JPH09501935A - N−アミノ−1−ヒドロキシアルキリデン−1,1−ビスホスホン酸の製造法 - Google Patents
N−アミノ−1−ヒドロキシアルキリデン−1,1−ビスホスホン酸の製造法Info
- Publication number
- JPH09501935A JPH09501935A JP7507758A JP50775895A JPH09501935A JP H09501935 A JPH09501935 A JP H09501935A JP 7507758 A JP7507758 A JP 7507758A JP 50775895 A JP50775895 A JP 50775895A JP H09501935 A JPH09501935 A JP H09501935A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- alkyl
- acid
- group
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 39
- 239000002253 acid Substances 0.000 title claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 59
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 20
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 19
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 17
- 230000007062 hydrolysis Effects 0.000 claims description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims description 16
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 11
- 238000010924 continuous production Methods 0.000 claims description 9
- 150000001412 amines Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 150000001768 cations Chemical class 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- JJMDCOVWQOJGCB-UHFFFAOYSA-N 5-aminopentanoic acid Chemical compound [NH3+]CCCCC([O-])=O JJMDCOVWQOJGCB-UHFFFAOYSA-N 0.000 claims description 4
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- WGNUNYPERJMVRM-UHFFFAOYSA-N 3-pyridylacetic acid Chemical compound OC(=O)CC1=CC=CN=C1 WGNUNYPERJMVRM-UHFFFAOYSA-N 0.000 claims description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims description 2
- 229960002684 aminocaproic acid Drugs 0.000 claims description 2
- 229950007593 homonicotinic acid Drugs 0.000 claims description 2
- 238000004679 31P NMR spectroscopy Methods 0.000 claims 2
- 239000004615 ingredient Substances 0.000 claims 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 claims 1
- UUANGAUMYPRUCC-UHFFFAOYSA-N 3-[butyl(methyl)azaniumyl]propanoate Chemical compound CCCCN(C)CCC(O)=O UUANGAUMYPRUCC-UHFFFAOYSA-N 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 150000007513 acids Chemical class 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000463 material Substances 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 14
- 239000002585 base Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000004809 Teflon Substances 0.000 description 6
- 229920006362 Teflon® Polymers 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- -1 1-Hydroxy-3- (methylpentylamino) propylidene Chemical group 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 238000002242 deionisation method Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- 229940089617 risedronate Drugs 0.000 description 3
- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 description 3
- 238000007711 solidification Methods 0.000 description 3
