.2H)
7.51-7.58(m.2H)
二钠盐的IR(红外)(KBr,Cm-1)结果
1479、1197、1158、1110、1071、928
二钠盐的MASS质谱(FAB)m/z 375(M+H)+
元素分析:C8H10O6S2P2Na2
计算值:C 25.68% H 2.70%
实测值:C 25.81% H 2.75%
实施例2
(4-甲硫苯基)硫代甲二膦酸四异丙酯(通式(1)中,R1=iPr、R2=4-MeSPh、R4=H)
采用与实施例1相同的方法,用9.00g叔丁醇钾、13.5g甲二膦酸四异丙酯、12.5g二(4-甲硫苯基)二硫化物进行缩合反应,过滤除去不溶物,对滤液进行同样的处理后,得到19.5g标题化合物的粗生成物(黄色油状物)。用HPLC分析纯度为95%,标题化合物的收率为92.6%。
实施例3
(4-甲硫苯基)硫代甲二膦酸四异丙酯(通式(1)中,R1=iPr、R2=4-MeSPh、R4=H)
在氩气流保护下,将13.7g二(4-甲硫苯基)二硫化物、9.43g叔丁醇钾的甲苯(120ml)悬浮液加热到50℃,添加13.8g甲二膦酸四异丙酯,加热到70℃反应1小时。将反应液冷却到常温后,滤出沉淀,用100ml甲苯洗涤沉淀,将洗涤液与滤液合并,用40ml 2N盐酸洗涤滤液三次,馏去溶剂,得20.9g标题化合物的粗生成物。用HPLC分析纯度为89.4%,收率93.6%。
实施例4
(4-甲硫苯基)硫代甲二膦酸四异丙酯(通式(1)中,R1=iPr、R2=4-MeSPh、R4=H)
在氩气保护下,将13.8g甲二膦酸四异丙酯、13.7g二(4-甲硫苯基)二硫化物的甲苯(120ml)悬浮液冷却到0-10℃,添加9.43g叔丁醇钾,反应1小时,此后反应液同例3一样进行处理,得到21.3g标题化合物的粗生成物,用HPLC分析纯度为91.5%,收率97.6%。
实施例5
(4-甲硫苯基)硫代甲二膦酸[通式(1)中,R1=H、R2=4-MeSPh、R4=H][用氧化镁作为金属氧化物的方法]
在氩气保护下,将0.99g叔丁醇钾、0.48g氧化镁的甲苯(10ml)悬浮液加热回流,然后加入1.32ml甲二膦酸四异丙酯,用分馏装置除去此时共沸的叔丁醇、按减少的溶剂量加入新甲苯,使反应浓度保持一定。操作30分钟后,加2.48g二(4-甲硫苯基)二硫化物的甲苯(10ml)溶液,继续加热回流4小时,共沸除去叔丁醇。此后将反应液冷却到室温、过滤除去含氧化镁的不溶性固体,在所得滤液中加入50ml 1.5当量盐酸,激烈搅拌,分离有机层,用10ml甲苯抽提水层三次,将有机层合并,用硫酸镁干燥后,馏去溶剂,得到标题的二膦酸四异丙酯与二硫化物的混合物,在20ml浓盐酸中将该粗生成物加热回流5小时后,用1.5当量盐酸将反应水溶液稀释到2倍,用8ml甲苯洗涤该水溶液三次,除去残留的二硫化物,将水溶液浓缩至干燥后得到白色固体,用丙酮-二氯甲烷将白色固体重结晶,得到1.23g标题化合物(收率93%、m.p=215-216℃分解)。然后,将干燥后所得的白色固体用碳酸钠在水中进行二钠化,再经活性炭处理、过滤、浓缩后,用乙醇-水重结晶,可制得相应的二膦酸的二钠盐(收率93%,m.p=300℃以上)
二钠盐质谱(MASS)(FAB)m/z 375(M+H)-
元素分析:C8H10O6S2P2Na2
计算值:C25.68% H2.70%
实测值:C25.71% H2.73%
实施例6
(4-甲硫苯基)硫代甲二膦酸[通式(1)中,R1=H、R2=4-MeSPh、R4=H][用氧化锌作为金属氧化物的方法]
用0.98g氧化锌代替实例5中的氧化镁进行同样的操作,得到标题化合物,收率90%。
实施例7
(4-甲硫苯基)硫代甲二膦酸[通式(1)中,R1=H、R2=4-MeSPh、R4=H][用氧化铜作为金属氧化物的方法]
用0.95g氧化铜代替实施例5中的氧化镁,进行同样的操作,得到标题化合物,收率85%。
实施例8
(4-氯苯基)硫代甲二膦酸[通式(1)中,R1=H、R2=4-Cl-Ph、R4=H]
用4、4′-二氯苯基二硫化物作为原料二硫化物,同实施例5一样进行操作,得到标题化合物,收率92%。
元素分析:C7H7O6ClSP2Na2
计算值:C23.19% H1.95%
实测值:C23.2% H1.93%
比较例1
(4-甲硫苯基)硫代甲二膦酸四异丙酯[通式(1)中,R1=iPr、R2=4-MeSPh、R4=H]
除不进行过滤除去硫醇盐不溶性物外,其它完全与实施例2一样进行操作,得到含标题化合物的反应粗生成物,用柱色谱精制得13.20g黄色油状标题化合物,收率65%。
工业上利用的可能性
从本发明的反应混合物或反应体系中除去烷基硫醇盐或芳基硫醇盐不溶性盐为特征的1-烷基硫代甲二膦酸化合物或1-芳基硫代甲二膦酸化合物的制法,与过去的方法相比,其收率明显提高,结果其精制方法更简单,在经济上和工业上极为有用。
Claims (9)
2.权利要求1所述的甲二膦酸化合物的制法,其特征在于,R3、R4均为氢,且所述反应是在碱的存在下进行。
3.权利要求2所述的甲二膦酸化合物的制法,其特征在于,所述反应是在碱和金属氧化物的存在下进行。
4.权利要求3所述的甲二膦酸化合物的制法,其特征在于,所述金属氧化物是从氧化镁、氧化锌和氧化铜中选出的至少一种。
5.权利要求3所述的甲二膦酸化合物的制法,其特征在于,所述金属氧化物的用量为甲二膦酸四烷基酯的1-5当量。
6.权利要求2所述的甲二膦酸化合物的制法,其特征在于,所述碱是从碱金属或碱土金属的氢化物、氨化物、烷基或醇盐中选出的至少一种。
7.权利要求2中所述的甲二膦酸化合物的制法,其特征在于,所述碱的用量为甲二膦酸四烷基酯的2-5当量。
8.权利要求2中所述的甲二膦酸化合物的制法,其特征在于,所述反应的溶剂采用非极性或低极性的非质子性溶剂。
9.权利要求2所述的甲二膦酸化合物的制法,其特征在于,所述反应温度在-20℃以上、溶剂的沸点以下。
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US (1) | US5886206A (zh) |
EP (1) | EP0725070B1 (zh) |
JP (1) | JP3493663B2 (zh) |
KR (1) | KR100369929B1 (zh) |
CN (1) | CN1055476C (zh) |
AT (1) | ATE235499T1 (zh) |
AU (1) | AU699641B2 (zh) |
CA (1) | CA2174435A1 (zh) |
DE (1) | DE69530064T2 (zh) |
ES (1) | ES2196075T3 (zh) |
FI (1) | FI961749A (zh) |
NO (1) | NO961540D0 (zh) |
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EP0100718A1 (fr) * | 1982-07-29 | 1984-02-15 | Sanofi S.A. | Produits anti-inflammatoires dérivés de l'acide méthylène-diphosphonique et leur procédé de préparation |
