CN1095722A - The method of amine direct phosphorylated synthesizing amino phosphoric acid salt and composition thereof in aqueous systems - Google Patents
The method of amine direct phosphorylated synthesizing amino phosphoric acid salt and composition thereof in aqueous systems Download PDFInfo
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- CN1095722A CN1095722A CN 93121248 CN93121248A CN1095722A CN 1095722 A CN1095722 A CN 1095722A CN 93121248 CN93121248 CN 93121248 CN 93121248 A CN93121248 A CN 93121248A CN 1095722 A CN1095722 A CN 1095722A
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 150000001412 amines Chemical class 0.000 title claims abstract description 15
- 239000000203 mixture Substances 0.000 title claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 8
- JZTPOMIFAFKKSK-UHFFFAOYSA-N O-phosphonohydroxylamine Chemical class NOP(O)(O)=O JZTPOMIFAFKKSK-UHFFFAOYSA-N 0.000 title claims abstract description 5
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims abstract description 54
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 150000001413 amino acids Chemical class 0.000 claims abstract description 31
- 239000000243 solution Substances 0.000 claims abstract description 31
- -1 amino acid ester Chemical class 0.000 claims abstract description 30
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003960 organic solvent Substances 0.000 claims abstract description 24
- 238000005406 washing Methods 0.000 claims abstract description 18
- 238000003756 stirring Methods 0.000 claims abstract description 14
- 150000002148 esters Chemical class 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 9
- 239000011707 mineral Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 150000007524 organic acids Chemical class 0.000 claims abstract description 3
- 235000005985 organic acids Nutrition 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 75
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 239000003513 alkali Substances 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000010189 synthetic method Methods 0.000 claims description 17
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- 239000003495 polar organic solvent Substances 0.000 claims description 15
- 239000011734 sodium Substances 0.000 claims description 14
- 238000000605 extraction Methods 0.000 claims description 13
- 238000007710 freezing Methods 0.000 claims description 13
- 230000008014 freezing Effects 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 11
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 11
- 229960001701 chloroform Drugs 0.000 claims description 11
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 claims description 10
- 235000002639 sodium chloride Nutrition 0.000 claims description 10
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 9
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 235000010755 mineral Nutrition 0.000 claims description 8
- 238000006386 neutralization reaction Methods 0.000 claims description 8
- 235000017550 sodium carbonate Nutrition 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 159000000000 sodium salts Chemical class 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000011575 calcium Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 229940061584 phosphoramidic acid Drugs 0.000 claims description 6
- 159000000007 calcium salts Chemical class 0.000 claims description 5
- 230000008030 elimination Effects 0.000 claims description 5
- 238000003379 elimination reaction Methods 0.000 claims description 5
- 125000000524 functional group Chemical group 0.000 claims description 5
- 239000011833 salt mixture Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229940059260 amidate Drugs 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000012141 concentrate Substances 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 125000003147 glycosyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 229920005862 polyol Polymers 0.000 claims description 4
- 150000003077 polyols Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
- 150000003818 basic metals Chemical class 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims description 2
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims description 2
- 239000004312 hexamethylene tetramine Substances 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 150000002989 phenols Chemical class 0.000 claims description 2
- 150000003333 secondary alcohols Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 229910052788 barium Inorganic materials 0.000 claims 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims 1
- 239000000920 calcium hydroxide Substances 0.000 claims 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims 1
- 235000011116 calcium hydroxide Nutrition 0.000 claims 1
- 125000000532 dioxanyl group Chemical group 0.000 claims 1
- 229910052725 zinc Inorganic materials 0.000 claims 1
- 229940024606 amino acid Drugs 0.000 description 34
- 239000000047 product Substances 0.000 description 17
- 238000004679 31P NMR spectroscopy Methods 0.000 description 12
- 230000006837 decompression Effects 0.000 description 11
- 239000010410 layer Substances 0.000 description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000011574 phosphorus Substances 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- 239000002798 polar solvent Substances 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- ZZIRWFZCZDOZFJ-UHFFFAOYSA-N ethyl acetate;2-methylpropan-2-ol Chemical compound CC(C)(C)O.CCOC(C)=O ZZIRWFZCZDOZFJ-UHFFFAOYSA-N 0.000 description 3
- 238000005554 pickling Methods 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229960001153 serine Drugs 0.000 description 3
- 108010016626 Dipeptides Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229910019440 Mg(OH) Inorganic materials 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000012046 mixed solvent Substances 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
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- ANVPJIVTLVQUNV-UHFFFAOYSA-N 1-[butyl(chloro)phosphoryl]butane Chemical compound CCCCP(Cl)(=O)CCCC ANVPJIVTLVQUNV-UHFFFAOYSA-N 0.000 description 1
- NGQQUXXTDZADNX-UHFFFAOYSA-N 2,3,4,5-tetrachlorofuran Chemical class ClC=1OC(Cl)=C(Cl)C=1Cl NGQQUXXTDZADNX-UHFFFAOYSA-N 0.000 description 1
- ICKHJNMKQISCQZ-UHFFFAOYSA-N 2-[chloro(propan-2-yl)phosphoryl]propane Chemical compound CC(C)P(Cl)(=O)C(C)C ICKHJNMKQISCQZ-UHFFFAOYSA-N 0.000 description 1
- FWEOQOXTVHGIFQ-UHFFFAOYSA-N 8-anilinonaphthalene-1-sulfonic acid Chemical class C=12C(S(=O)(=O)O)=CC=CC2=CC=CC=1NC1=CC=CC=C1 FWEOQOXTVHGIFQ-UHFFFAOYSA-N 0.000 description 1
- 206010006956 Calcium deficiency Diseases 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
- 208000007443 Neurasthenia Diseases 0.000 description 1
- ZQBZAOZWBKABNC-UHFFFAOYSA-N [P].[Ca] Chemical compound [P].[Ca] ZQBZAOZWBKABNC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- ANSUDRATXSJBLY-VKHMYHEASA-N methyl (2s)-2-amino-3-hydroxypropanoate Chemical compound COC(=O)[C@@H](N)CO ANSUDRATXSJBLY-VKHMYHEASA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical class OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Abstract
The present invention relates to a kind of amine direct method of phosphorylated synthesizing amino phosphoric acid salt and based mixtures in aqueous systems; this method is with a certain amount of amino acid or amino acid ester; peptide; peptide ester or amine be water-soluble-mixing solutions of polar solvent-alkali-tetracol phenixin in; add the carbon tetrachloride solution contain equivalent or excessive slightly phosphoryl chloride; stir down at-10 ℃～30 ℃; make its reaction 0.5～20 hour; revolve and desolvate; being acidified to the pH value with mineral acid is 1～3; or with the aqueous solutions of organic acids washing, at last with organic solvent or mixed extractant solvent; washing; dry; be spin-dried for.