- 230000008023 solidification Effects 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000012089 stop solution Substances 0.000 description 2
- KZMOFWIRXNQJET-UHFFFAOYSA-N (1-phosphono-2-pyridin-3-ylethyl)phosphonic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)CC1=CC=CN=C1 KZMOFWIRXNQJET-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- UURVVRAGBFTTCJ-UHFFFAOYSA-N 2-amino-2-methylpropanedioic acid Chemical compound OC(=O)C(N)(C)C(O)=O UURVVRAGBFTTCJ-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 235000003932 Betula Nutrition 0.000 description 1
- 241000219429 Betula Species 0.000 description 1
- 238000006027 Birch reduction reaction Methods 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 239000004135 Bone phosphate Substances 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 238000011437 continuous method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012045 crude solution Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 238000009736 wetting Methods 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
-
- 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
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
-
- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
- C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
Landscapes
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.構造式I [式中、Zは、 (a)H2N−C2-5アルキル−; (b) 〔ここで、R5−はC1-5アルキルであり、Yは、 (i)水素; (ii)C1-5アルキル; (iii)R6O; (iv)R6S; (v)R6R6N; (vi)ハロゲン; (ここで、R6はH又はC1-5アルキルである) から選択される〕;及び (c)C2-6アルキル−(N−CH3)C2H4− からなる群から選択され;且つ R1は、 (ここで、Xは−OH又はClである) からなる群から選択された成分である] の化合物。 2.R1が: (ここで、XはOH又はClである) からなる群から選択された成分である、式H2N−C2-5アルキル−R1有する請 求項1に記載の化合物。 3.式H2N−CH2−CH2−CH2−R1を有する請求項2に記載の化合物。 4.R1が であり、 (a)分子量=295; (b)外部参照標準としてH3PO4(δ0.0)を用いた161.98MHzでの31P NMR ;δ3.8(t,JPP=13.5,JPH=669.4)及びδ15.9(d,JPP=13.5);及び (c)外部参照標準としてジオキサン(δ67.4)を用いた100.61MHzでの13C N MR;δ83.2(td,JCP=134.9,10.4),δ41.2,δ31.8(d,JCP=3.2),δ23 .8(t,JCP=6.4) を特徴とする請求項3に記載の化合物。 5.R1が、 であり、 (a)分子量=462; (b)外部参照標準としてH3PO4(δ0.0)を用いた161.98MHzでの31P NMR ;δ12.9(t,JPP=17.1),8.0(t,JPP=17.1);及び (c)外部参照標準としてジオキサン(δ67.4)を用いた100.61MHzでの13C N MR;δ86.4(ddd,JCP=139.7,129.3,15.3),δ41.0,δ33.3,δ23.0(m) であることを特徴とする請求項3に記載の化合物。 6.式: 〔式中、R5はC1-5アルキルであり、R1及びYは上記と同義である〕 を有する請求項1に記載の化合物。 7.R5がCH2であり、Y=Hである請求項6に記載の化合物。 8.式: C2-6アルキル−(N−CH3)C2H4−R1 を有する請求項1に記載の化合物。 9.構造式I: [式中、Zは、 (a)H2N−C2-5アルキル−; (b) 〔ここで、R5−はC1-5アルキルであり、Yは、 (i)水素; (ii)C1-5アルキル; (iii)R6O; (iv)R6S; (v)R6R6N; (vi)ハロゲン; (ここで、R6はH又はC1-5アルキルである) から選択される〕;及び (c)C2-6アルキル−(N−CH3)C2H4− からなる群から選択され;且つ R1は、 (ここで、Xは−OH又はClである) からなる群から選択された成分である] の化合物の連続製造法であって、 (a)式: Z−COOH (式中、Zは上記と同義である) のカルボン酸を、メタンスルホン酸(MSA)中で H3PO3及びPCl3と、又は場合によってMSA中でPCl3と連続的に混合し ; (b)式Iの化合物を含む流出混合物に水性塩基を連続的に加えて、式IIA、II B 又はIIC: (式中、Zは上記と同義であり、Mは、一価、二価又は三価のカチオンで ある) の化合物を生成させ; (c)式IIA、IIB又はIICの化合物を加水分解して、式IIIA、IIIB又はIII C : の化合物を生成させる ことからなる方法。 10.