TW200425897A - Process for preparation of cyclic prodrugs of PMEA and PMPA - Google Patents
Process for preparation of cyclic prodrugs of PMEA and PMPA Download PDFInfo
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- TW200425897A TW200425897A TW092132357A TW92132357A TW200425897A TW 200425897 A TW200425897 A TW 200425897A TW 092132357 A TW092132357 A TW 092132357A TW 92132357 A TW92132357 A TW 92132357A TW 200425897 A TW200425897 A TW 200425897A
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- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims description 25
- 125000004122 cyclic group Chemical group 0.000 title description 18
- 229940002612 prodrug Drugs 0.000 title description 10
- 239000000651 prodrug Substances 0.000 title description 10
- 230000008569 process Effects 0.000 title description 9
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 title description 5
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 150000003839 salts Chemical group 0.000 claims abstract description 47
- 229930024421 Adenine Natural products 0.000 claims abstract description 30
- 229960000643 adenine Drugs 0.000 claims abstract description 30
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000005859 coupling reaction Methods 0.000 claims abstract description 17
- 230000008878 coupling Effects 0.000 claims abstract description 13
- 238000010168 coupling process Methods 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract 4
- RRVFYOSEKOTFOG-UHFFFAOYSA-N 1-phenylpropane-1,3-diol Chemical compound OCCC(O)C1=CC=CC=C1 RRVFYOSEKOTFOG-UHFFFAOYSA-N 0.000 claims abstract 3
- 239000002253 acid Substances 0.000 claims description 94
- 238000006243 chemical reaction Methods 0.000 claims description 63
- -1 nitro Chemical group 0.000 claims description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 59
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 43
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 33
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 28
- 239000000126 substance Substances 0.000 claims description 27
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 23
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 21
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 239000007789 gas Chemical group 0.000 claims description 14
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 14
- 230000003287 optical effect Effects 0.000 claims description 12
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 11
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 11
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 10
- 238000012360 testing method Methods 0.000 claims description 10
- 210000004907 gland Anatomy 0.000 claims description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 8
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 235000006408 oxalic acid Nutrition 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000011976 maleic acid Substances 0.000 claims description 6
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 5
- 229910017604 nitric acid Inorganic materials 0.000 claims description 5
- 239000011975 tartaric acid Substances 0.000 claims description 5
- 235000002906 tartaric acid Nutrition 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 239000011347 resin Substances 0.000 claims description 4
- 229920005989 resin Polymers 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Chemical group 0.000 claims description 3
- 238000010494 dissociation reaction Methods 0.000 claims description 3
- 230000005593 dissociations Effects 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 150000007857 hydrazones Chemical class 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 claims 7
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 claims 4
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 claims 2
- 229960005375 lutein Drugs 0.000 claims 2
- 239000001656 lutein Substances 0.000 claims 2
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 claims 2
- 235000012680 lutein Nutrition 0.000 claims 2
- DSWNRHCOGVRDOE-UHFFFAOYSA-N n,n-dimethylmethanimidamide Chemical compound CN(C)C=N DSWNRHCOGVRDOE-UHFFFAOYSA-N 0.000 claims 2
- BLDHGACEPAYSQL-UHFFFAOYSA-N n,n-dipropylmethanimidamide Chemical compound CCCN(C=N)CCC BLDHGACEPAYSQL-UHFFFAOYSA-N 0.000 claims 2
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 claims 2
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 claims 2
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 claims 2
- SRXJZMLETPOSSJ-UHFFFAOYSA-N 1-bromo-2-propylbenzene Chemical compound CCCC1=CC=CC=C1Br SRXJZMLETPOSSJ-UHFFFAOYSA-N 0.000 claims 1
- KWOHONYYAXGTMN-UHFFFAOYSA-N 2,2-dimethyl-4-oxopentanoic acid Chemical compound CC(=O)CC(C)(C)C(O)=O KWOHONYYAXGTMN-UHFFFAOYSA-N 0.000 claims 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims 1
- REJHVSOVQBJEBF-OWOJBTEDSA-N 5-azaniumyl-2-[(e)-2-(4-azaniumyl-2-sulfonatophenyl)ethenyl]benzenesulfonate Chemical compound OS(=O)(=O)C1=CC(N)=CC=C1\C=C\C1=CC=C(N)C=C1S(O)(=O)=O REJHVSOVQBJEBF-OWOJBTEDSA-N 0.000 claims 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical group [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical group [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 claims 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 claims 1
- YYBFUGSMRANVTF-UHFFFAOYSA-N butanedioic acid;methane Chemical compound C.OC(=O)CCC(O)=O YYBFUGSMRANVTF-UHFFFAOYSA-N 0.000 claims 1
- 235000015165 citric acid Nutrition 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 150000004985 diamines Chemical class 0.000 claims 1
- 229960004488 linolenic acid Drugs 0.000 claims 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 claims 1
- 239000011733 molybdenum Chemical group 0.000 claims 1
- 229910052750 molybdenum Chemical group 0.000 claims 1
- 229960005181 morphine Drugs 0.000 claims 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Natural products O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 238000011426 transformation method Methods 0.000 claims 1
- 230000001131 transforming effect Effects 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 abstract description 6
- 238000000746 purification Methods 0.000 abstract description 4
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 abstract 1
- SUPKOOSCJHTBAH-UHFFFAOYSA-N adefovir Chemical compound NC1=NC=NC2=C1N=CN2CCOCP(O)(O)=O SUPKOOSCJHTBAH-UHFFFAOYSA-N 0.000 abstract 1
- 125000001309 chloro group Chemical group Cl* 0.000 abstract 1
- 238000002955 isolation Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 54
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 52
- 229910052739 hydrogen Inorganic materials 0.000 description 44
- 239000001257 hydrogen Substances 0.000 description 44
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 27
- 229910052757 nitrogen Inorganic materials 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 235000019441 ethanol Nutrition 0.000 description 22
- 238000003756 stirring Methods 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 20
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- 239000003814 drug Substances 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
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- 125000000217 alkyl group Chemical group 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 150000002009 diols Chemical class 0.000 description 9
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 9
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- 238000004458 analytical method Methods 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 238000002309 gasification Methods 0.000 description 7
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
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- 229910052786 argon Chemical group 0.000 description 6
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
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- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 6
- 239000001294 propane Substances 0.000 description 6
- 235000019260 propionic acid Nutrition 0.000 description 6
- OAKURXIZZOAYBC-UHFFFAOYSA-N 3-oxopropanoic acid Chemical compound OC(=O)CC=O OAKURXIZZOAYBC-UHFFFAOYSA-N 0.000 description 5
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- 239000008346 aqueous phase Substances 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