Description
The present invention relates to contain the method for amino brothers amine or amino acid, peptide class and ester thereof the synthetic N-phosphorylated thing of direct phosphorylated in Aquo System, belong to the preparing technical field of organic compound.
Amino acid, peptide class and protein are the most basic biochemical substances, and many active small peptides are the important chemical messengers of linking up information between cell and organ.Phosphorus is the central element of life, and it has participated in the Conversion of energy of life entity, information transmission and metabolic processes.Phosphoryl amino acid and peptide class are that a class has higher bioactive compound; be widely used in many fields such as agricultural chemicals, medicine, health care, immunity, will have opened purposes widely in medicine, makeup, healthcare products, food and feed additive field.This compounds as the enzyme transition state analog, is that other material is difficult to replace as haptens in the research of immune catalytic antibody in the research of the inhibitor of enzyme.Some amino (acid) phosphoric acid salt has been applied to treat phosphorus calcium deficiency, neurasthenia and tetter, and many phosphinylidyne small peptides are analgesia, depressor of great use.Therefore, invention synthetic method simpler, convenient, that yield is high, product purity is good is significant.
Prior art once had the report that carries out amino acid whose N-phosphorylated or O-phosphorylated with the dialkyl phosphoryl chloride.As European patent EP 0085488A, the Japanese Patent spy opens clear 58-297921, but all carries out in non-aqueous system.In order to increase its solvability, the former needs carboxyl esterification, and the latter needs amino, carboxyl to protect simultaneously.Carry out N-or O-phosphorylated again, need saponification, acidifying could obtain N-dialkoxy phosphinylidyne amino acid at last.This method not only step is numerous and diverse, and yield is low, and product purity is poor.Serious racemization takes place during saponification easily, and the-oxyl on the phosphoryl is facile hydrolysis also.In addition, selected in the past dialkyl phosphoryl chloride is phenyl and benzyl mostly, and experiment shows that their N-phosphinylidyne product stability is relatively poor.Even so, the little peptide of many phosphorylated still adopts this method, and the method that obtains phosphoryl amino acid or peptide in aqueous systems is also arranged.As using dialkyl sulfide substituted phosphorus oxychloride (R
2P(S) Cl) direct N-phosphoryl amino acid or little peptide in aqueous systems.But latter's product and natural phosphinylidyne amino acid, textural difference is very big, has lost the meaning of research.
Single-oxyl phosphoryl amino acid is synthetic also report, as phenyl phosphinylidyne dichloro at Ba(OH)
2Can not have functional group's amino acid reaction in the aqueous solution with the minority side chain, obtain the barium salt of phosphamide list phenyl acid esters, but most of amino acid and peptide and inapplicable, the phosphorus acylation reaction of alkyl phosphinylidyne dichloro in water do not appear in the newspapers as yet.
With phosphorus oxychloride in aqueous systems in the presence of MgO or NaOH directly N-phosphoryl amino acid or little peptide report is also arranged, but it is low all to fail to solve yield, reaction is difficult to control, the complicated problem of purifying of being difficult for of product.The evaluation of product lacks enough foundations.The simple and direct synthetic method but the phosphorus oxychloride direct method be can yet be regarded as is so its best synthesis technique is worth exploring.
Purpose of the present invention be exactly to seek a kind of easy and be easy to realize with the equal direct universal synthesis method of each seed amino acid of highly selective N-phosphorylated, little peptide and ester thereof, brothers amine in the aqueous solution of single acyl chlorides of phosphorus, two acyl chlorides, three acyl chlorides.Synthetic method is greatly simplified, and product yield height, purity are good.