EP0339237A2 (en) * | 1988-03-31 | 1989-11-02 | Symphar S.A. | Phenol substituted gem-diphosphonate derivatives, process for their preparation and pharmaceutical compositions containing them |
EP0603401A1 (en) * | 1992-07-10 | 1994-06-29 | Toray Industries, Inc. | Methanediphosphonate derivative, production thereof, and pharmaceutical use thereof |
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JPH0377894A (ja) * | 1989-08-18 | 1991-04-03 | Toray Ind Inc | メチレンジホスホン酸化合物 |
JP3341303B2 (ja) * | 1991-07-11 | 2002-11-05 | 東レ株式会社 | メチレンジホスホン酸誘導体、その製造方法およびその医薬用途 |
WO1994019359A1 (en) * | 1993-02-25 | 1994-09-01 | Toray Industries, Inc. | Process for producing methanediphosphonate compound |
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1995
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- 1995-08-24 AT AT95929223T patent/ATE235499T1/de not_active IP Right Cessation
- 1995-08-24 KR KR1019960702109A patent/KR100369929B1/ko not_active IP Right Cessation
- 1995-08-24 DE DE69530064T patent/DE69530064T2/de not_active Expired - Fee Related
- 1995-08-24 CA CA002174435A patent/CA2174435A1/en not_active Abandoned
- 1995-08-24 US US08/632,421 patent/US5886206A/en not_active Expired - Fee Related
- 1995-08-24 EP EP95929223A patent/EP0725070B1/en not_active Expired - Lifetime
- 1995-08-24 JP JP50794896A patent/JP3493663B2/ja not_active Expired - Fee Related
- 1995-08-24 ES ES95929223T patent/ES2196075T3/es not_active Expired - Lifetime
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- 1996-02-13 TW TW085101794A patent/TW327173B/zh active
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Publication number | Priority date | Publication date | Assignee | Title |
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EP0100718A1 (fr) * | 1982-07-29 | 1984-02-15 | Sanofi S.A. | Produits anti-inflammatoires dérivés de l'acide méthylène-diphosphonique et leur procédé de préparation |
EP0339237A2 (en) * | 1988-03-31 | 1989-11-02 | Symphar S.A. | Phenol substituted gem-diphosphonate derivatives, process for their preparation and pharmaceutical compositions containing them |
EP0603401A1 (en) * | 1992-07-10 | 1994-06-29 | Toray Industries, Inc. | Methanediphosphonate derivative, production thereof, and pharmaceutical use thereof |
Also Published As
Publication number | Publication date |
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DE69530064T2 (de) | 2003-12-18 |
CA2174435A1 (en) | 1996-02-29 |
EP0725070A1 (en) | 1996-08-07 |
EP0725070A4 (en) | 1997-10-22 |
EP0725070B1 (en) | 2003-03-26 |
CN1137276A (zh) | 1996-12-04 |
AU699641B2 (en) | 1998-12-10 |
KR100369929B1 (ko) | 2003-04-08 |
WO1996006100A1 (fr) | 1996-02-29 |
NO961540L (no) | 1996-04-18 |
FI961749A0 (fi) | 1996-04-23 |
US5886206A (en) | 1999-03-23 |
TW327173B (en) | 1998-02-21 |
KR960705831A (ko) | 1996-11-08 |
NO961540D0 (no) | 1996-04-18 |
FI961749A (fi) | 1996-04-23 |
JP3493663B2 (ja) | 2004-02-03 |
ATE235499T1 (de) | 2003-04-15 |
DE69530064D1 (de) | 2003-04-30 |
AU3265095A (en) | 1996-03-14 |
ES2196075T3 (es) | 2003-12-16 |
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