LV10867B - Process for the preparation of azamacrocyclic or acyclic aminophosphonate ester derivatives - Google Patents
Process for the preparation of azamacrocyclic or acyclic aminophosphonate ester derivatives Download PDFInfo
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- LV10867B LV10867B LVP-94-99A LV940099A LV10867B LV 10867 B LV10867 B LV 10867B LV 940099 A LV940099 A LV 940099A LV 10867 B LV10867 B LV 10867B
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- LV
- Latvia
- Prior art keywords
- formula
- thf
- tetrahydrofuran
- triene
- paraformaldehyde
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 104
- 238000002360 preparation method Methods 0.000 title claims description 30
- -1 acyclic aminophosphonate ester Chemical class 0.000 title claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 110
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 41
- 229920002866 paraformaldehyde Polymers 0.000 claims description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 150000002148 esters Chemical class 0.000 claims description 26
- 230000007062 hydrolysis Effects 0.000 claims description 24
- 238000006460 hydrolysis reaction Methods 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000003446 ligand Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 17
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 16
- 239000007983 Tris buffer Substances 0.000 claims description 14
- XTTGYFREQJCEML-UHFFFAOYSA-N tributyl phosphite Chemical compound CCCCOP(OCCCC)OCCCC XTTGYFREQJCEML-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 229910052700 potassium Inorganic materials 0.000 claims description 12
- 229910052708 sodium Inorganic materials 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 9
- QOPBTFMUVTXWFF-UHFFFAOYSA-N tripropyl phosphite Chemical compound CCCOP(OCCC)OCCC QOPBTFMUVTXWFF-UHFFFAOYSA-N 0.000 claims description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 8
- 239000006184 cosolvent Substances 0.000 claims description 8
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 6
- VPGQJHBMALMMJQ-UHFFFAOYSA-N 1-(pyridin-2-ylmethyl)-1,4,7,10-tetrazacyclododecane Chemical compound C=1C=CC=NC=1CN1CCNCCNCCNCC1 VPGQJHBMALMMJQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 5
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims description 3
- 125000003916 ethylene diamine group Chemical group 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 7
- LUMVCLJFHCTMCV-UHFFFAOYSA-M potassium;hydroxide;hydrate Chemical compound O.[OH-].[K+] LUMVCLJFHCTMCV-UHFFFAOYSA-M 0.000 claims 5
- 238000000926 separation method Methods 0.000 claims 4
- 238000002955 isolation Methods 0.000 claims 3
- 238000007363 ring formation reaction Methods 0.000 claims 3
- DEVWEFBXXYMHIL-UHFFFAOYSA-N CCCOP(O)=O Chemical compound CCCOP(O)=O DEVWEFBXXYMHIL-UHFFFAOYSA-N 0.000 claims 2
- WCJLOEFXANROAO-UHFFFAOYSA-N CCCCOP(O)=O Chemical compound CCCCOP(O)=O WCJLOEFXANROAO-UHFFFAOYSA-N 0.000 claims 1
- FJHPGVWPKINBMP-UHFFFAOYSA-H [Ca++].[Ca++].[Ca++].[O-]P([O-])=O.[O-]P([O-])=O.[O-]P([O-])=O Chemical compound [Ca++].[Ca++].[Ca++].[O-]P([O-])=O.[O-]P([O-])=O.[O-]P([O-])=O FJHPGVWPKINBMP-UHFFFAOYSA-H 0.000 claims 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 229940042400 direct acting antivirals phosphonic acid derivative Drugs 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 150000003007 phosphonic acid derivatives Chemical class 0.000 claims 1
- 238000011084 recovery Methods 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 101150054171 thf1 gene Proteins 0.000 claims 1
- 150000005671 trienes Chemical class 0.000 claims 1
- 238000005481 NMR spectroscopy Methods 0.000 description 33
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 18
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 16
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 14
- 125000000217 alkyl group Chemical group 0.000 description 13