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- 239000011541 reaction mixture Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 150000000185 1,3-diols Chemical class 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
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- 239000007864 aqueous solution Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical class ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
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Landscapes
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
200425897 玫、發明說明: 【發明所屬之技術領域】 本發明揭露一種具有被可被取代之六環芳烴基 #丙_旨的9-(2·膦,氧基乙基)腺嗓呤及㈣必鱗醇 甲氧基丙基)腺嘌呤之合成步驟。更精確的說明,本發明^ 一合成具有可被鹵素族取代之環狀苯基_u_丙酯^具有 順向立體化學結構之9-(2-膦酸甲氧基乙基)腺過a R_9_(2-膦醯曱氧基丙基)腺嘌呤。 )腺不7及 【先前技術】 以下敘述之先前技術乃為提供協助了解本發明,但並 不承認或表示本發明所有的發表皆於完整之參考資料中摘 錄。 9-(2_膦醯-甲氧基乙基)腺嘌呤(PMEA),R_9_(2_膦醯-甲氧 基丙基)腺嘌呤(PMPA)以及相類似物(美國專利號 4,808,716 ;美國專利號5,142,0510)皆為具有抗病毒活性之 磷酸鹽,包括抗B型肝炎及人類愛滋病病毒(De Clercq技认, Antiviral Res. 8:261-7(1987) ; Balzarini et al, Biochem200425897 Rose, description of the invention: [Technical field to which the invention belongs] The present invention discloses a 9- (2 · phosphine, oxyethyl) adenine and pyridine having a hexacyclic aromatic hydrocarbon group #propyl_ which may be substituted. Synthetic steps of squamyl methoxypropyl) adenine. More precisely, the present invention ^ a synthesis of a cyclic phenyl _u_propyl ester which can be substituted by a halogen group ^ 9- (2-phosphonomethoxyethyl) gland a R_9_ (2-phosphinofluoroxypropyl) adenine. ) Gland No. 7 and [Prior Art] The prior art described below is provided to assist in understanding the present invention, but does not acknowledge or indicate that all publications of the present invention are extracted from the complete reference materials. 9- (2-Phosphinofluorene-methoxyethyl) adenine (PMEA), R_9_ (2-Phosphinofluorene-methoxypropyl) adenine (PMPA) and similar (US Patent No. 4,808,716; US Patent No. 5,142,0510) are phosphates with antiviral activity, including anti-hepatitis B and human AIDS virus (De Clercq, Antiviral Res. 8: 261-7 (1987); Balzarini et al, Biochem
Biophys· Res. Commun· 219(2):337-41(1996))。9_(2-膦醯曱氧 基乙基)腺嘌呤的Dipivaloyloxy曱基酯(BisPOMPMEA)是 臨床上用來治療B型肝炎的藥物(Benhamou et al.,Lanccet 358(9283):718-23(2001))。除此之外,亦有一些研究顯示這 類的化合物也具有抗癌症的活性(Murono et al.,Cancer Res. 61(21):7875-7(2001)。 11 200425897 含有磷酸的化合物及其鹽類在人體生理狀態下酸鹼 值高,因此通常口服此類藥物的生物可吸收性低、細胞滲 透性低並且此類藥物只能分佈至某些組織中(例如中樞神經 系統)。除此之外,這類的酸也含有其他特性阻礙期發展成 為藥物使用,包括因其於腎臟的清除率高故血漿中的半衰 期短以及毒性問題(如腎及腸胃道)等(Bijsterb〇sch et al.,Biophys. Res. Commun. 219 (2): 337-41 (1996)). Dipivaloyloxy amidin (BisPOMPMEA) of 9- (2-phosphinoethoxyethyl) adenine is a drug used clinically to treat hepatitis B (Benhamou et al., Lanccet 358 (9283): 718-23 (2001 )). In addition, some studies have shown that such compounds also have anticancer activity (Murono et al., Cancer Res. 61 (21): 7875-7 (2001). 11 200425897 Phosphoric acid-containing compounds and their salts In the physiological state of the human body, the pH value is high, so oral administration of such drugs generally has low bioabsorbability, low cell permeability, and such drugs can only be distributed to certain tissues (such as the central nervous system). In addition, this type of acid also contains other properties that hinder the development of drug use, including short half-life in plasma and toxicity issues (such as the kidney and gastrointestinal tract) due to its high clearance to the kidney (Bijsterbosch et al. ,
Antimicrob Agents Chemother· 42(5):1146-50(1998))。環狀的 填酸酯也用於描述9-(2-膦醯甲氧基乙基)腺嘌呤及其類似 物。這類的環狀磷酸酯如下圖所示Antimicrob Agents Chemother. 42 (5): 1146-50 (1998)). Cyclic fillers are also used to describe 9- (2-phosphinomethylmethoxyethyl) adenine and its analogs. This type of cyclic phosphate is shown in the figure below
環狀沒被取代之1,3丙酯的9-(2-膦醯甲氧基乙基)腺嘌呤化 &物被合成後在活體中測試顯示其並無活性存在。歐盟專 利號EP0481214B1中舉例說明9-(2-膦醯甲氧基乙基)腺嘌 呤的環狀藥物前趨物的丨,3位置沒被取代。這個發明人 (Starrett et al” J· Med· Chem· 37:1857-1864(1994))此應用及 後績文章的發表更進一步揭露他們所發現的這個化合物並 無口服之生物可利用性且無生物活性。這個化合物在低的 酸驗值下不穩定如研究顯示環狀厂广工氟十义丙醋易水 解不穩定快速形成環狀被打開之單體結構。 12 200425897 【發明内容】 本發明揭露—新穎性並可增強之非對應異構物超過的 量順向異構體合成環狀】韻基·〗,3趟翻_旨的9_(2- 膦酿f氧基乙綱封及R_9_(2伽f氧私基)腺嗓吟 之合成步驟。在本伽之合成過射藉由連結的方法使順 向異構物增加。另—方面也在合成過財經由溫度變化使 得順向異構物的數量增加。而藉由加入反應物的順序不同 也使順向異構物·量增加。更進—步㈣由加入的酸及 結晶鹽_量增加也使得欲得狀軸異構物產量增加。 另-方面使用結晶溶劑於合成過程中也使得順向異構物的 數量增加。 另-方面,本發明揭露一種方法可產生具有V連結於其 s化學立體結構之純順向環酯。 本赉明揭硌製備此化合物之方法,化合物之結構是如化 學式I所示:The 9- (2-phosphinofluorenylmethoxyethyl) adenine & cyclic unsubstituted 1,3 propyl ester was synthesized and tested in vivo to show that it has no activity. EU Patent No. EP0481214B1 exemplifies that the cyclic drug precursor of 9- (2-phosphinomethylmethoxyethyl) adenine is not substituted at position 3 of the drug. The application of this inventor (Starrett et al "J. Med. Chem. 37: 1857-1864 (1994)) and the publication of subsequent articles further revealed that the compound they found had no oral bioavailability and no biological Activity. This compound is not stable at low acid test values. Studies have shown that the cyclic plant Glycofluorodecapropionate is easily hydrolyzed, unstable and quickly forms a ring-opened monomer structure. 12 200425897 [Summary of the Invention] The present invention discloses- Novel and enhanced non-corresponding isomers over the amount of cisomers to synthesize a cyclic ring] rhyme group, 3 times to turn _purpose of 9_ (2-Phosphine-based foxyethyl group seal and R_9_ (2 Gamma oxygen radical) Synthetic steps of glandular vocals. Synthetic radiation in Bengal has increased the cis isomer by the connection method. In addition, it has also been synthesized. Financial and cis isomers are changed by temperature changes. The amount of the isomers increases. And the amount of cis isomers is increased by the different order of adding the reactants. In addition, the amount of the added isomers and the amount of crystalline salts also increase the yield of the desired isomers. On the other hand, the use of crystallization solvents in the synthesis process also makes the The number of isomeric compounds is increased. On the other hand, the present invention discloses a method which can produce a pure cyclic cyclic ester having a V-linked chemical stereostructure. The present invention discloses a method for preparing this compound. The structure of the compound is As shown in Chemical Formula I:
化學式I 在此分子式中Μ與V之間彼此護為順向,μρ〇3Η2是由含 有9-(2_膦酿_甲氧基乙基)腺嘌呤與R-9-(2-膦酿-甲氧基丙基) 腺嘌呤中所挑選出來的磷酸;而¥指的是苯基選擇性置換 上1-2個氟、氯、溴族群的分子;包括連結上一個^苯丙烷 200425897 t t -1,3-二醇,這裡的苯基可以被置換成Mp〇Ci2或氮被置換 的類似物。 另外,本發明所揭露的方法及鹽類的形式可用來萃取及 純化所欲得到之異構物。 定義 本舍明中除了其他另以說明之例外,所用到之特殊名詞 將於以下描述定義其意義。 4正己烧”指的是目前市面上可見到用於高效液相層析儀 試驗之溶液,其組成包括有95%正己烷、甲基環丙烷及甲 基戊烷。 一烧基”指的是化合物中有兩個烧基。這裡指的”烧基,, 是飽和之脂肪族包括直鏈、枝鏈及環狀族群。飽和之烷基 包括甲基、乙基、異丙基及環丙基。 “選擇性的被置換”或”被置換”包括烷基族被一或二個置 換基置換,而這些置換基由低烷基、低芳烴基及鹵素族中 選出。這些置換基較常是鹵素族。 順向化學立體結構指六個組成物鍵上V族與jyj族之 間的位置關係。下面的化學式即表示順向化學立體結構。Chemical formula I In this molecular formula, M and V are protected from each other in a forward direction, μρ〇3Η2 is composed of 9- (2-phosphine_methoxyethyl) adenine and R-9- (2-phosphine- Methoxypropyl) selected phosphoric acid in adenine; and ¥ refers to a phenyl molecule that selectively replaces 1-2 fluorine, chlorine, and bromine groups; including a ^ phenylpropane 200425897 tt -1 , 3-diol, where the phenyl group can be replaced with MpoCi2 or an analogue in which nitrogen is replaced. In addition, the methods and salt forms disclosed in the present invention can be used to extract and purify the desired isomers. Definitions The special terms used in this repertoire, unless otherwise stated, will define their meanings as described below. "N-hexane" refers to the solutions currently available on the market for high-performance liquid chromatography testing. Its composition includes 95% n-hexane, methylcyclopropane, and methylpentane. "One-carbon" refers to There are two alkyl groups in the compound. "Alkyl" refers to saturated aliphatics including straight-chain, branched-chain and cyclic groups. Saturated alkyls include methyl, ethyl, isopropyl and cyclopropyl. "Selective substitution" Or "substituted" includes the replacement of the alkyl group by one or two substituents, and these substituents are selected from the lower alkyl group, the lower aromatic hydrocarbon group, and the halogen group. These substituent groups are more often the halogen group. The ortho chemical stereostructure Refers to the positional relationship between the V and jyj groups on the six composition bonds. The following chemical formula represents the forward chemical stereostructure.