Content of the present invention is:
Amine is the directly method of phosphorylated synthesizing amino phosphoric acid salt and composition thereof following four chemical equation realization of foundation respectively in aqueous systems:
(A) the building-up reactions formula of N-dialkyl phosphoramide types compound is:
Its synthetic method is: with a certain amount of amino acid or amino acid ester or amine water-soluble～mixing solutions of alcohol～alkali～tetracol phenixin in, add the carbon tetrachloride solution contain equivalent or excessive slightly phosphoryl chloride, stir down at-10 ℃～30 ℃, make its reaction 0.5～20 hour, revolve and desolvate, being acidified to pH value with mineral acid is 1～3, or with aqueous solutions of organic acids washing, at last with organic solvent or mixed extractant solvent, washing, drying, be spin-dried for;
(B) the building-up reactions formula of phosphoramidic acid monoester compound is:
Polar organic solvent wherein is dioxane or tetrahydrofuran (THF);
Its synthetic method is: with a certain amount of amino acid, the peptide class, amino acid ester, peptide, peptide ester or aminated compounds be water-soluble～polar organic solvent～alkali～carbon tetrachloride solution in, as splashing into the carbon tetrachloride solution that contains equivalent or excessive slightly alkyl phosphinylidyne dichloro in tetrachloro furans or the dioxane～water～triethylamine (excessive),-10 ℃～30 ℃ stirring reactions 0.5～20 hour, preferably 5～6 hours, with general organic solvent (as 1, the 2-ethylene dichloride, trichloromethane, sherwood oil, ethyl acetate, hexanaphthene, the trimethyl carbinol, methylene dichloride, isopropylcarbinol, butanols, primary isoamyl alcohol, tertiary amyl alcohol, dimethylbenzene, ether and toluene), collection eccysis decon, the Na of adding equivalent
2CO
3Or NaOH, with neutralization extraction with revolve triethylamine, add CaCl
2Or NaCl, necessity is that the elimination insolubles is spin-dried for or adds Virahol or acetone freezing and crystallizing, can obtain sodium salt or calcium salt.
(C) the building-up reactions formula of phosphoramidic acid salt compounds is:
Polar organic solvent wherein is any in dioxane, tetrahydrofuran (THF), Virahol, the secondary-tertiary alcohol;
Its synthetic method is: with a certain amount of amino acid, the peptide class, amino acid ester, peptide, peptide ester or aminated compounds be water-soluble～polar organic solvent～alkali～carbon tetrachloride solution in, as splashing into the carbon tetrachloride solution that contains equivalent or excessive slightly alkyl phosphinylidyne dichloro in tetrahydrofuran (THF) or Virahol or the dioxane～water～triethylamine (excessive),-10 ℃～30 ℃ following stirring reactions 0.5～20 hour, preferably 5～6 hours, with general organic solvent (as 1, the 2-ethylene dichloride, trichloromethane, sherwood oil, ethyl acetate, hexanaphthene, the trimethyl carbinol, methylene dichloride, isopropylcarbinol, butanols, primary isoamyl alcohol, tertiary amyl alcohol, dimethylbenzene, ether and toluene), collection eccysis decon, the Na of adding equivalent
2CO
3Or NaOH, with neutralization extraction with revolve triethylamine, add CaCl
2Or NaCl, necessity is that the elimination insolubles is spin-dried for or adds Virahol or acetone freezing and crystallizing, can obtain sodium salt or calcium salt;
(D) the synthetic reaction formula of the mixture of phosphoro-amidate, phosphoramidic acid monoesters N-dialkyl phosphamide compound is:
Wherein said polar organic solvent is methyl alcohol, ethanol, propyl alcohol or butanols;
Its synthetic method is: with a certain amount of amino acid, the peptide class, amino acid ester, peptide, peptide ester or aminated compounds be water-soluble～polar organic solvent～alkali～carbon tetrachloride solution in, splash into the carbon tetrachloride solution that contains equivalent or excessive slightly alkyl phosphinylidyne dichloro,-10 ℃～30 ℃ following stirring reactions 0.5～20 hour, preferably 5～6 hours, with general organic solvent (as 1, the 2-ethylene dichloride, trichloromethane, sherwood oil, ethyl acetate, hexanaphthene, the trimethyl carbinol, methylene dichloride, isopropylcarbinol, butanols, primary isoamyl alcohol, tertiary amyl alcohol, dimethylbenzene, ether and toluene), collection eccysis decon, the Na of adding equivalent
2CO
3Or NaOH, with neutralization extraction with revolve triethylamine, react afterwards with equivalent sodium hydroxide or yellow soda ash or other alkali as (Ca(OH)
2, Ba(OH)
2, Mg(OH)
2, Fe(OH)
2, Zn(OH)
2, to regulate PH be 10～11, after washing with above-mentioned organic solvent extracting, concentrates or add the pure freezing of correspondence, can separate out sodium salt or other metal-salt of mix products; Also can regulate PH with sodium hydroxide or yellow soda ash earlier is 10～11, adds the mineral acid water-soluble salt of corresponding other metal as (CaCl after collection is washed and concentrated
2, BaCl
2, FeCl
2, ZnCl
2, MgCl
2) heat filtering removes insolubles, and use the small amount of thermal water washing.Add acetone, Virahol or corresponding alcohol again, freezing, crystallization can obtain other metal salt mixture such as mixing prod;
In above-mentioned four reaction formula, R, R
1And R
2Be respectively that carbonatoms is the alkyl of any functional group in the alkyl of 0-18 or the imidazolyl that has hydroxyl, aryl, halogen, glycosyl, alkoxyl group, ester group protection amino, R
1And R
2Can be ring-type, straight or branched, can be interconnected to ring; R
3And R
4Be respectively alkyl or the alkyl that has any functional group in hydroxyl, aryl, halogen, glycosyl, alkoxyl group, ester group, protection amino, the imidazolyl; perhaps (b) is that any M in natural amino acid, synthesizing amino acid, amino acid derivative and the little peptide is basic metal (K, Na), alkaline-earth metal (Ca, Mg; Ba; Zn, ion Fe) or quaternary amine.
The alcohol of reactant is primary alconols such as methyl alcohol, ethanol, propyl alcohol, butanols or ethylene glycol, propylene glycol, 1, the 4-butyleneglycol, and 1, water-soluble polyols such as 5-pentanediol, glycerol, ROH is that secondary alcohol or phenols are that class is mainly phosphoro-amidate.