- 239000000243 solution Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 125000002015 acyclic group Chemical group 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000004679 31P NMR spectroscopy Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229940120146 EDTMP Drugs 0.000 description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RCXMQNIDOFXYDO-UHFFFAOYSA-N [4,7,10-tris(phosphonomethyl)-1,4,7,10-tetrazacyclododec-1-yl]methylphosphonic acid Chemical compound OP(O)(=O)CN1CCN(CP(O)(O)=O)CCN(CP(O)(O)=O)CCN(CP(O)(O)=O)CC1 RCXMQNIDOFXYDO-UHFFFAOYSA-N 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- NFDRPXJGHKJRLJ-UHFFFAOYSA-N edtmp Chemical compound OP(O)(=O)CN(CP(O)(O)=O)CCN(CP(O)(O)=O)CP(O)(O)=O NFDRPXJGHKJRLJ-UHFFFAOYSA-N 0.000 description 3
- 150000003009 phosphonic acids Chemical class 0.000 description 3
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 3
- 238000000607 proton-decoupled 31P nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002518 distortionless enhancement with polarization transfer Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 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 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 238000008947 Amm Methods 0.000 description 1
- 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 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 239000012614 Q-Sepharose Substances 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 229940090960 diethylenetriamine pentamethylene phosphonic acid Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- DUYCTCQXNHFCSJ-UHFFFAOYSA-N dtpmp Chemical compound OP(=O)(O)CN(CP(O)(O)=O)CCN(CP(O)(=O)O)CCN(CP(O)(O)=O)CP(O)(O)=O DUYCTCQXNHFCSJ-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 238000000079 presaturation Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 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
- C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
-
- 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (34)
- LV 10867 AZAMAKROCIKLISKU VAI ACIKLISKU AMLNOFOSFONSKĀBJU ESTERU ATVASINĀJUMU IEGŪŠANAS METODE PATENTA FORMULA 1. Azamakrociklisku vai aciklisku aminofosfonskābju esteru atvasinājumu iegūšanas metode, kas ietver vismaz viena sekundāra vai primāra slāpekļa atoma aizvietošanu ar vismaz vienu daļu no formulas -CH2PO3RR1 (I) kur: R ir H vai C i*C 5 alkilgrupa, ar nosacījumu, ka katrs R ir tā pati grupa; Rl ir C1-C5 alkilgr.. H, Na vai K; ar nosacījumu, ka katrs R un R* ir tā pati grupa, kad ir C1-C5 alkilgrupa. kas ietver attiecīga neaizvietota amīna savienojuma reaģēšanu ar trialkilfosfītu un paraformaldehīdu, lai iegūtu atvasinājumus ar formulu (I), kur visi R un R^ ir Cl-C5 alkilgr.. un (a) neobligāti sekojošu ' bāzisku hidrolīzi ūdeni, lai iegūtu savienojuma ar formulu (I) atvasinājumus, kur R ir C1-C5 alkilgr. un Rl ir H, Na vai K; un/vai (b) neobligāti sekojošu skābu hidrolīzi, lai iegūtu savienojuma ar formulu (I) atvasinājumus, kur visi R un R* ir H.
- 2. Metode, saskaņā ar 1. punktu, kur produkta ar formulu (I> atvasinājumā visi R un Rl ir C1-C5 alkilgrupa.
- 3. Metode, saskaņā ar 2. punktu, 1,4,7,10-tetraazaciklododekān--1,1,7,10-metilēndibutilfosfonāta iegūšanai, kas ietver ciklēna reaģēšanu ar tributilfosfitu un paraformaldehīdu tetrahidrofurānā (THF). 2
- 4. Metode, saskaņā ar 2. punktu, 1,4,7,10-tetraazaciklododekān--1,4,7,10-metilēndietilfosfonāta iegūšanai, kas ietver ciklēna reaģēšanu ar trietilfosfitu un paraformaldehīdu tetrahidrofurānā (THF).
- 5. Metode, saskaņā ar 2. punktu, N,N'-bis(metilēndimetilfosfo-nāt)-2,ll-diaza[3.3](2,6)pidinofāna iegūšanai, kas ietver 2,11--diaza[3.3ļ(2,6)pidinofāna reaģēšanu ar trimetilfosfitu un paraformaldehīdu tetrahidrofurānā (THF).
- 6. Metode, saskaņā ar 2. punktu, N,N’-bis(metilēndietilfosfonāt)--2,1 l-diazaf3.31(2,6)pidinofāna iegūšanai, kas ietver 2,11--diazaf3.3](2,6)pidinofāna reaģēšanu ar trietilfosfitu un paraform-aldehidu tetrahidrofurānā (THF).