另一個順向化學立體結構V和Μ的位置同在平面的上方 化學式如下圖表示。 14 〜〇夕7The positions of the other forward chemical stereostructures V and M are above the plane. The chemical formula is shown in the figure below. 14 〜〇 夕 7
N6-被置換指的是在嘌呤環中六個碳的位置被加上胺 _員。氮6-通常被置換成二烷基胺亞曱基,在Rl的位置通常 為佐不只_於-至四個碳之非環式麟基、五至六個碳 之%狀烧基、笨甲基、苯乙基或R1族-起形成六氫喷咬、N6-substitution refers to the addition of an amine member at six carbon positions in the purine ring. The nitrogen 6- is usually replaced by a dialkylamine sulfenyl group, and the position of R1 is usually not only _4 to non-cyclic linyl groups of four to six carbons, five percent to six carbons of sulfonyl groups, stilbenes Group, phenethyl or R1 group-to form hexahydrojet,
“二烧基胺基乙烯基亞胺,,指的是功能基或置換如下之結 構:"Dialkylaminovinylimine refers to a functional group or a structure substituted with the following:
在此R基可以但不只限制為具有一個至四個碳之非環 狀烷基、五至六個碳之環狀烷基、苯基、苯乙基或或以基 以嘧啶、氧氮陸圜及咯烷的形式共同存在。 “鏡像異構物超過的百分比(〇/(>ee),,指光學純度。可由下列方 程式計算得知: [ElziIS] X 1〇〇 = 〇/0R _ 〇/os [R] + [S] 15 指的是R同分異構物的數量而指的是指的是s 同分異構物之數量。當R同分異構物佔多數時這個方程式 可鼻出鏡像異構物的百分比。 所謂的”d.e·,,指的是非對應異構物超過的量。可由下列 方程式計算得知: X 觸=%[廣刮-%[及命] [膺向]+[及劍 非對應異構物”指的是化合物中之二個或多個不對稱 中心中具有相同之置換基並進行相同形式之化學反應,這 二化學反應中非對應異構物具有不同之生理特性,置換基 存在於相對不同之方位空間中,並可能有不同之生物特性。 消旋性’’指一個由相同化合物之等量的右旋和左旋組 成之不具光學活化能力之化合物或混合物。 鏡像異構物”指的是-對化學化合物巾它的分子結構 此彼此間具有鏡像關係。 “酸分解係數,,(Ka)指的是酸離子化之平衡係數,例如 HA指的是一個弱酸則:Here, the R group can be, but is not limited to, acyclic alkyl having one to four carbons, cyclic alkyl having five to six carbons, phenyl, phenethyl, or pyrimidine, oxazepine And the form of pyridine coexist. "The percentage of mirror image isomers exceeded (0 / (> ee) refers to optical purity. It can be calculated from the following equation: [ElziIS] X 1〇〇 = 〇 / 0R _ 〇 / os [R] + [S ] 15 refers to the number of R isomers and refers to the number of s isomers. When R isomers account for the majority, this equation can give out the percentage of mirror isomers . The so-called "de ·" refers to the excess of non-corresponding isomers. It can be calculated from the following equation: X touch =% [广 广-% [和 命] [膺 向] + [和 剑 非 对 异 异"Structure" means that two or more asymmetric centers in a compound have the same substituent group and perform the same form of chemical reaction. In these two chemical reactions, the non-corresponding isomers have different physiological characteristics, and the substituent group exists. In relatively different azimuthal spaces, and may have different biological characteristics. Racemic `` means a compound or mixture without optical activation capacity consisting of the same amount of right-handed and left-handed compounds of the same compound. Mirror isomers " Refers to-the chemical structure of the chemical compound has a mirror between each other Relationship "acid decomposition coefficients ,, (Ka) refers to the ionization equilibrium coefficient of acids, such as HA refers to a weak acid is:
Ka ^([H+][A']/[HA]) 鹵素”指的是氣、溴或氟。 藥物4趨物”本發明中指的是任何M化合物將之加 入-生物系統中經由個別或相互結合自發性化學反應、酵 素催化化學反應、加上/或代謝化學反應,產生—生物活化 16 200425897 之化合物。標準之藥物前趨物是將藥物本生加上在體内可 被切斷之基群所組成,這類基群例如HO-、HS-、HOOC-、 。標準藥物前趨物包括但不只限制在酸酯上為烷基、 方香族、芳烷基、酮洛芬異丙基、氧烷基酸基氧烷基及羥 基、硫基及胺基的酯基與一個芳香基、一個氧烷酸基、胺 基酸基、磷酸鹽或硫酸鹽。上述加入的基群為一範例,並 未詳盡論述,本發明亦可應用此技術領域以製作其他已知 但不同之藥物前趨物。如此製作出來的化合物化學式工的藥 物前趨物之範在本發财。藥物前趨物必須具有進行 某些化學雛以產生具有生物活性之化合物或者為一具生 物活性之化合物_物。在某些範财,藥物前趨物具有 生物活性’但通常比祕本身的活性小,可當作透過改善 藥物生物可吸紐、麵動力料雜轉改賴物魏 及女全性。具生物活性之化合物舉例包括抗癌藥物及抗病 毒藥物。 内乙酉曰、%狀1,3-丙羥醋,,、”環狀丨,3_丙 烧醋”及”環狀1,3-丙烷自旨,,指下列化合物: V 乂 —Ρ、。J> 2’ “促進”指的是改善或增加特殊的^性。 “加量,,指的是增加—反正中特殊異構物產生增加的量。 17 200425897 “製藥上可接受之鹽類”包括具有化學式為包括具有化 學式I街生出之結合本發明化合物與一有機或無機酸或驗 的化合物鹽類,因此這類鹽類可安全的使用於動物。適合 的酸類包括醋酸、乙二酸、笨磺酸(+)-7,7-雙甲基_2_氧雙環 [2·2·1]庚烧-1-甲烷磺酸、擰檬酸、丨}乙烧石黃酸、十二酿石备 酸、延胡索酸、醣庚酸、葡萄糖酸、葡糖醛酸、馬尿酸、 半乙酸、溴化氫、鹽酸、峨化氫、2_氫化乙烧績g楚、乳酸、 乳糖酸,馬林酸,甲烧績酸、甲溴酸、甲基硫酸、2_苯續酸、 硝酸、油酸、4,4’-甲基二〇强基_2_二甲酚_、磷酸、多半 乳糖醛酸、硬酯酸、琥珀酸、硫酸、磺基柳酸、單寧酸、酒 石酸、對苯二曱酸及對甲苯石黃酸.。 在本文及專利範圍中所提及之所熟知的化學物質的縮 寫及通俗名稱在下文中提供之。 CHfl2;雙氯甲烷或氣化甲烯 DCM;雙氣曱烷 (-)-DIP-Cl; 氯氣化甲硼烧化合物 DMAP;4-二甲胺基嘧啶 DMF;二甲基縮醛 HC1;氣化氫 KI;錤化钾Ka ^ ([H +] [A '] / [HA]) Halogen "refers to gas, bromine, or fluorine. Drugs 4" in the present invention refers to any M compound added to the biological system via individual or mutual Combining spontaneous chemical reactions, enzyme-catalyzed chemical reactions, and / or metabolic chemical reactions to produce—bioactive 16 200425897 compounds. Standard drug prodrugs consist of the drug's natural origin plus groups that can be cut off in the body, such as HO-, HS-, HOOC-,. Standard drug prodrugs include, but are not limited to, esters that are alkyl, fragrant, aralkyl, ketoprofen isopropyl, oxyalkyl acid oxyalkyl, and hydroxy, thio, and amine esters on the acid ester And an aromatic group, an alkanoic acid group, an amino acid group, a phosphate or a sulfate. The above-mentioned added group is an example and is not discussed in detail. The present invention can also be applied to this technical field to make other known but different drug prodrugs. The prodrugs of the chemical formulas of the compounds produced in this way are now rich. Drug prodrugs must have some chemical brooding to produce a biologically active compound or be a biologically active compound. In some cases, drug prodrugs are biologically active, but are usually less active than the secret drug itself, and can be used to improve the bioavailability of drugs, the conversion of facial energy compounds, and women's sexuality. Examples of biologically active compounds include anticancer drugs and antiviral drugs. The content of the internal acetone is 1,3-propoxyhydroxy vinegar, "cyclic 丨, 3-propane vinegar", and "cyclic 1,3-propane", which refers to the following compounds: V 乂 -P. J > 2 '"Promote" refers to the improvement or increase of special properties. "Additional amount" refers to the increase-anyway, the increase in the production of special isomers. 17 200425897 "Pharmaceutically acceptable salts" includes salts having a chemical formula that includes compounds of the present invention and an organic or inorganic acid or a compound derived from a compound of formula I. Therefore, such salts can be safely used in animals. . Suitable acids include acetic acid, oxalic acid, benzenesulfonic acid (+)-7,7-bismethyl_2_oxabicyclo [2 · 2 · 1] heptane-1-methanesulfonic acid, citric acid, 丨} Ethyl pyroxanthic acid, dodecanedioic acid, fumaric acid, glycoheptanoic acid, gluconic acid, glucuronic acid, horse uric acid, hemiacetic acid, hydrogen bromide, hydrochloric acid, ethiol, 2_hydrogenated ethyl alcohol g Chu, lactic acid, lactobionic acid, maleic acid, methylalanic acid, methyl bromic acid, methylsulfuric acid, 2-benzoic acid, nitric acid, oleic acid, 4,4'-methyldioxo_2_2 Xylenol_, phosphoric acid, polygalacturonic acid, stearic acid, succinic acid, sulfuric acid, sulfosalic acid, tannic acid, tartaric acid, terephthalic acid and p-toluenexanthate. Abbreviations and popular names of well-known chemical substances referred to herein and in the scope of the patent are provided below. CHfl2; Dichloromethane or vaporized methylene DCM; Digasmidine (-)-DIP-Cl; Chlorinated methylboron compound DMAP; 4-dimethylaminopyrimidine DMF; dimethyl acetal HC1; gasification Hydrogen KI; potassium tritide
MgS04;硫酸鎂 MTBE;曱基第三丁基醚 18 200425897MgS04; magnesium sulfate MTBE; fluorenyl tertiary butyl ether 18 200425897
NaCl;氯化納NaCl; sodium chloride
NaOH;氫氧化鈉NaOH; sodium hydroxide
PyBOP;氟磷酸苯環***^-基—氧基三嘧啶烷基 石粦 TEA;三乙胺 THF;四氫喃 TMSC1;氯甲基石夕三甲烧 bisPOMPMEA;二(三甲基乙氧甲基)_9_(2__ 甲氧基乙基)腺嘌呤(阿德福韋dipiv〇xil) 、在本文及專利範圍中所提及之所熟知的藥物縮寫及通 俗名稱在下文中提供之。 PMEA; 9-(2-膦醯甲氧基乙基)腺嗓呤(阿德福韋) (R)-PMPA; R-9♦膦酸甲氧基丙基)腺嗓呤(特洛 福韋) 本發明為-環狀1·芳烴基_U姻的9_(2_膦醯甲氧基 乙基)腺嘌呤及R-9-(2-膦醯曱氧基丙基)腺嘌呤之合成步 驟’決定合成物的立體化學結構。藉由本發明之合成步驟 所產生之化合物為具有順向立體化學結構之環狀p苯基 -u-丙醋之9-(2_膦醯甲氧基乙基)腺嗓吟及棘(2_麟酿甲 氧基丙基)腺嗓呤。本發明中的—部份為闡述丨·芳香族煙基 U-丙醋化學立體結射切亞胺上㈣分子被定義為第 -個碳,乃經由合成相互對掌之L芳香麵ti,3_丙烧二 19 ‘JO 7 /PyBOP; Benzotriazole fluoro-phenyl-oxytripyrimidinyl alkyl fluorite TEA; Triethylamine THF; Tetrahydro TMSC1; Chloromethyl stone trimethyl bisPOMPMEA; bis (trimethylethoxymethyl) _9_ (2__methoxyethyl) adenine (adefovir dipivoxil), well-known drug abbreviations and popular names mentioned in the text and patent scope are provided below. PMEA; 9- (2-Phosphinomethylmethoxyethyl) adenine (Adefovir) (R) -PMPA; R-9Phosphonium methoxypropyl) Adenine (Trolfovir ) The present invention is a step of synthesizing 9- (2-phosphinofluorenylmethoxyethyl) adenine and R-9- (2-phosphinofluorenyloxy) adenine, which are cyclic 1 · aralkylyl group. 'Determines the stereochemical structure of the composition. The compound produced by the synthesis step of the present invention is a cyclic p-phenyl-u-propionic acetic acid 9- (2-phosphinofluorenylmethoxyethyl) gland throat and spine (2_ Lin brewed methoxypropyl) adenine. Part of the present invention is explained. ·· The aromatic nicotyl U-propionate chemical stereo-epithelium-cutting imine molecule is defined as the first carbon, which is synthesized by the L aromatic surfaces ti, 3 _ Bing burning two 19 'JO 7 /
產生順向非對應異構物決定因素乃為反應溫度及加入對掌 -鮮的次序和被保護之母二_酸。 丄本毛明魏部分卿魏魏分子與下躲構中的第 /、個碳原子相結合的方法。The determinants of the generation of the non-corresponding isomers are the reaction temperature and the addition of the opposite palm-fresh sequence and the protected diacid.丄 本 Mao Mingwei Part of the method of combining the Wei and Wei molecules with the / th carbon atom in the lower hiding structure.