The consumption of phosphorus reagent can be 1～2.5 equivalent, when synthetic alkali acidic amino acid or little peptide, can obtain single or two phosphorylated thing, but too much will increase hydrolysis and become peptide to become the ester by product with phosphorus, the reaction preference that improves in shortage.
Aqueous solvent adds for the solvability of improving amino acid or peptide is beneficial to its smooth N-phosphorylated, for its ester class or primary, parahelium class, can add water, alcohol, polar solvent.But moisture or pure system reaction is smooth in the same old way.
Alcohol, polar organic solvent add C in order to increase the profit mutual solubility
1～C
5Any alcohol all can, the polar solvent dioxane is effective.As do not add alcohol, the polar solvent yield will significantly reduce.And reaction not exclusively, and by product is many.It is favourable to reaction that water-soluble bigger amino acid is added phase-transfer catalyst.
Alkaline reagents can be acid binding agents such as any mineral alkali such as sodium hydroxide, yellow soda ash, sodium bicarbonate or organic bases such as Trimethylamine 99, triethylamine, xylidene(s), N-first morpholine, diethyl-aniline, hexamethylenetetramine, their effect is a maintenance system alkalescence, the hydrochloric acid that neutralization produces is beneficial to amino dissociating.Consumption can also can obtain higher yields for (1～20 equivalent) adds equivalent alkali, and highly basic may cause the serious racemization of amino acid or little peptide, so organic bases is better.The alkali of several reactions is preferable with the triethylamine effect.
Temperature of reaction gets final product in room temperature, can lower the temperature or heat up in case of necessity.Low-temp reaction is favourable to the generation of principal product.Reaction times is according to the reactant difference, can be from half an hour to 24 hour, and the short period of time reaction will reduce the racemization of amino acid or peptide.The amino acid esters time lengthening there is no benefit.
Organic solvent extract is 1, any in 2-ethylene dichloride, trichloromethane, sherwood oil, ethyl acetate, hexanaphthene, the trimethyl carbinol, methylene dichloride, isopropylcarbinol, butanols, primary isoamyl alcohol, tertiary amyl alcohol, dimethylbenzene, ether and the toluene, or any in described solvent liquid before any two kinds such as sherwood oil～trimethyl carbinol, hexanaphthene～butanols, the ethyl acetate～trimethyl carbinol arranged.With mixed extractant solvent (c
1, c
2) time, obtained very satisfied effect.One of extraction agent solvent can be ether, chloroform, tetracol phenixin, ethyl acetate, and another kind is strong and boiling point and water-soluble moderate C of polarity
4～C
5Any brothers tertiary alcohol.The ratio of the two can be regulated arbitrarily according to product property.The trimethyl carbinol～ethyl acetate is more economic and general mixed extractant.And available anhydrous Na
2SO
4Or MgSO
4Dry.Therefore above-mentioned mixed solvent system is expected that to prepare the method for classes of compounds as follows obtaining widespread use aspect the polar material extraction:
N-dialkyl phosphoramide types compound: (C
1)
The amino acid (or peptide) of 10mmol is dissolved in 5ml water～5ml ethanol～5ml NEt
3Mixed system in, specified phosphoryl chloride that places ice bath to stir to add equivalent down and the CCl of 5ml
4Mixed solution stir 6～8h.Add 20～50ml moisture then and go organic phase, wash (2X15ml) two times with ether, with hcl acidifying to pH value is 2, uses three times (3X40ml) of the mixed solvent trimethyl carbinol～ethyl acetate (1: 1.5) extraction again, uses anhydrous Na at last with saturated common salt water washing secondary (2X20ml)
2SO
4Or MgSO
4Dry, be spin-dried for, promptly get pure product, yield is 70～95%.Control suitable rate of addition, increase the compatibility of system, the adding of violent stirring and polar solvent and long reaction times are the keys that obtains better yield.
Or with 10ml amino acid ester or its hydrochloride of amine, 5ml water～5ml ethanol～5mlNEt
3Mixed system in, specified phosphoryl chloride that places ice bath to stir to add equivalent down and the CCl of 5ml
4Mixed solution stirring reaction after 2 hours, with ethyl acetate extraction three times (3X20ml), merge, use pickling lixiviating impurity again, saturated common salt washing secondary, drying is threaded onto and promptly gets pure product, yield 85～95%.
Phosphoramidic acid monoester class compound: (C
2)
With a certain amount of amino acid, peptide class, amino acid ester, peptide, peptide ester or aminated compounds water-soluble～polar organic solvent～alkali～carbon tetrachloride solution, as splashing into the carbon tetrachloride solution that contains equivalent or excessive slightly alkyl phosphinylidyne dichloro in dichloro six ring～water～triethylamine (excessive), stirred 0.5～20 hour preferably 5～6 hours down at-10 ℃～30 ℃.With general organic solvent (as 1,2-ethylene dichloride, trichloromethane, sherwood oil, ethyl acetate, cyclohexane, the trimethyl carbinol, methylene dichloride, isopropylcarbinol, butanols, primary isoamyl alcohol, dimethylbenzene, ether and toluene), collection eccysis decon, the Na of adding equivalent
2CO
3Or NaOH, with neutralization extraction with revolve triethylamine.Add CaCl
2Or NaCl, the elimination insolubles is spin-dried for or adds Virahol or acetone freezing and crystallizing in case of necessity, can obtain sodium salt or calcium salt, pure product yield 70～85%.