- 7. Metode, saskaņā ar 2. punktu, N-(2-piridilmetil)-N,,N ",N"'-tns-(metilēndietilfosfonāt)-1,4,7,10-tetraazaciklododekāna iegūšanai, kas ietver N-(2-piridilmetil)-l,4,7,10-tetraazaciklododekāna reaģēšanu ar trietilfosfitu un paraformaldehīdu tetrahidrofurānā (THF).
- 8. Metode, saskaņā ar 2. punktu, N-(2-piridilmetil)-N’,N",N'"-tris-(metilēndipropilfosfonāt)-1,4,7,10-tetraazaciklododekāna iegūšanai, kas ietver N-(2-piridilmetil)-l,4,7,10-tetraazaciklododekāna reaģēšanu ar tripropilfosfitu un paraformaldehīdu tetrahidrofurānā (THF).
- 9. Metode, saskaņā ar 2. punktu, 3,6,9,15-tetraazabicik-lo[ 9.3. llpentadeka-1(15),11,13-triēn-3,6,9-metilēndietilfosfonāta iegūšanai, kas ietver 3,6,9,15-tetraazabicik 1 of9.3.lļpentadeka--1(15),11,13-triēna reaģēšanu ar trietilfosfitu un paraformaldehīdu tetrahidrofurānā (THF).
- 10. Metode, saskaņā ar 2. punktu, 3,6,9,15-tetraazabicik-lo[9.3. llpentadeka-1(15),11,13-triēn-3,6,9-metilēndi(n-propil)fosfo-nāta iegūšanai, kas ietver 3,6,9,15-tetraazabiciklo[9.3.llpentadeka- LV 10867 3 -l(15),11.13*triēna reaģēšanu ar tripropilfosfitu un paraform-aldehīdu tetrahidrofurānā (THF).
- 11. Metode, saskaņā ar 2. punktu, 3,6,9,15-tetraazabicik-lo[9.3.1]pentadeka-l(15),ll,13-triēn-3,6,9-metilēndi(n-butibfosfo-nāta iegūšanai, kas ietver 3,6,9,15-tetraazabiciklof9.3.1]pentadeka--1(15),11,13-triēna reaģēšanu ar tributilfosfitu un paraform-aldehidu tetrahidrofurānā (THF).
- 12. Metode, saskaņā ar 1. punktu, kur produkta ar formulu (I) atvasinājumos visi R ir H, Na vai K un visi R^ ir C1-C5 alkilgrupa.
- 13. Metode, saskaņā ar 12. punktu, 1,4,7,10-tetraciklododekān--1,4,7,10-tetrametilēnbutilfosfonāta tetrakālija sāls iegūšanai, kas ietver ciklēna reaģēšanu ar tributilfosfitu un paraformaldehīdu tetrahidrofurānā (THF), lai iegūtu 1,4,7,10-tetraazaciklododekān--1 ,4 ,7,10-metilēndibutilfosfonātu, sekojošu iegūtā starpprodukta izdalīšanu, un tad bāzisku hidrolīzi'ar KOH ūdens un dioksāna kosolventā, lai iegūtu vēlamo produktu.
- 14. Metode, saskaņā ar 12. punktu, N,N’-bis(metilēnfosfonskābes etilesterj-2,ll-diaza[3.3](2,6)pidinofana iegūšanai, kas ietver 2,11--diaza[3.3](2,6)pidinofāna reaģēšanu ar trietilfosfītu un paraformaldehīdu tetrahidrofurānā (THF), lai iegūtu N,N‘--bis(metilēndietilfosfonāt)-2,l l-diazaf3.31(2,6)pidinofānu, sekojošu iegūtā starpprodukta izdalīšanu, un tad bāzisku hidrolīzi ar KOH ūdeni, lai iegūtu vēlamo produktu.
- 15. Metode, saskaņā ar 12. punktu, 3,6,9,15-tetraazabicik-ΙοΓ 9.3.1 ļpen tadeka-l( 15),11,13-triēn-3,6,9-metilēn(n-butil)fo3fonāta tris<kālija sāls) iegūšanai, kas ietver 3,6,9,15-tetraazabicik-1οΓ9-3.1 ļpentadeka-1( 15),11,13-triēna reaģēšanu ar tributilfosfitu un paraformaldehīdu tetrahidrofurānā (THF), lai iegūtu 3,6,9,15--tetraazabiciklo[9.3.1 ļpentadeka-1( 15), ll,13-triēn-3,6,9-metilēn-di(n-butil)fosfonātu, sekojošu iegūtā starpprodukta izdalīšanu, un 4 tad bāzisku hidrolīzi ar KOH ūdens un dioksāna kosolventā, lai iegūtu vēlamo produktu.