本發明更進—步_反應後順向同分異構物的濃度可經由 細夂鹽的選擇性結晶另外加人萃取物增加之,本發明之順 向指的為環狀磷酸鹽鏈上的審碳鍵與碳_芳香族烴基鍵幾 何關係n步增加軸同分麟物濃度的方法為經由 將酸額外的鹽類再結晶。 合成具有欲得之化學立體結構之環狀丨·芳香族烴基 丙酯的1(2-膦醯甲氧基乙基)腺嘌呤及R_9_(2_膦醯甲氧基 丙基)腺嘌呤,乃開始於腺嘌呤與一卣素取代苯環上的氯分 孑之聚合合成步驟。最後合成之化合物具有兩個立體中 心,分別為分別為(1)甲亞胺上的碳分子在立體異構物結構 上被疋義為第一個碳分子,(2)環狀鱗酸鹽鏈上的磷分子。 20 200425897 在化學立體結構第—個碳似產生晴巾職物的對掌還 原反應以及碟分子的手徵性乃為非對映異構物選擇與母碟 酸及對掌二_結合。本發騎欲得之順向同分異構物, =指的順向為環_酸鹽鏈上_.與碳-苯基鍵之同 分異構物關係’經倾鹽的選擇性結晶萃取後所得之產物。 本發明化合物之製備 本毛明中化合物之製備乃為置換本發日种化合物之製備 乃^置換叫《甲氧紅基胸呤上之六環以丙烧雙 酉曰藥物丽趨物,其類似物如化學式Ϊ所示: v 〇\ 〇々 X )The present invention goes one step further—the concentration of cis isomers after the reaction can be increased by selective crystallization of the fine phosphonium salt and added with an extract. The cis direction of the present invention refers to the cyclic phosphate chain. The method of examining the geometric relationship between carbon bonds and carbon-aromatic hydrocarbyl bonds in n steps to increase the concentration of homologs is to recrystallize additional salts of acids. Synthesis of 1 (2-phosphinofluorenylmethoxyethyl) adenine and R_9_ (2-phosphinofluorenylmethoxypropyl) adenine, a cyclic aromatic aromatic propyl ester with a desired chemical stereostructure, It begins with the polymerization and synthesis of adenine and chlorohydrazone on the benzene ring. The final synthesized compound has two stereo centers, namely (1) the carbon molecule on the methylimine is defined as the first carbon molecule in the stereoisomer structure, and (2) the cyclic squamate chain Molecule on the ground. 20 200425897 In the chemical stereostructure, the first carbon seems to produce a palladium reduction reaction and the chirality of the dish molecule is a diastereomer choice for the combination of the master dish acid and the palmitate. This isomer is the orthoisomer, = the forward direction is the cyclic acid salt chain. The isomer relationship with the carbon-phenyl bond is' selective crystallization extraction with decanted salt The resulting product. Preparation of the compound of the present invention The preparation of the compound in the present invention is to replace the preparation of the Japanese compound of the present invention. As shown in Chemical Formula Ϊ: v 〇 \ 〇々X)
Μ 〇/ 化學式I 在此: 丙基)腺嘌呤族群所Μ 〇 / Chemical formula I is here: propyl) adenine family
彼此互為順向’Μρ〇3Η2為—含有9_障曱氧 基乙基)腺嘌呤與(R)_9_(2_膦醯甲氧I 選出之石粦酸; v為笨基,可選雛的置換丨_2個氣 並且為藥物合成學切接受之餘。%、漠刀子 本發明㈣—雜轉觀料„之化合物:Mutually forward to each other 'Mρ〇3Η2 is-containing 9_ barrier ethoxyethyl) adenine and (R) _9_ (2_ phosphine methoxyl I selected carnic acid; v is a benzyl, optional chick The replacement of 丨 2 gas and the acceptance of pharmacological synthesis.%, The compound of the present invention ㈣-heterozygous compounds of the invention:
21 ^0042589721 ^ 00425897
化學式II 在此: MMP〇3H2為-由含有9令膦醯曱氧基乙基)腺噪吟 與(R)_9必膦酿甲氧基丙基)腺嗓呤族群所選出之碟酸鹽; V為笨環,可選擇性的置換1-2個氟、氯、溴分子; 亚且為藥物合成學上可接受之鹽類。 另一方面指的是該類化合物的鹽類與曱烧石黃酸或琥珀酽 結合。 另一方面所指的鹽類與曱烷磺酸相結合。 本發明的另一部份為製備化學式II之化合物Chemical formula II is here: MMP〇3H2 is-a salt selected from the group consisting of 9-ring phosphine ethoxyethyl) adenine and (R) _9 biphosphine methoxypropyl) adenine family; V is a stupid ring, which can selectively replace 1-2 fluorine, chlorine, and bromine molecules; and is a pharmaceutically acceptable salt. On the other hand, it refers to the combination of salts of this type of compound with pyroxanthin or succinic acid. The salts referred to on the other hand are combined with pinanesulfonic acid. Another aspect of the invention is the preparation of compounds of formula II
VV
化學式II 在此: MP〇3H2為-含有9必麵甲氧基乙基)腺嗓吟與 (R)9 (2_膦酿甲氧基丙基)腺嘌呤族群所選出之構酸鹽,· v 為氣苯; 並且為藥物合成學上可接受之鹽類。 另方面指的是該類化合物的鹽類與甲烷磺酸結合。 本發明的另一部份為製備化學式Π之化合物 22Chemical formula II is here: MP〇3H2 is-a structurate selected from the group consisting of 9-bis (methoxymethyl) adenine and (R) 9 (2-phosphine-methoxypropyl) adenine, · v is benzene; and is a pharmaceutically synthetically acceptable salt. The other aspect refers to the combination of salts of such compounds with methanesulfonic acid. Another aspect of the present invention is the preparation of the compound of formula Π 22
化學式II 在此: _脚0典為一含有9倾酿甲氧基乙基)腺嗓岭與 =膦酿甲氧基丙基)腺噪呤族群所選出之石舞酸鹽;V # =笨’亚且為藥物合成學上可接受之鹽類。 方面扎的疋该類化合物的鹽類與曱烷碏酸結合。 h 1伤香族烴基 > 丙烧·1,3-二醇的合成 八 ^知有許多合成方法來製備1,3_二醇。這些適當的方法 17 :、下述兩大類’分別為U消’旋性卜(芳香族煙基)_丙院 醇的口成,2)對掌性(芳香族烴基)_丙炫],二醇 的合成。 1,1消旋性κ芳香族烴基)-丙燒-1,3,-二醇的合成 入U-雙經基化合物可由文獻上由幾個著名之合成方法 口成之。置換芳香乙駿可經由加人醋酸躲基的鐘稀醇鹽 經醋化還原反應(如路徑Α)用以製備消旋性(芳香族烴基) 丙垸-1,3-二醇(Turner, J.〇rg. Chem 55:4744〇99〇))。另一個 製傷方法為,將料格林觸加幻铺基丙燒_^ 也可得到1·(料烴置換)峨妙工醇(路徑B)。這個方法 可促使不同備置換的芳香烴齒化物轉換成(芳香煙置 換H3-丙炫-二醇(Coppi et ai” j· 〇rg· Chem 23 200425897 53:911(1998))。芳香烴ii化物也可被用於合成2-被置換被置 換丙烷二醇,藉由海克反應與1,3-二氧-4-烯的還原與水解 反應相結合(Sakamoto et al·,Tetrahedron Lett. 33:6845 (1992))。嘧啶、奎寧、異奎寧丙烷各醇衍生物可被氧化成 1-被置換-1,3-二醇,藉由氮-氧化物的形成重組醋酐反應(路 徑 C) (Yamamoto et al” tetrahedron 37:1871(1981))。不同種 類之芳香族乙醛藉由乙烯基格林試劑的加入與氫硼化反應 也可被轉換成1-被置換-1,3-二醇(路徑D)。Chemical formula II is here: _ foot 0 is a stone salt selected from the group consisting of 9-thin methoxyethyl) adenophylline and = phosphine methoxypropyl) adenine; V # = 笨'Asian is a pharmaceutically synthetically acceptable salt. Aspects of this compound are salts of this compound in combination with arsenic acid. h 1 Botanical Group > Synthesis of Propane and 1,3-diols There are many known synthetic methods to prepare 1,3-diols. These suitable methods 17 :, the following two major categories are "U" racemic bu (aromatic nicotinyl) _ propionol, 2) palladium (aromatic hydrocarbon group) _ Pingxuan], two Synthesis of alcohol. Synthesis of 1,1 racemic κ aromatic hydrocarbon group) -propane-1,3, -diol The U-dibasic compound can be synthesized from several well-known synthetic methods in the literature. Substituted aromatic ethyls can be used to prepare racemic (aromatic hydrocarbon groups) propane-1,3-diol (Turner, J) via acetic reduction reaction (such as path A) with a dilute alkoxide added with acetic acid hiding group. Rg. Chem 55: 4744 0099)). Another method for making injuries is to add 1 · (replacement of hydrocarbons) to emirolol (path B) by contacting the green with succinylpyridine. This method can promote the conversion of different prepared aromatic hydrocarbon dentates into (aromatic smoke replacement H3-propanyl-diol (Coppi et ai "j · 〇rg · Chem 23 200425897 53: 911 (1998)). Aromatic hydrocarbon iiides It can also be used to synthesize 2-substituted substituted propanediol, which is combined with the reduction and hydrolysis reaction of 1,3-diox-4-ene by Heike reaction (Sakamoto et al., Tetrahedron Lett. 33: 6845 (1992)). The pyrimidine, quinine, and isoquinine propane alcohol derivatives can be oxidized to 1-substituted-1,3-diol, and the acetic anhydride reaction is reorganized by the formation of nitrogen oxides (path C ) (Yamamoto et al ”tetrahedron 37: 1871 (1981)). Different types of aromatic acetaldehyde can also be converted to 1-substituted-1,3-di by the addition of vinyl Green reagent and hydroboration reaction. Alcohol (path D).