Phosphoramidic acid salt compounds: (C
3)
With a certain amount of amino acid, peptide, and ester or aminated compounds water-soluble～polar organic solvent～alkali～tetracol phenixin in, in tetrahydrofuran (THF) or dioxane～water～triethylamine, splash into the carbon tetrachloride solution of the phosphorus oxychloride that contains equivalent, stirred preferably 5～6 hours 0.5～20 hour at-10 ℃～30 ℃, with common organic solvents (as 1, the 2-ethylene dichloride, trichloromethane, sherwood oil, ethyl acetate, hexanaphthene, the trimethyl carbinol, methylene dichloride, ether) collection eccysis decon, the NaOH or the Na of adding equivalent
2CO
3Or other alkali such as Ca(OH)
2, Ba(OH)
2, Fe(OH)
2, Zn(OH)
2Deng, regulating PH is 10～11, after washing with above-mentioned solvent collection, concentrates or adds the pure freezing of correspondence, can separate out the metal-salt of product.
C
1, C
2, C
3The synthetic method and the c of class mixture (additive)
aClass is identical, and just polar solvent should be selected corresponding alcohol (ROH) for use, as primary alconol such as methyl alcohol, ethanol, propyl alcohol, butanols or ethylene glycol, propylene glycol, 1,4-butyleneglycol, 1, water-soluble polyols such as 5-pentanediol, glycerol etc.
C
1, C
2The synthetic method of class mixture and C
2Class is identical, and just polar solvent should be selected corresponding alcohol (ROH) for use, as primary alconol such as methyl alcohol, ethanol, propyl alcohol, butanols or ethylene glycol, propylene glycol, 1,4-butyleneglycol, 1, water-soluble polyols such as 5-pentanediol, glycerol etc.; Phosphorus reagent should be used alkyl phosphinylidyne dichloro instead.
Back equivalent sodium hydroxide or yellow soda ash or other alkali such as Ca(OH have been reacted)
2, Ba(OH)
2, Mg(OH)
2, Fe(OH)
2, Zn(OH)
2Regulating PH is 10～11, after washing with above-mentioned organic solvent extracting, concentrates or adds the pure freezing of correspondence, can separate out sodium salt or other metal-salt of mix products; Also can regulate PH with sodium hydroxide or yellow soda ash earlier is 10～11, adds the mineral acid water-soluble salt of corresponding other metal as (CaCl after collection is washed and concentrated
2, BaCl
2, FeCl
2, ZnCl
2, MgCl
2) heat filtering removes insolubles, and use the small amount of thermal water washing.Adding the content that acetone, Virahol or corresponding alcohol, freezing, crystallization can obtain other metal salt mixture such as mixing prod again can use
31PNMR or HPLC determine.
Method A: dialkyl group phosphorylated amine (C
1Class)
Embodiment 1.O-sec.-propyl, O-normal-butyl phosphorylated L-Serine: (method A)
With L-Serine (1.05g, 10mmol) be dissolved in 5ml water, in 5ml ethanol and the 5ml triethylamine, ice bath is chilled to 0 ℃ and slowly drips the O-sec.-propyl, (2.14g, 5ml carbon tetrachloride solution 10mmol) reacted 6 hours O-normal-butyl phosphoryl chloride, add 20ml water, tell organic layer, (2 * 15ml) wash water layer, and the residue water layer is 2 with 1N hcl acidifying to pH value with ether, with the trimethyl carbinol-ethyl acetate (1: 1.5) extraction three times (3 * 40ml), organic layer washes twice with saturated common salt, and anhydrous magnesium sulfate drying is removed organic solvent, obtain oily matter and be product, heavy 2.4g productive rate 85%.
Structure determination result: NHCH(CH i-Pro(BuO) P(O)
2OH) COOH
31P NMR δ＝6.9ppm
13C NMR 173.8（8.8），56.0，64.1（2.9）13.5，18.6 32.1（7.3） 65.8（5.9）
Embodiment 2.O, O-di-isopropyl phosphorylated L-L-Ala
(0.89g 10mmol) is dissolved in 5ml water, and in 5ml ethanol and the 5ml triethylamine, ice bath is cooled to 0 ℃ with the L-L-Ala, drip O, O-di-isopropyl phosphoryl chloride (2.0g, 5ml 10mmol), carbon tetrachloride solution reaction 8 hours, the same operation obtains white solid, heavy 2.4g, productive rate 90%.
Structure determination result: (i-PrO)
2P-NHCH(CH)
3COOH
31P NMR 5.5ppm
31C NMR 175.2（4.9）49.3 20.4（2.9）23.6（5.5）72.1（5.9）
Embodiment 3.O, O-di-n-butyl phosphorylated L-serine methylester (method A)
(1.56g 10mmol) is dissolved in 5ml to the hydrochloride of L-serine methylester, in 5ml ethanol and the 5ml triethylamine, the ice bath cooling drips di-n-butyl phosphoryl chloride (2.3g, 5ml carbon tetrachloride solution 10mmol) down, reacted 2 hours, three times (3 * 20ml), merging adds 0.1N salt pickling once (20ml) with ethyl acetate extraction, twice (2 * 20ml) of saturated common salt washing, anhydrous magnesium sulfate drying, decompression are removed organic solvent and are promptly obtained the heavy 2.7g of colorless oil, productive rate 90%.