- 16. Metode, saskaņā ar 12. punktu, 3,6,9,15-tetraazabicik-lo[9.3.1ļpentadeka-l( 15),1 l,13-triēn-3,6,9-metilēn(n-propil)fosfonā-ta trisCkālija sāls) iegūšanai, kas ietver 3,6,9,15-tetraazabicik-lo[9.3.11pentadeka-l( 15),11,13-triēna reaģēšanu ar tripropilfosfitu un paraformaldehīdu tetrahidrofurānā (THFj, lai iegūtu 3,6,9,15--tetraazabicikloi9.3.1 ]pentadeka-l( 15),11,13-triēn-3,6,9-metilēn-di(n-propil)fosfonātu, sekojošu iegūtā starpprodukta izdalīšanu un tad bāzisku hidrolīzi ar KOH ūdenī, lai iegūtu vēlamo produktu.
- 17. Metode, saskaņā ar 12. punktu, 3,6,9,15-tetraazabicik-lo[9.3.1ļpentadeka-1(15),1 l,13-triēn-3,6,9-metilēnetilfosfonāta trisikālija sāls) iegūšanai, kas ietver 3,6,9,15-tetraazabicik-lo[9.3.l]pentadeka-l(15),l 1,13-triēna reaģēšanu ar trietilfosfitu un paraformaldehīdu tetrahidrofurānā (THF), lai iegūtu 3,6,9,15--tetraa7.abiciklo[9.3.1]pentadeka-l( 15),ll,l3-triēn-3,6,9-meulēndie-tilfosfonātu, sekojošu iegūtā starpprodukta izdalīšanu, un tad bāzisku hidrolīzi ar KOH ūdeni, lai iegūtu vēlamo produktu.
- 18. Metode, saskaņā ar 12. punktu, N-(2-piridilmetil)-N',N",N"'--tris(metilēnfosfonskābes etilester)-l,4,7,10-tetraazaciklododekāna iegūšanai, kas ietver N-(2-piridilmetil)-l,4,7,10-tetraazaciklo-dodekāna reaģēšanu ar trietilfosfitu un paraformaldehīdu tetrahidrofurānā (THF), lai iegūtu N-(2-piridilmetil)-N ,N'',N '--trisimetilēndietilfosfonāt)-1,4,7,10-tetraazaciklododekānu, sekojošu iegūtā starpprodukta izdalīšanu un tad bāzisku hidrolīzi ar KOH ūdenī, lai iegūtu vēlamo produktu.
- 19. Metode, saskaņā ar 12. punktu, N-(2-piridilmetil)-N ,N",N "--tris(metilēnfosfonskābes propilester)-1,4,7,10-tetraazaciklodode-kāna iegūšanai, kas ietver N-(2-piridilmetil)-l,4,7,10-tetraaza-ciklododekāna reaģēšanu ar tripropilfosfitu un paraformaldehīdu tetrahidrofurānā (THF), lai iegūtu N-(2-piridilmetil)-N',N',,N'"- 5 LV 10867 -tris(metilēndipropilfosfonāt)-l,4,7,10-tetraazaciklododekānu, sekojošu iegūtā starpprodukta izdalīšanu un tad bāzisku hidrolīzi ar KOH ūdeni, lai iegūtu vēlamo produktu.
- 20. Metode, saskaņā ar 1. punktu, kur produkta ar formulu (I) atvasinājumos visi R un Rl ir H, Na vai K.
- 21. Metode, saskaņā ar 20. punktu, N,N’-bis(metilēnfosfon-skābes)-2,ll-diaza[3.3](2,6)pidinofana iegūšanai, kas ietver 2,11--diaza[3.3](2,6)pidinofana reaģēšanu ar trimetilfosfitu un paraform-aldehīdu tetrahidrofurānā (THF), lai iegūtu N,N’-bis(meti-lēndimetilfosfonāt)-2,ll-diaza[3.3](2,6)pidinofanu, starpprodukta hidrolizi ar karstu HC1 un vēlamā produkta izdalīšanu.