式I: H2N−C2-5アルキル−R1 〔式中、R1は、 (ここで、Xは−OH又はClである) からなる群から選択された成分である〕 の化合物を連続的に製造するための請求項9に記載の方法であって、 (a)式: H2N−C2-5アルキル−COOH のアミノアルカンカルボン酸を、メタンスルホン酸(MSA)の存在下 にPCl3及びH3PO3と、あるいは場合によって、MSAの存在下にPCl3と 連続的に混合し; (b)式Iの化合物を含む混合物を連続的に取り出すことからなる方法。 11.(a)式Iの化合物を含む混合物に、式MOH、MHCO2又はMCO2の 水性塩基を連続的に加えて、式IIA及びIIB又はIIC: (式中、R2は、末端アミン又はプロトン化末端アミンで置換されたC2-5 アルキルであり、Mは、塩基の一価、二価又は三価のカチオンである) の化合物を生成させ; (b)式IIA、IIB又はIICの化合物を含む混合物を連続的に取り出す ことをさらに含む請求項10に記載の方法。 12.水性塩基が約5%〜約50%の濃度を有する請求項11に記載の方法。 13.水性塩基が約50%の濃度を有する請求項12に記載の方法。 14.水性塩基がNaOHである請求項11に記載の方法。 15.取り出した式IIの化合物を含む混合物を加水分解して、式III: の化合物又はその塩を生成させることをさらに含む請求項11に記載の方法。 16.約3.0〜12.0のpHで加水分解を行う請求項15に記載の方法。 17.約5のpHで加水分解を行う請求項16に記載の方法。 18.110℃〜約175℃の温度で加水分解を行う請求項17に記載の方法。 19.温度が約140℃である請求項18に記載の方法。 20.カルボン酸が、 (a)2−アミノイソ酪酸; (b)3−アミノプロパン酸; (c)4−アミノ酪酸; (d)5−アミノ吉草酸; (e)6−アミノカプロン酸; (f)3−ピリジル酢酸;及び (g)N−ブチル−N−メチル−3−アミノプロピオン酸からなる群から選択さ れた成分である請求項9に記載の方法。 21.45℃〜約100℃の温度で実施される請求項13に記 載の方法。 22.約90℃の温度で実施される請求項24に記載の方法。 23.式III: (式中、R2は末端がアミンで置換されたC2-5アルキルである) の化合物又はその塩の連続製造法であって、 (a)式: H2N−C2-5アルキル−COOH のアミノアルカンカルボン酸を、メタンスルホン酸(MSA)の存在下に PCl3及びH3PO3と、あるいは場合によって、MSAの存在下にPCl3と連 続的に混合し; (b)式I: H2N−C2-5アルキル−R1 〔式中、R1は、 (ここで、XはOH又はClである) からなる群から選択された成分である〕 の流出化合物に水性塩基を連続的に添加して、式II: (式中、Mは塩基の一価、二価又は三価のカチオンである) の化合物を生成させ; (c)式IIの化合物を含む流出混合物を加水分解して、式IIIの化合物を生成さ せる ことからなる方法。
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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US11175193A | 1993-08-25 | 1993-08-25 | |
US111,751 | 1993-08-25 | ||
US23964094A | 1994-05-09 | 1994-05-09 | |
US286,151 | 1994-08-04 | ||
US08/286,151 US5510517A (en) | 1993-08-25 | 1994-08-04 | Process for producing N-amino-1-hydroxy-alkylidene-1,1-bisphosphonic acids |
PCT/US1994/009620 WO1995006052A1 (en) | 1993-08-25 | 1994-08-24 | Process for producing n-amino-1-hydroxy-alkyl-idene-1,1-bisphosphonic acids |
Publications (2)
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JPH09501935A true JPH09501935A (ja) | 1997-02-25 |
JP3675818B2 JP3675818B2 (ja) | 2005-07-27 |
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JP50775895A Expired - Lifetime JP3675818B2 (ja) | 1993-08-25 | 1994-08-24 | N−アミノ−1−ヒドロキシアルキリデン−1,1−ビスホスホン酸の製造法 |
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US (1) | US5510517A (ja) |
EP (1) | EP0715631B1 (ja) |
JP (1) | JP3675818B2 (ja) |
KR (1) | KR100261202B1 (ja) |
CN (2) | CN1067079C (ja) |
AT (1) | ATE160352T1 (ja) |
AU (2) | AU692468B2 (ja) |
BR (1) | BR9407563A (ja) |
CA (1) | CA2169561C (ja) |
CY (1) | CY2086B1 (ja) |
CZ (1) | CZ290185B6 (ja) |
DE (1) | DE69406936T2 (ja) |
DK (1) | DK0715631T3 (ja) |
ES (1) | ES2109731T3 (ja) |
FI (1) | FI115526B (ja) |
GR (1) | GR3025450T3 (ja) |
HK (1) | HK1008883A1 (ja) |
HR (1) | HRP940479B1 (ja) |
HU (1) | HU217362B (ja) |
LV (1) | LV12189B (ja) |
NZ (1) | NZ273458A (ja) |
RO (1) | RO115524B1 (ja) |
RU (1) | RU2154647C2 (ja) |
SI (1) | SI0715631T1 (ja) |
WO (1) | WO1995006052A1 (ja) |
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1994
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