Structure determination: (n-BuO)
2PNHCH(CH
2OH)-COOMe
31P NMR 7.6 ppm
13P NMR 171.5（4.4），56.0，63.7（5.9），51.4（OMe），12.9，18.0，31.6（5.9），65.6（5.9）
Embodiment 4.O, O-di-isopropyl phosphinylidyne imidazoles (method A)
(0.68g 10mmol) is dissolved in 5ml water, in 5ml ethanol and the 5ml triethylamine with imidazoles, 0 ℃ drips di-isopropyl phosphoryl chloride (2.0g down, 5ml carbon tetrachloride solution 10mmol) reacted 2 hours, used ethyl acetate extraction three times (3 * 20ml), merge and use 0.1N salt pickling once (20ml), twice of saturated common salt washing (2 * 20ml), anhydrous magnesium sulfate drying, removal of solvent under reduced pressure, obtain white solid, the about 2.0g productive rate 85% of weight.
Structure determination:
MW, 232
31P NMR -7.9ppm
13C NMR 138.7（5.8），130.3（13.2），118.3（7.3） 22.4（4.4），73.3（4.4）
Embodiment 5.O, O-ethyl phosphorylated L-L-Ala (method D)
L-L-Ala (0.89g, 10mmol) be dissolved in 5ml water, in 5ml ethanol and the 10ml triethylamine, the cryosel cooling slowly drips phosphorus oxychloride (1.53g under (10～0 ℃) down, 5ml carbon tetrachloride solution 10mmol), reacted 5 hours, organic solvent is removed in decompression, and twice (2 * 20ml), water layer is acidified to PH=3 to water layer in frozen water with extracted with diethyl ether, with ethyl acetate-trimethyl carbinol (1: 1.5) extraction 3 times (3 * 20ml), merge, (2 * 20ml) use anhydrous magnesium sulfate drying, and organic solvent is removed in decompression with saturated common salt washing 2 times, obtain the heavy 1.0g of look solid, productive rate 44%.
Structure determination: (EtO)
2P-NCH(CH
3) COOH,
31P 7.6ppm
13C NMR，ppm（H
2）177.2（8.8），50.8，22.0（2.9） 17.3（7.3），64.0（4.4）
Method B. phosphoramidic acid monoesters class (C
2Class)
Embodiment 6.O-ethyl, phosphorylated Serine disodium salt (method B)
(1.05g 10mmol) is dissolved in 5ml water to the L-Serine, in 5ml dioxane and the 6ml triethylamine, the ice bath cooling drips O-ethyl phosphinylidyne dichloro (1.63g, 5ml carbon tetrachloride solution reaction 10mmol) 12 hours down, organic solvent is removed in decompression, and water layer adding sodium hydroxide (0.8g, 20mmol), PH=11, reacted 4 hours, organic bases, lyophilize are removed in decompression, obtain the heavy 1.9g of white solid, productive rate 73%.
Structure determination: EOPO
2NaNHCH(CH
2OH) COONa
31P NMR 5.8ppm
13C NMR 177.6，57.7，63.6 55.6，14.8
Method C. phosphoramidic acid salt (C
3) class
Embodiment 7. phosphorylated L-L-Ala trisodium salts (method C)
(0.89g 10mmol) is dissolved in 5ml water to the L-L-Ala, in 5ml dioxane and the 10ml triethylamine, cryosel cooling (10～0 ℃) down slowly drips phosphorus oxychloride (1.53g, 5ml carbon tetrachloride solution 10mmol) reacted 6 hours, and organic solvent is removed in decompression, water layer hydro-oxidation sodium transfers to PH=11, reacted 4 hours, organic amine is removed in decompression, and lyophilize obtains white solid, heavy 1.4g, productive rate 60%.
Structure determination: PO
3Na
2NHCH(CH
3) COONa
‘HNMR（D
2O）
31PNMR 7.67ppm
3.65～3.75ppm（M，1H，-CH）
1.40-1.43ppm（d，3H，-CH
3）
Method D: dialkyl phosphamide salt, monoalkyl phosphamide disalt, phosphamide three salt mixture (C
1, C
2, C
3)
The mixture (method D) of the sweet dipeptides of embodiment 8. phosphorylated
(1.32g 10mmol) is dissolved in 5ml water, in 5ml ethanol and the 10ml triethylamine with sweet dipeptides, (organic solvent is removed in decompression for 1.53g, 5ml carbon tetrachloride solution reaction 10mmol) 12 hours slowly to drip phosphorus oxychloride under the cryosel cooling (10～0 ℃), water layer adds sodium hydroxide (1.2g, 30mml) reaction is 6 hours, and organic bases is removed in decompression, adds acetone, freezing, obtain white solid, heavy 1.2g, productive rate 50%
Structure determination: (EtO)
2PCONHCH
2CONHCH
2COONa
Content 50%,
31PNMR, 13.6ppm
EtO（NaO）P（O）NHCH
2CONHCH
2COONa
Content 28%,
31PNMR, 9.5ppm
（NaO）
2P（O）NHCH
2CONHChCOONa
Content 22%,
31PNMR, 6.1ppm
Embodiment 9. phosphorylated Serine salt mixtures (method C)
(1.05g 10mmol) is dissolved in 5ml water to the L-Serine, slowly drips O-ethyl phosphonic acid chlorine (1.65g under the ice bath cooling (0 ℃) in 5ml ethanol and the 6ml triethylamine, 5ml carbon tetrachloride solution reaction 10mmol) 6 hours, organic solvent is removed in decompression, twice (2 * 20ml) of extracted with diethyl ether of water layer, add NaOH and transfer to PH=11, reacted 6 hours, organic bases is removed in decompression, with the trimethyl carbinol-ethyl acetate extraction (1.5: 1) drying, desolventize, obtain white solid, heavy 2.1g, productive rate 82%.