- 22. Metode, saskaņā ar ļ. punktu, kur trialkilfosfits ir tri(Cl-C4 --alkiDfosfīts.
- 23. Metode, saskaņā ar 1. punkta daļu (a), kur ūdens bāze ir sārmu metāla hidroksīds.
- 24. Metode, saskaņā ar 1. punkta daļu (a), kurR vai R* grupa ir C3-C5 alkilgr., un klāt ir organisks kosolvents, kas jaucas ar ūdeni.
- 25. Metode, saskaņā ar 1. punktu, kur savienojuma ar formulu (I) atvasinājums ir azamakrociklisks ligands, kur R un Rl abi vienādi ir C1-C5 alkilgr., un temperatūra tiek noturēta zem 40 °C reakcijas pirmās stundas laikā.
- 26. Metode, saskaņā ar 1. punktu, kur savienojuma ar formulu (I) atvasinājums ir azamakrociklisks ligands, kur R un R^ abi vienādi ir Cl-C5 alkilgr.. un klāt ir bezūdens šķidrums.
- 27. Metode, saskaņā ar 26. punktu, kur šķidrums ir aprotonisks polārs šķīdinātājs vai spirts. 6
- 28. Metode, saskaņā ar 27. punktu, kur šķīdinātājs ir tetrahidrofurāns.
- 29. Metode, saskaņā ar 1. punktu, kur savienojuma ar formulu (I) atvasinājums ir aciklisks amīns, kur R un abi vienādi ir Cl-C5alkilgrupa,un temperatūra tiek noturēta zem 40 °C reakcijas pirmās stundas laikā.
- 30. Metode, saskaņā ar 29. punktu, kur trialkilfosfīts un paraformaldehīds tiek savienoti un sākumā atdzesēti, pēc tam kontrolējot tiek pievienots aciklisks amīns, pie kam temperatūra tiek noturēta, izmantojot ledus vannu.
- 31. Metode, saskaņā ar 29. punktu, kur aciklisks amīns ir etilēndiamīns, dietilēntriamīns vai trietilēntetraamīns.
- 32. Metode, saskaņā ar 31. punktu, kur bāziska hidrolizē dod mono-alkilfosfonātus.
- 33. Metode, saskaņā ar 32. punktu, kur skāba hidrolizē dod attiecīgus fosfonskābes atvasinājumus, kuri ir etilēndiamino-tetrametilēnfosfonskābe, dietilēntriaminopentametilēnfosfonskābe vai trietilēntetraaminoheksametilēnfosfonskābe.
- 34. Metode, saskaņā ar 1. punktu, kur azamakrocikliskus vai acikliskus aminofosfonātu atvasinājumus attēlo ar formulu A - (N-CH2CH2-N)q-Z (II) kur: q ir vesels skaitlis no 1 līdz 5 ieskaitot; A var būt 0, 1 vai 2 1. punkta formulas (I) daļas vai ūdeņradis; Z var būt 0, 1 vai 2 1. punkta formulas (I) daļas vai ūdeņradis; LV 10867 7 ar nosacījumu, ka ir pārstāvēta vismaz viena, A vai Z, 1. punkta formulas (I) daļa un A un Z var būt savienoti, lai iegūtu ciklisku 5 savienojumu.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/065,963 US5714604A (en) | 1993-05-06 | 1993-05-06 | Process for the preparation of azamacrocyclic or acyclic aminophosphonate ester derivatives |
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| Publication Number | Publication Date |
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| LV10867A LV10867A (lv) | 1995-10-20 |
| LV10867B true LV10867B (en) | 1996-08-20 |
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| Country | Link |
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| US (1) | US5714604A (lv) |
| EP (1) | EP0698029B1 (lv) |
| JP (1) | JP3556669B2 (lv) |
| KR (1) | KR100311560B1 (lv) |
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| AT (1) | ATE172978T1 (lv) |
| AU (1) | AU682190B2 (lv) |
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| CZ (1) | CZ290993B6 (lv) |
| DE (1) | DE69414382T2 (lv) |
| DK (1) | DK0698029T3 (lv) |
| DZ (1) | DZ1777A1 (lv) |
| EE (1) | EE03159B1 (lv) |
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| ES (1) | ES2123137T3 (lv) |
| FI (1) | FI115632B (lv) |