VCHO + CH3C02RVCHO + CH3C02R
B VMX + OHCCH3CH2OR·B VMX + OHCCH3CH2OR
HOHO
VCHO + CH2=CHMXVCHO + CH2 = CHMX
V X vch2ch2ch2ohV X vch2ch2ch2oh
Aryl, R = Alkyl, R· = benzyl, M=Mg or Li, X=Halide or null v-芳香私基’ 烷基,R,=苯基,M=鎂或鋰,鹵族 分子或無 ι·2對m(芳香煙基)_丙烧妙二醇的合成·· 經由化學或酵素方法所產生之各種不同已知二乙醇的 對掌解析可用於二醇鏡 像異構物的製備(Harada et al,加㈣腦丨机^ (产))被置換的3-芳香烴基各含氧丙酸或醋類的金屬催 化氫化轉換反麵—有效率製備為—有效率製備光學上純 24 200425897 的水杨酸或S旨之R或S異構物(Comprehensive AsymmetricAryl, R = Alkyl, R · = benzyl, M = Mg or Li, X = Halide or null v-aromatic private alkyl, R, = phenyl, M = magnesium or lithium, halogen molecule or free Synthesis of 2 pairs of m (aromatic nicotinyl) _propanediols .... Parameter analysis of various known diethanols produced by chemical or enzyme methods can be used for the preparation of diol mirror isomers (Harada et al (Increase the brain 丨 machine ^ (produced)) The reverse side of the metal catalytic hydrogenation conversion of each of the 3-aromatic hydrocarbon groups containing oxypropionic acid or vinegar-efficient preparation-efficient production of optically pure salicylica Acid or S isomer R or S (Comprehensive Asymmetric
Catalysis,Jacobsen,Ε· N·,Pfaltz,A·,Yamamoto, R (Eds),Catalysis, Jacobsen, E · N ·, Pfaltz, A ·, Yamamoto, R (Eds),
Springer, (1999); Asymmetric Catalysis in Organix Synthesis, Noyori,R·,John Wiley,(1994))。這類的水揚酸或酯類產物可 被更進一步還原產生所須知1-(芳香烴基)—丙烷―丨,二醇 (路徑A)。高壓氫化或氫轉換反應的貝塔酮酸或酯受質可被 以不同的方法製備,例如苯乙酮與存在鹼中的二甲基碳酸 鹽縮合反應(Chuetal·,J· HetChem· 22:1033 (1985)),藉由酯 類的縮合反應(Turner et al·,J· Org· Chem· 54:4229 (1989))或 芳香烴基鹵化反應製備之(Kobayashi etal·,Tetrahedron Lett. 27:4745(1986))。另一種製備方法為,鏡像異構物上純的ι3_ 一醇可經由貝塔-經乙基芳香煙基_的衍生物或貝塔_酮酸 衍生物的對掌硼氫化合物還原反應而製備之(路徑 B)(Ramachandran,et al·,Tetrahedron Lett· 38:761 (1997》。其 它一種製備方法為,一般市面上可取得之桂皮醇在不對稱 環氧化作用催化反應下可轉換成環氧基乙醇。這些環氧乙 醇被Red_A1還原產生鏡像上純的1,3-二醇(路徑C)(Gao, et al·,J· Org· Chem· 53:4081(1980))。醇醛縮合作用為另一熟知 用以合成對掌1,3-被氧化產物,其起始反應物為芳香乙醛 (路徑路桉 D)(Mukaiyama Org· React· 28:203(1982))。 25 200425897 vcoch2co2rSpringer, (1999); Asymmetric Catalysis in Organix Synthesis, Noyori, R., John Wiley, (1994)). This type of salicylic acid or ester product can be further reduced to produce the required 1- (aromatic hydrocarbon group) -propane, a diol (path A). Betaone acids or ester substrates under high-pressure hydrogenation or hydrogen conversion reactions can be prepared in different ways, such as the condensation reaction of acetophenone with dimethyl carbonate in a base (Chuetal ·, J · HetChem · 22: 1033 ( 1985)), prepared by condensation reaction of esters (Turner et al., J. Org. Chem. 54: 4229 (1989)) or aromatic hydrocarbon halogenation reaction (Kobayashi etal., Tetrahedron Lett. 27: 4745 (1986 )). Another preparation method is that the pure ι3_ monoalcohol on the mirror image isomer can be prepared by the reduction reaction of beta-boron hydrogen compound with a beta-ethyl aromatic nicotinyl derivative or a beta-keto acid derivative (path B) (Ramachandran, et al., Tetrahedron Lett. 38: 761 (1997). Another preparation method is that the general available commercially available cinnitol can be converted into epoxyethanol under asymmetric epoxidation. These epoxy alcohols are reduced by Red_A1 to produce pure 1,3-diols on the mirror (path C) (Gao, et al., J. Org. Chem. 53: 4081 (1980)). Aldol condensation is another It is well known to synthesize 1,3-oxidized products of palmar, and its starting reactant is aromatic acetaldehyde (Eucalyptus avenae D) (Mukaiyama Org. React. 28: 203 (1982)). 25 200425897 vcoch2co2r
vcoch2r· Yvcoch2r · Y
cc
VCHOVCHO
vch=chch2ohvch = chch2oh
V = Aryl,R = Alkyl or h, R- = _ch2OH,C02R V=芳香族,烷基或氬、r,二曱醇基或甲酸基 本發明中酮酸的中間產物乃由分子是A中的苯氣化合 物中以一i素分子取代之,而苯氯化合物中可在苯環上任 何一個位置乙1-2個鹵素分子取代之。在最適的結構中,假 設R2是函素分子則則R3為氳分子,假設R3為南素分子則 R2為氬分子。在本發明的其中一部份,分子式A為3_氣化 氯苯醯,另一部份分子式A為2-氯化溴苯醯。本發明中最 後合成之化合物第一個碳在次甲亞胺立構中心上的碳之位 置。 R2 R3V = Aryl, R = Alkyl or h, R- = _ch2OH, C02R V = Aromatic, alkyl or argon, r, dimethyl alcohol or formic acid The basic product of the keto acid in the basic invention is that the molecule is benzene in A Gas compounds are replaced by a molecule of i, and benzene chloride compounds can be replaced by 1-2 halogen molecules at any position on the benzene ring. In the most suitable structure, assuming R2 is a functional molecule, then R3 is a tritium molecule; assuming R3 is a southern molecule, R2 is an argon molecule. In one part of the present invention, the molecular formula A is 3-gasified chlorophenylhydrazone, and the other molecular formula A is 2-bromochlorophenylhydrazone. The position of the first carbon of the last compound synthesized in the present invention at the carbon at the sternocenter of the methineimine. R2 R3
R4R4
分子式A 分子式A的化合物與三甲基矽烷醋酸鹽及二異丙氨基 鋰(為原位二異丙氨基與正丁基鋰反應所得)反應得到含氧_ 26 200425897 丙酸。氫氧基丙酸乃由丙酸與㈠_DIP-氣反應合成,接著氫 氧丙酸被還原成對掌1,3-二醇,如下列分子式b所示:Formula A The compound of formula A is reacted with trimethylsilyl acetate and lithium diisopropylamino (which is obtained by the reaction of in-situ diisopropylamino with n-butyllithium) to obtain oxygen containing 26 200425897 propionic acid. Hydroxypropionic acid is synthesized by the reaction of propionic acid with ㈠_DIP-gas. Then, the propionic acid is reduced to para 1,3-diol, as shown in the following formula b:
Formula BFormula B