Structure determination: (EtO)
2P(O) NHEH(CH
2OH) COONa
Content 40%, 31PNMR, 8.1ppm
EtO（NaO）P（O）NHCH（CH
2OH）COONa
Content 40%,
31PNMR, 5.8ppm
Claims (4)
1, the method for a kind of amine direct phosphorylated synthesizing amino phosphoric acid salt and composition thereof in aqueous systems is characterized in that this synthetic method realizes according to following four chemical equation respectively:
(1) the building-up reactions formula of N-dialkyl phosphoramide types compound is:
Its synthetic method is: with a certain amount of amino acid or amino acid ester or amine water-soluble～mixing solutions of alcohol～alkali～tetracol phenixin in, add the carbon tetrachloride solution contain equivalent or excessive slightly phosphoryl chloride, stir down at-10 ℃～30 ℃, make its reaction 0.5～20 hour, revolve and desolvate, being acidified to pH value with mineral acid is 1～3, or with aqueous solutions of organic acids washing, at last with organic solvent or mixed extractant solvent, washing, drying, be spin-dried for;
(2) the building-up reactions formula of phosphoramidic acid monoester compound is:
Wherein said polar organic solvent is dioxane or tetrahydrofuran (THF);
Its synthetic method is: with a certain amount of amino acid, the peptide class, amino acid ester, peptide ester or aminated compounds be water-soluble～polar organic solvent～alkali～carbon tetrachloride solution in, as splashing into the carbon tetrachloride solution that contains equivalent or excessive slightly alkyl phosphinylidyne dichloro in tetrahydrofuran (THF) or the dioxane～water～triethylamine (excessive),-10 ℃～30 ℃ stirring reactions 0.5～20 hour, preferably 5～6 hours, with general organic solvent (as 1, the 2-ethylene dichloride, trichloromethane, sherwood oil, ethyl acetate, cyclohexane, the trimethyl carbinol, methylene dichloride, isopropylcarbinol, butanols, primary isoamyl alcohol, tertiary amyl alcohol, dimethylbenzene, ether and toluene) collection eccysis decon, the Na of adding equivalent
2CO
3Or NaOH, with neutralization extraction with revolve triethylamine, add CaCl
2Or NaCl, necessity is that the elimination insolubles is spin-dried for or adds Virahol or acetone freezing and crystallizing, can obtain sodium salt or calcium salt;
(3) the building-up reactions formula of phosphoramidic acid salt compounds is:
Wherein said polar organic solvent is any in dioxane, tetrahydrofuran (THF), Virahol, the secondary-tertiary alcohol;
Its synthetic method is: with a certain amount of amino acid, the peptide class, amino acid ester, peptide, peptide ester or aminated compounds be water-soluble～polar organic solvent～alkali～carbon tetrachloride solution in, as splashing into the carbon tetrachloride solution that contains equivalent or excessive slightly alkyl phosphinylidyne dichloro in tetrahydrofuran (THF) or Virahol or the dioxane～water～triethylamine (excessive),-10 ℃～30 ℃ following stirring reactions 0.5～20 hour, preferably 5～6 hours, with general organic solvent (as 1, the 2-=ethylene dichloride, trichloromethane, sherwood oil, ethyl acetate, cyclohexane, the trimethyl carbinol, methylene dichloride, isopropylcarbinol, butanols, primary isoamyl alcohol, tertiary amyl alcohol, dimethylbenzene, ether and toluene), collection eccysis decon, the Na of adding equivalent
2CO
3Or NaOH, with neutralization extraction with revolve triethylamine, add CaCl
2Or NaCl, necessity is that the elimination insolubles is spin-dried for or adds Virahol or acetone freezing and crystallizing, can obtain sodium salt or calcium salt;
(4) the synthetic reaction formula of the mixture of phosphoro-amidate, phosphoramidic acid monoesters N-dialkyl phosphamide compound is:
Wherein said polar organic solvent is methyl alcohol, ethanol, propyl alcohol or butanols;
Its synthetic method is: with a certain amount of amino acid, the peptide class, amino acid ester, peptide ester or aminated compounds be water-soluble～polar organic solvent～alkali～carbon tetrachloride solution in, splash into the carbon tetrachloride solution that contains equivalent or excessive slightly alkyl phosphinylidyne dichloro,-10 ℃～30 ℃ following stirring reactions 0.5～20 hour, preferably 5～6 hours, with general organic solvent (as 1, the 2-ethylene dichloride, trichloromethane, sherwood oil, ethyl acetate, ring alkane in the sixth of the twelve Earthly Branches, the trimethyl carbinol, methylene dichloride, isopropylcarbinol, butanols, primary isoamyl alcohol, tertiary amyl alcohol, dimethylbenzene, ether and toluene), collection eccysis decon, the Na of adding equivalent
2CO
3Or NaOH, with neutralization extraction with revolve triethylamine, react afterwards with equivalent sodium hydroxide or yellow soda ash or other alkali as (Ca (OH)
2Ba (OH)
2, Mg (OH)
2, Fe (OH)
2, Zn (OH)
2, to regulate PH be 10～11, after washing with above-mentioned organic solvent extracting, concentrates or add the pure freezing of correspondence, can separate out sodium salt or other metal-salt of mix products; Also can regulate PH with sodium hydroxide or yellow soda ash earlier is 10～11, adds the mineral acid water-soluble salt of corresponding other metal as (CaCl after collection is washed and concentrated
2, BaCl
2, FeCl
2, ZnCl
2, MgCl
2) heat filtering removes insolubles, and use the small amount of thermal water washing.Add acetone, Virahol or corresponding alcohol again, freezing, crystallization can obtain other metal salt mixture such as mixing prod;
In above-mentioned four reaction formula, described R, R
1And R
2Be respectively that carbonatoms is the alkyl of any functional group in the alkyl of 0-18 or the imidazolyl that has hydroxyl, aryl, halogen, glycosyl, alkoxyl group, ester group protection amino, R
1And R
2Can be ring-type, straight or branched, can be interconnected to ring; R
3And R
4Be respectively alkyl or the alkyl that has any functional group in hydroxyl, aryl, halogen, glycosyl, alkoxyl group, ester group, protection amino, the imidazolyl, perhaps (b) is any in natural amino acid, synthesizing amino acid, amino acid derivative and the little peptide; M be basic metal (K, Na) or alkaline-earth metal (Ca, Mg, Ba, Zn, ion Fe) or quaternary amine.