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| LT (1) | LT3713B (lv) |
| LV (1) | LV10867B (lv) |
| MA (1) | MA23186A1 (lv) |
| NO (1) | NO304742B1 (lv) |
| PL (1) | PL180756B1 (lv) |
| RO (1) | RO115883B1 (lv) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1996030377A1 (en) * | 1995-03-27 | 1996-10-03 | Isis Pharmaceuticals, Inc. | Nitrogenous macrocyclic compounds |
| US6207826B1 (en) | 1995-03-27 | 2001-03-27 | Isis Pharmaceuticals, Inc. | Macrocyclic compounds having nitrogen-containing linkages |
| JP2003501488A (ja) * | 1999-06-11 | 2003-01-14 | ネオルックス コーポレイション | 骨髄抑制のための高投与量放射性核種錯体 |
| US7094885B2 (en) * | 1999-07-11 | 2006-08-22 | Neorx Corporation | Skeletal-targeted radiation to treat bone-associated pathologies |
| EP1225903A2 (en) * | 1999-10-18 | 2002-07-31 | The Dow Chemical Company | Aminoalkylenephosphonates for treatment of bone disorders |
| US6794371B1 (en) * | 1999-10-18 | 2004-09-21 | The Dow Chemical Company | Aminoalkylenephosphonates for treatment of bone disorders |
| US6565828B2 (en) * | 2000-04-07 | 2003-05-20 | Bristol-Myers Squibb Company | Macrocyclic chelants for metallopharmaceuticals |
| CA2434302A1 (en) * | 2001-01-08 | 2002-08-15 | Neorx Corporation | Therapeutic and diagnostic compounds, compositions, and methods |
| EP1438318B1 (en) * | 2001-10-22 | 2005-11-09 | Texas Tech University | Tissue specific fluorescent chelates |
| US20030133872A1 (en) * | 2001-10-22 | 2003-07-17 | Kiefer Garry E. | Radiopharmaceutical agent for the treatment of early stage cancer |
| WO2003051403A1 (en) | 2001-12-13 | 2003-06-26 | Dow Global Technologies Inc. | Treatment of osteomyelitis with radiopharmaceuticals |
| US20050112066A1 (en) * | 2003-11-26 | 2005-05-26 | Concat Lp, A California Limited Partnership | Complexes of cyclic polyaza chelators with cations of alkaline earth metals for enhanced biological activity |
| US20060210479A1 (en) * | 2004-08-10 | 2006-09-21 | Dow Global Technologies Inc. | Targeting chelants and chelates |
| CN112442069A (zh) * | 2019-08-28 | 2021-03-05 | 广东广山新材料股份有限公司 | 一种带有胺基的含磷阻燃剂及其制备方法和应用 |
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| US5362476A (en) * | 1984-10-18 | 1994-11-08 | Board Of Regents, The University Of Texas System | Alkyl phosphonate polyazamacrocyclic cheates for MRI |
| GB8817185D0 (en) * | 1988-07-19 | 1988-08-24 | Interox Chemicals Ltd | Organic polyphosphonates |
| GB8903023D0 (en) * | 1989-02-10 | 1989-03-30 | Parker David | Chemical compounds |
| US5342936A (en) * | 1989-02-10 | 1994-08-30 | David Parker | Tetra-aza macrocycles and processes for their preparation |
| AU649001B2 (en) * | 1989-11-27 | 1994-05-12 | Chelator Llc | MRI image enhancement of bone and related tissue using complexes of paramagnetic cations and polyphosphonate ligands |
| US5236695A (en) * | 1989-11-27 | 1993-08-17 | Concat, Ltd. | MRI image enhancement of bone and related tissue using complexes of paramagnetic cations and polyphosphonate ligands |
| US5385893A (en) * | 1993-05-06 | 1995-01-31 | The Dow Chemical Company | Tricyclopolyazamacrocyclophosphonic acids, complexes and derivatives thereof, for use as contrast agents |
| US5606053A (en) * | 1995-05-02 | 1997-02-25 | Johnson Matthey Plc | Process for preparing 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane |
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