分子式B 對掌中心第一個碳的位置在此步驟中以確立,而鏡像物的 比例則待後續其他步驟中獲得之。 2.0 9-(2·膦醯甲氧基乙基)腺嘌呤的合成 不同製備9-(2-膦醯曱氧基乙基)腺嘌呤及[9-(2_膦 酉进曱氧基丙基)腺嘌呤與其相類似物的方法已於許多文獻 中被敘述(Arimilli w a/·, W0 99/04774; Schultze ❹/·, Tetrahedron Letters 1998? 39? 1853-1856; Bischofberger U.S. 55514?798? U.S. 55686?629; Holy etal., U.S. 4,659,825, U.S· 4,808,716, U.S· 5,130,427, U.S.5,142,051)並且於本技術 領域中所熟知。這些製備的方法在此被修改後用以製備欲 得之化合物,這些合成方法經修改後不預期的被發現較過 去文獻中提到的合成方法可同時減少萃取的時間與純化步 驟。本發明之丙酸中***的萃取非進行合成過程中下一個 步驟所必要的。並發現在這合成過程中不需經過純化即可 將酯類去保護基。 27 200425897 在典型的合成方法中,腺嘌呤與被置換或無被置換的 碳酸乙烯酯和一鹼基產生9-羥基乙基腺嘌呤,接著9_經基 乙基腺嘌呤與Ts0CH2P(0)0Et2更進一步被烷化。最後一個 步驟則負責***的水解以產生9-(2-膦酿曱氧基乙基)腺$ 呤及R-9-(2-膦醯曱氧基丙基)腺嘌呤及它們的類似物。The position of the first carbon in the center of the molecular formula B is established in this step, and the proportion of the mirror image is to be obtained in other subsequent steps. 2.0 Synthesis of 9- (2.Phosphinofluorethoxyethyl) adenineDifferent preparation of 9- (2-Phosphinofluorethoxyethyl) adenine and [9- (2-Phosphinofluorenyloxypropyl) The method of adenine and its analogues has been described in many literatures (Arimilli wa / ·, W0 99/04774; Schultze ze / ·, Tetrahedron Letters 1998? 39? 1853-1856; Bischofberger US 55514? 798? US 55686 ? 629; Holy etal., US 4,659,825, US 4,808,716, US 5,130,427, US 5,142,051) and are well known in the art. These preparation methods have been modified here to prepare the desired compounds. These synthetic methods have been modified unexpectedly and have been found to reduce both extraction time and purification steps compared to the synthetic methods mentioned in the literature. The extraction of ether in propionic acid according to the invention is not necessary for the next step in the synthesis process. It was found that esters can be deprotected without purification during this synthesis. 27 200425897 In a typical synthesis, adenine produces 9-hydroxyethyl adenine with substituted or unsubstituted vinyl carbonate and a base, followed by 9-acetyl ethyl adenine and Ts0CH2P (0) 0Et2 It is further alkylated. The last step is responsible for the hydrolysis of diethyl ether to produce 9- (2-phosphinoethoxyethyl) adenine and R-9- (2-phosphinoethoxypropyl) adenine and their analogs.
3·第六個氮去保護基之雙氣化9_(2_膦醯甲氧基乙基)膝 嘌呤之合成 再另一個步驟中9-(2-膦醯甲氧基乙基)腺嘌呤之氯化 可藉由利用氣化乙二醯基與二曱基甲醯胺結合來產生第六 個氮去保護基之雙氯化9-(2-膦醯甲氧基乙基)腺嘌呤。二 甲基甲_在氣化的過程巾不但形成—維爾斯邁爾氯化物 吳’也保護胺基在第六個碳的位置。這麵倾的氯化中 間產物被發現具有異轉的雛並可改善整_產率並且 保護的氯化巾間產物被發現具有易溶解的雜並可改善整 個的產率並且及產物之非對映異構比率。_其他的保護 基如酿基、舰碳基、料烴碳基、雜烴基碳基亦可以 促進所欲得產物之雙統及非對映異構比率。 28 2004258973. The synthesis of the double gasification of the sixth nitrogen deprotection group, 9_ (2-phosphinofluorenylmethoxyethyl) knee purine, in another step Chlorination can be accomplished by combining the gasification of ethylenedifluorenyl with dimethylmethanamine to produce a dinitrogen 9- (2-phosphinofluorenylmethoxyethyl) adenine as the sixth nitrogen deprotecting group. Not only does dimethylformate form during the gasification process—Willsmayer chloride Wu ’also protects the amine group at the sixth carbon position. This dumped chlorinated intermediate product was found to have offspring and improved overall yield and the protected chlorinated interstitial product was found to have easily soluble impurities and improve the overall yield and the product was unsuitable. Enantiomeric ratio. _ Other protective groups such as fermented, navy, carbon, and heterocarbon can also promote the duplex and diastereomeric ratios of the desired product. 28 200425897
4·雙氣填酸與對掌二醇的偶合作用 被保護之母磷酸二路與對掌二醇在一鹼性的環境下產 生在低溫可溶解之二氣甲垸被保護的中間產物。 4.1順向藥物前趨物鹽之結晶 被偶合之磷酸與對掌二醇在溫和酸性環境下的第六個 氮的位置去保護基並且將合成的產物以甲烷磺酸結晶之, 產生順向熱前趨物,形献學純度92_93%的f《練醋鹽 (分子式C)。反向異構物為主要不純產物,並且細醇類如 甲醇將最後的產物在結晶可產生純度達以上的非對映4. Coupling of digas filling acid and para-palladiol. Protected mother phosphoric acid two-way and para-palladium glycol in a basic environment produces a protected intermediate product that is soluble in digas formamidine at low temperature. 4.1 The crystal of the prodrug salt of the forward drug is deprotected by the coupling of phosphoric acid and p-palladiol in the mildly acidic environment at the sixth nitrogen and the synthesized product is crystallized as methanesulfonic acid to generate forward heat. The antecedent, the f-refined vinegar salt (molecular formula C) with a purity of 92-93%. The reverse isomers are mainly impure products, and fine alcohols such as methanol will crystallize the final product to produce diastereomers with purity above.
分子式C 利用其他的酴錮白妊桕_Molecular formula C makes use of other
曰门這個用以合成這個用以合成9仆膦酸甲氧基乙 29 200425897 基)腺嗓吟的步驟亦可應用於合成其他的两块醇乙氧基化 合物或(R)9-(2-磷醯甲丙基)衍生物。 土 4.2 9_即,4-軸_(SM+M•(幡21似二氧痛南 _2_基J甲氧基乙基}腺嘌呤曱石黃酸酯的合成: 9识2,4-順向傅(+>4侦苯从氧^拉:氧-鱗南^ 基]甲氧基乙基}腺討料_旨(分子式c)經由經由八個步 驟而合成’以腺料與鮮聚合合成相為耻。最後合 成產物(分子式Q包括兩個立體巾心,相郭)次甲亞胺 上的第-個碳及(2)環狀碟酸鏈上的碟分子。母填酸與對掌 二醇的非對映異構選擇偶合作用之酮酸中間產物的對掌還 原反應及碌分子對手性徵作用在第一個碳上的化學立體結 構所付到之順向異構物指的是異構物間關係及環狀填酸 鍵上.碳鍵和碳-苯鍵之間的關係,此異構物乃經由甲烧續 酸鹽選擇性結晶萃取後得之。 對革一醇及母石粦酸的起始合成原料已修飾後的步驟合 成之。對掌二醇由3_氯化氯笨經由三個步驟合成,母填酸 則由腺嘌呤經四個步驟合成。 人最、冬所知之而純度順向立體異構物乃經由一未知的偶 合步驟將母魏及對掌二_合產生最終之立體異構物產 物。 一 9-(2-膦酿曱氧基乙基}腺嗓呤與消旋二醇利用脫水劑如 -&己基舰二亞胺與六氟魏苯并三如_基氧基三吼 30 200425897 2基贴二?基_/錢溶射作用產生,且溫度必須 提同(至少為攝氏100度),才能完成使前述之偶合作用。 1 ^一反應以相触少之非職異構物超過的量進行之(欲得 順向異構物之_)。獨齡令人_是,當反應溫 度較低日^ ’料應異構物超賴量的改善程度被明顯注意 t這部分的發日賴為雙氯活化9·(2·義甲氧基乙基)腺 "為更具反應性的化學作用。本發明者乃欲將雙 氣化9-(2’_氧基乙基)腺糾與二醇在較低的溫度反 應之,又氯化9_(2_膦醯甲氧基乙基〉腺嗓呤由標準的氯化 作用製備而成。氣化作關雙氯解度低,因此偶合反 應在低溫時作用複雜。相對應的,發明者尋求第六個氮上 的保護基有助於雙氯·解度。其巾—個較麵傾基為 氮_(二烷基胺基甲基亞胺)。 氮-(二烷基胺基甲基亞胺)_保護的雙氣9_(2_膦醯甲氧基 乙基)腺嘌呤的合成乃將9-(2-膦醯曱氧基乙基)腺嘌呤置於 一二烷基曱醯胺如二甲基曱醯胺、二曱基乙醯胺、二甲基 丁醯胺、氮-醛基嘧啶或氮-醛基四氧陸圜的環境中與草酸醯 氯在二氯甲烷中。The process of synthesizing the 9-phosphonomethoxyethoxy 29 200425897 group) gland throat can also be applied to the synthesis of other two alcohol ethoxy compounds or (R) 9- (2- Phosphonium methylpropyl) derivative. Soil 4.2 9_that is, 4-axis_ (SM + M • (幡 21 like dioxolamine_2_ylJmethoxyethyl) adenine ocherite xanthate: 9, 2,4- Forward (+ > 4 detection of benzene from oxygen ^ pull: oxygen-linanyl) methoxyethyl} gland charge _ purpose (molecular formula c) through eight steps to synthesize 'with gland material and fresh It is ashamed to polymerize to synthesize the phase. The final synthesis product (molecular formula Q includes two three-dimensional towel cores, phase Guo) the first carbon on the methineimine and (2) the disk molecule on the cyclic disk acid chain. The diastereoselective coupling of the ketoacid intermediates of paradiols and the reduction reaction