2, synthetic method as claimed in claim 1 is characterized in that R wherein
1, R
2, R
3And R
4Be with a kind of alkyl class, described (b) is any in natural amino acid, synthesizing amino acid, amino acid derivative or the little peptide.
3, synthetic method as claimed in claim 1, the ROH that it is characterized in that reactant wherein is primary alconols such as methyl alcohol, ethanol, propyl alcohol, butanols or ethylene glycol, propylene glycol, 1, the 4-butyleneglycol, 1, water-soluble polyols such as 5-pentanediol, glycerol, ROH is that secondary alcohol or phenols are that class is mainly phosphoro-amidate.
4, synthetic method as claimed in claim 1 is characterized in that alkali in wherein said water～alcohol～alkali～tetracol phenixin mixing solutions is that any described in mineral alkali sodium hydroxide, yellow soda ash, sodium bicarbonate, calcium hydroxide and organic bases Trimethylamine 99, triethylamine, xylidene(s), N-first morpholine, diethyl-aniline, the hexamethylenetetramine is any in hydrochloric acid, sulfuric acid and the phosphoric acid in order to the acidifying mineral acid.Described organic solvent in order to extraction is 1, any in 2-ethylene dichloride, trichloromethane, sherwood oil, ethyl acetate, hexanaphthene, the trimethyl carbinol, methylene dichloride, isopropylcarbinol, butanols, primary isoamyl alcohol, tertiary amyl alcohol, dimethylbenzene, ether and the toluene, or any in described solvent liquid before any two kinds such as sherwood oil～trimethyl carbinol, hexanaphthene～butanols, the ethyl acetate～trimethyl carbinol arranged.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93121248A CN1043896C (en) | 1993-12-31 | 1993-12-31 | Method for synthetizing phosphoroamidate and its mixture from amines in water system by direct phosphorylating |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93121248A CN1043896C (en) | 1993-12-31 | 1993-12-31 | Method for synthetizing phosphoroamidate and its mixture from amines in water system by direct phosphorylating |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1095722A true CN1095722A (en) | 1994-11-30 |
| CN1043896C CN1043896C (en) | 1999-06-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93121248A Expired - Fee Related CN1043896C (en) | 1993-12-31 | 1993-12-31 | Method for synthetizing phosphoroamidate and its mixture from amines in water system by direct phosphorylating |
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| Country | Link |
|---|---|
| CN (1) | CN1043896C (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014515044A (en) * | 2011-03-23 | 2014-06-26 | ダウ グローバル テクノロジーズ エルエルシー | Phosphorus-containing flame retardant for polyurethane foam |
| CN106317162A (en) * | 2015-06-29 | 2017-01-11 | 深圳翰宇药业股份有限公司 | Preparation method of N-phosphorylated polypeptide |
| CN107955061A (en) * | 2017-11-15 | 2018-04-24 | 连云港恒运药业有限公司 | The preparation method of Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2 key intermediate |
| CN108329519A (en) * | 2018-01-31 | 2018-07-27 | 福建师范大学 | A kind of polyhydroxy phosphate flame retardants and the preparation method and application thereof |
| CN108793807A (en) * | 2018-07-11 | 2018-11-13 | 济南大学 | A kind of bridge light reinforced concrete phosphamide corrosion inhibitor and preparation method thereof |
| CN114487169A (en) * | 2022-01-05 | 2022-05-13 | 宁波大学 | Chiral amino acid detection method |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1079726A (en) * | 1993-04-09 | 1993-12-22 | 清华大学 | N-phosphorylated thing and synthetic new method thereof |
-
1993
- 1993-12-31 CN CN93121248A patent/CN1043896C/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014515044A (en) * | 2011-03-23 | 2014-06-26 | ダウ グローバル テクノロジーズ エルエルシー | Phosphorus-containing flame retardant for polyurethane foam |
| CN106317162A (en) * | 2015-06-29 | 2017-01-11 | 深圳翰宇药业股份有限公司 | Preparation method of N-phosphorylated polypeptide |
| CN107955061A (en) * | 2017-11-15 | 2018-04-24 | 连云港恒运药业有限公司 | The preparation method of Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2 key intermediate |
| CN107955061B (en) * | 2017-11-15 | 2021-07-30 | 连云港恒运药业有限公司 | Preparation method of degarelix key intermediate |
| CN108329519A (en) * | 2018-01-31 | 2018-07-27 | 福建师范大学 | A kind of polyhydroxy phosphate flame retardants and the preparation method and application thereof |
| CN108793807A (en) * | 2018-07-11 | 2018-11-13 | 济南大学 | A kind of bridge light reinforced concrete phosphamide corrosion inhibitor and preparation method thereof |
| CN114487169A (en) * | 2022-01-05 | 2022-05-13 | 宁波大学 | Chiral amino acid detection method |
| CN114487169B (en) * | 2022-01-05 | 2024-01-16 | 宁波大学 | Chiral amino acid detection method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1043896C (en) | 1999-06-30 |
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