of the ketoacid intermediates and the chiral stereochemistry of the molecular chirality on the first carbon refer to the orthoisomers. It is the relationship between the isomers and the cyclic acid-filling bond. The relationship between the carbon bond and the carbon-benzene bond, this isomer is obtained after selective crystallization and extraction of methanesulfonic acid salt. And the starting synthesis material of the mother lithenic acid has been modified in the following steps. Peptanediol is synthesized from 3-chlorochlorobenzyl through three steps, and the mother filling acid is synthesized from adenine through four steps. Winter knows purity The stereoisomers are the final stereoisomer product that is combined with the parent Wei and the palmarium through an unknown coupling step. 9- (2-Phosphinoethoxyethyl) adenosine and racemate Glycols are produced using dehydrating agents such as-& hexyl diimide and hexafluoroweibenzotriazol 30-yloxy-triazine 30 200425897 2-based dioxin / dissolving, and the temperature must be the same (at least 100 degrees Celsius) in order to complete the above-mentioned coupling. 1 ^ a reaction is carried out with less than the amount of non-serviceable isomers (to get the isomer of _). The age alone is _ Yes, when the reaction temperature is low, the improvement degree of the expected excess amount of isomers is obviously noticeable. This part of the hair is based on the dichloride-activated 9 · (2 · methoxymethoxyethyl) gland " For a more reactive chemical action, the inventors wanted to react the digasified 9- (2'_oxyethyl) adenosine with a diol at a lower temperature, and then chlorinate 9_ (2_phosphine)醯 Methoxyethyl> Adenine is prepared by standard chlorination. Gasification is a low degree of dichlorolysis, so the coupling reaction is complicated at low temperatures. Correspondingly, the inventors sought The protective group on the sixth nitrogen contributes to the degree of dichloride · solution. One of its more basic groups is nitrogen_ (dialkylaminomethylimine). Nitrogen- (dialkylaminomethyl) Immine) -protected digas 9_ (2-phosphinomethylmethoxyethyl) adenine is synthesized by placing 9- (2-phosphinomethylethyl) adenine in a dialkylphosphonium amine Such as dimethylammonium amine, diethylammonium amine, dimethyl butylammonium amine, nitrogen-aldehyde pyrimidine or nitrogen-aldehyde tetraoxolidine in an environment with oxalic acid chloride in dichloromethane.
31 獨425897 5·〇雙氣化加入之順序與溫度的影響: 甲醯胺的等級愈高(二甲基與較高等級)會產生一較嗜 脂雙氣化特性。這個嗜脂的雜可使雙氯化之三氣甲烧溶 解度較好。在-三乙胺過多的環境中將雜二醇加入至雙 氯化中間產物可使反應完全’但反應結果發财適當的非 對應異構物超過的量。在本發明中若將反應物的加入順序 反之(雙氣被加入於^醇/驗混合物)’可改善非對應異構物超 過的量(順向:反向=72:29)。令人驚觸是發明者發現反應 物加入的稱與-低溫度的方法可增加非對應異構物超過 的量使得產物勸於產生順向異構物。結果於表丨中顯示 之(如項目1-3)。31 Du 425897 The effect of the order and temperature of the double gasification: The higher the level of formamidine (dimethyl and higher grades) will produce a more lipophilic double gasification characteristics. This lipophilic impurity can make the trichloride trichloride pyrolysis better. The addition of heterodiol to the dichlorinated intermediate in an environment where -triethylamine is excessive can complete the reaction ', but the reaction results in an excess of an appropriate non-corresponding isomer. In the present invention, if the order of adding the reactants is reversed (double gas is added to the alcohol / test mixture) ', the excess amount of non-corresponding isomers can be improved (forward: reverse = 72:29). Surprisingly, the inventors found that the method of adding and reacting the reactants with low temperature can increase the amount of non-corresponding isomers so that the product persuades to produce the isomers. The results are shown in Table 丨 (such as items 1-3).
cis=川員向,trans=反向 32 200425897cis = Sichuan direction, trans = Reverse direction 32 200425897
cis=川貝向,trans=反向 33 表1 加入之順序與溫度的影響 項 a R族群 ~~~~~~~~~_ 溶劑 溫度 (攝 氏 度) 添加物 順向: 反向 1 甲基 二氯 -70 雙氯加至二醇 75:25 —— ——__ 甲烷 2 曱基 二氯 _50 雙氣加至二醇 71:29 甲烷 3 曱基 二氯 0 雙氣加至二醇 63:36 —--- ~~一 -~~~—— 曱烷 4 曱基 二氯 -50 二醇加至雙氯 57:42 —-- ~~~~— 曱烷 5 乙基 二氣 -50 驗加至混合物 66:34 1__ ---- 甲烷 表也顯示較多的順向:反向比率可藉由偶合反應過程 中溫度的降低而達成。如項目1-3所示。 雙氯被加入二醇不預期的產生優點,雙氣仍較適於存 在溶液中進行轉換。當賴基的R為甲基時,絲產生之 雙氣仍鱗於泥漿中。令人驚綱是,加人織過量之嘴 啶時(1.1當量),雙氣泥漿被分解了。這可能是因為氣化氫 34 425897 的一當量產生中和反應,結果使得自由鹼基雙氯比雙氯化 氯化氫的溶解度高。 粗轉反應之混合物產生後被置於一水/二氣甲烷隔板中 激發且萃取出之偶合混合物被以處於酒精中之流入醋酸影 響氮去保護基。cis = Chuanbei direction, trans = reverse 33 Table 1 The order of addition and the influence of temperature a R group ~~~~~~~~~ _ Solvent temperature (degrees Celsius) Additive forward: Reverse 1 Methyl di Chlorine-70 Dichloro added to glycol 75:25 —— __ Methane 2 fluorenyl dichloride _50 Digas added to glycol 71:29 Methane 3 fluorenyl dichloride 0 Digas added to diol 63:36 ----- ~~-~-~~~ —— Phenane 4 fluorenyl dichloro-50 diol added to dichloro 57:42 --- ~~~~ — pinane 5 ethyl digas-50 addition To the mixture 66:34 1__ ---- The methane meter also shows more forward: the reverse ratio can be achieved by reducing the temperature during the coupling reaction. As shown in items 1-3. Dichloromethane has the unexpected advantages of being added to diols. Digass are still more suitable for conversion in solution. When R of lycyl is methyl, the double gas produced by the silk is still in the mud. Surprisingly, the double gas slurry was decomposed when we added an excessive amount of acetone (1.1 equivalent). This may be due to the neutralization reaction of one equivalent of hydrogenated gas 34 425897. As a result, free base dichloride is more soluble than dichlorinated hydrogen chloride. After the crude conversion reaction mixture was generated, it was placed in a mono-water / digas methane separator, and the extracted and extracted coupling mixture was flowed with acetic acid in alcohol to affect the nitrogen deprotection group.
(順向:反向=75:25) (順向:反向=75:25) 5·1順向異構物鹽的形成與溶劑: 當偶合/去保護基順序與對掌二醇反應完成後(s或 R) ’可觀察到非對應異構物超過的量相等(50%),並且發現 順向鏡像異構物在反應過程中不像順向消旋作用產生結 晶。令人驚訝的是,順向:反向混合物比例75:25的某些鹽 類的形成會使得欲得之順向非對映異構物產生結晶作用。 一些用以製備之鹽類及在固態及過濾之非對應異構物超過 的量如表2所示。 35 表2 鹽類 過濾、 順向異構物鹽類及結晶溶劑 溶劑 固態 —--- 一 (順向:反 向) 自由驗基 琥珀酸 乙醇 75:25 82:18 左旋酒石酸 乙醇 70:30 右旋酒石酸 乙醇 76:24 順丁烯二酸 乙醇 66:31 甲烧石黃酸 乙醇:丙酮 93:7 左旋順丁稀二 乙醇:丙_ 56:43 酸 (順向:反 向) 右旋順丁烯二乙醇:_ 56;43 酸 70:30 85:15 77:23 88:12 57:43 93:6 95:2 順向:反向混合物_ 75:25的甲烧磺酸鹽可產生最多 欲得之順向非對映異構物(93:7)。去倾機可經由加入一弱 酸如在酒精溶劑的醋酸,接著如乙醇、曱烧俩在去保護 基完成後加人反應如溶液中。關發現曱_酸選擇性鱼 欲得之順向非對映異構物相結晶。粗_料酸鹽通^ 含有5-7%的反相異構物,而且最後的結晶作用可減少吊、 異構物1-3%。表3試著列出—些在結晶溶劑***。夕反向 36 200425897 以一含有4%反相異構物的樣本溶解在下列的溶劑中, 順向異構物的量增加。 表3 最後再結晶溶劑 —-~-- 溶劑 *體積(毫升)/ 回復百分比 A%反相 -------- 克 甲醇 ------ 2.5 71.8 1.0 乙醇 10.5 86.4 1.6 異丙醇 48 88.4 2.2 曱醇/曱苯(1/1) 5.0 58.8 1.0 曱醇/異丙醇(1/1) 4.0 85.0 2.0 甲醇/異丙醇(2/5) 7.0 89.2 2.5 曱醇/乙醇(2/5) 7.0 83.4 2.7 曱醇/丙酮(1/1) 4.0 73.2 1.2 *表中的體積為每個樣本每克。 本發明中所使用的化合物和它們的製備發法可被更進 一步了解,藉由這些範例的合成步驟說明這些化合物是如 何被製備。這些範例並不意味本發明侷限於此等實例所揭 示之内容,各種不同已知或未來發展出之化合物,只要落 入本發明的範圍中皆可要求主張。 【實施方式】 範例1: 3-(3-氣苯)3-氧-丙酸(1)的製備 將一 12公升3頸圓底燒瓶裝瓶裝置在自動攪拌器上, 37 200425897 亚置入漏斗(2公升)。錢氣充滿燒瓶並加入二異丙胺 (636 ¾升)和四氫喃(U〇公升)。雜拌物冷卻至攝氏零 下20度。緩慢攪拌加入正丁基鋰(1·8公升之2·5莫耳濃度 於己烧),將溫度保持在攝氏零下2〇度至零下28度間。完 全加入後(30分鐘),將漏斗以已烷(3〇毫升)沖洗,攪拌之 溶液溫度降至攝氏零下62度。再緩賴拌加人三甲基魏 乙酯(300公克),溫度維持在攝氏零下6〇度。待加入完畢 後(約30分鐘),在攝氏零下6〇度攪拌15分鐘。緩慢攪拌 加入3-氣化苯甲酰氯(295毫升),溫度維持在攝氏零下⑻ 度。待加入完畢(約65分鐘),將冷卻冰浴移開,繼續攪拌 反應溶液1.25小時,溫度緩慢上升至攝氏〇度。將反應的 燒瓶置於冰浴中冷卻,再將水(1·8公升)加入攪拌中的溶 液。撥拌反應溶液1〇分鐘,以甲基叔丁驗(1〇公升)稀釋。 將下層水溶液分離出來並收集到一裝置在自動攪拌器上的 圓底燒瓶。加入甲基叔丁醚(L8公升),將攪拌的反應液置 於冰/谷中冷卻至攝氏1〇度以下。加入濃鹽酸(3⑻毫升之 12莫耳濃度溶液)並且劇烈攪拌。在水溶液相中加入濃鹽酸 (30毫升)酸化,並再次以甲基叔丁醚(1〇公升)萃取。結合 甲基叔丁醚的萃取液,以大約10%氣化鈉溶液(1公升)沖 洗’乾餘(硫酸鎂,70公克),過濾、並在低壓下濃縮,得827 公克之黃色固體。將這未經純化的固體混在已烷(2.2公升) 中成泥狀,並移至一裝置於自動攪拌器上的圓底燒瓶。將 38 200425897 混合物在攝氏10度以下攪拌1小時,然後過濾,以已烧(4 x 100毫升)沖洗,乾燥至重量不變(-30英吋水銀柱,室溫, 14小時)。以磁振氫光譜分析儀分析此樣品,並且接下來所 有的樣品都以凡瑞安雙子星200百萬赫茲光譜儀進行分 析。將樣品溶解在所指示的溶劑中,以化學位移做為殘留 溶劑的指標。 回收=309公克 淡黃色粉末1(68.6%)。 磁振氫光譜分析儀(丙酮-6氘)H.l (s,2氫),7·5_81 (m, 4氫) , 範例2:(S)_3-(3_氯苯)_3·强基丙酸(2)的製備(Forward: reverse = 75: 25) (Forward: reverse = 75: 25) 5.1 Formation of cis isomer salt and solvent: When the coupling / deprotection sequence is completed with p-palladiol After (s or R) 'it can be observed that the non-corresponding isomers exceed the same amount (50%), and it is found that the cis mirror image isomers do not produce crystals during the reaction like cis racemization. Surprisingly, the formation of certain salts in the forward: reverse mixture ratio of 75:25 can cause the desired diastereomer to crystallize. Some of the salts used for the preparation and the excess of the non-corresponding isomers in the solid and filtered are shown in Table 2. 35 Table 2 Salt filtration, cis isomer salt and crystallization solvent solvent solid state ----- (forward: reverse) free test succinate ethanol 75:25 82:18 L-tartrate ethanol 70:30 right Tartrate ethanol 76:24 Maleic acid ethanol 66:31 Methyl luteol fumarate ethanol: Acetone 93: 7 L-maleic acid: Propane 56:43 Acid (forward: reverse) D-cis Ethylene glycol: _ 56; 43 acid 70:30 85:15 77:23 88:12 57:43 93: 6 95: 2 forward: reverse mixture _ 75:25 methanesulfonate can produce the most desire The resulting diastereomer (93: 7). The descaling machine can be added by adding a weak acid such as acetic acid in an alcoholic solvent, followed by ethanol and sintering, and adding a reaction such as a solution after the deprotection group is completed. Guan found that the hydrazone-acid-selective fish crystallizes the desired diastereomeric phase. The crude salt contains 5 to 7% of the reversed-phase isomers, and the final crystallization can reduce the hanging and isomers by 1-3%. Table 3 tries to list some of these in a crystallization solvent system. Xifeng 36 200425897 A sample containing 4% of the reverse-phase isomer was dissolved in the following solvent, and the amount of cis-isomer increased. Table 3 Solvents for final recrystallization ----- solvent * volume (ml) / recovery percentage A% reversed phase -------- g methanol ------ 2.5 71.8 1.0 ethanol 10.5 86.4 1.6 isopropanol 48 88.4 2.2 Methanol / Isobenzene (1/1) 5.0 58.8 1.0 Methanol / Isopropanol (1/1) 4.0 85.0 2.0 Methanol / Isopropanol (2/5) 7.0 89.2 2.5 Methanol / Ethanol (2 / 5) 7.0 83.4 2.7 Methanol / acetone (1/1) 4.0 73.2 1.2 * The volume in the table is per gram per sample. The compounds used in the present invention and their methods of preparation can be further understood, and the synthetic steps of these examples show how these compounds are prepared. These examples do not mean that the present invention is limited to what is disclosed in these examples. Various known or future compounds may be claimed as long as they fall within the scope of the present invention. [Embodiment] Example 1: Preparation of 3- (3-gasbenzene) 3-oxo-propionic acid (1) A 12 liter 3-necked round bottom flask was bottled on an automatic stirrer, 37 200425897 was placed in a funnel (2 liters). Fill the flask with money and add diisopropylamine (636 ¾ liters) and tetrahydrofuran (U0 liters). Cool the mix to minus 20 degrees Celsius. Slowly add n-butyllithium (2.5 mols in 1.8 liters in hexane) and keep the temperature between -20 ° C and -28 ° C. After the addition was complete (30 minutes), the funnel was rinsed with hexane (30 ml), and the temperature of the stirred solution was reduced to -62 ° C. Slowly add trimethylwethyl ethyl ester (300 g) and maintain the temperature at minus 60 degrees Celsius. After the addition is complete (about 30 minutes), stir for 15 minutes at minus 60 degrees Celsius. Slowly stir and add 3-gasified benzoyl chloride (295 ml), keeping the temperature at minus ⑻C. After the addition is complete (about 65 minutes), remove the cooling ice bath and continue to stir the reaction solution for 1.25 hours. The temperature slowly rises to 0 ° C. The reaction flask was cooled in an ice bath, and water (1.8 liters) was added to the stirred solution. Stir the reaction solution for 10 minutes and dilute with methyl tert-butyl acetate (10 liters). The lower aqueous solution was separated and collected in a round-bottomed flask mounted on an automatic stirrer. Methyl tert-butyl ether (L8 liters) was added, and the stirred reaction solution was cooled in ice / valley to below 10 ° C. Add concentrated hydrochloric acid (3 milliliters of a 12 mol solution) and stir vigorously. The aqueous phase was acidified by adding concentrated hydrochloric acid (30 ml), and extracted again with methyl tert-butyl ether (10 liters). Combined with the methyl tert-butyl ether extract, the dry residue (magnesium sulfate, 70 g) was washed with about 10% sodium vaporized solution (1 liter), filtered, and concentrated under reduced pressure to obtain 827 g of a yellow solid. This unpurified solid was mixed in hexane (2.2 liters) to form a slurry, and transferred to a round bottom flask equipped on an automatic stirrer. Stir the 38 200425897 mixture below 10 degrees Celsius for 1 hour, then filter, rinse with burnt (4 x 100 ml), and dry to constant weight (-30 inch mercury column, room temperature, 14 hours). This sample was analyzed with a magneto-hydrogen spectrometer, and all subsequent samples were analyzed with a Van Ryan Gemini 200 megahertz spectrometer. Dissolve the sample in the indicated solvent and use the chemical shift as an indicator of the residual solvent. Recovered = 309 grams of light yellow powder 1 (68.6%). Magnetic vibrational hydrogen spectrometer (acetone-6 deuterium) Hl (s, 2 hydrogen), 7 · 5_81 (m, 4 hydrogen), Example 2: (S) _3- (3_chlorobenzene) _3 · strong propionic acid (2) Preparation
將一 12公升3頸圓底燒瓶裝 漏(1公升)。將燒瓶以氮氣充滿, 應液中, 將- 12公升3頸圓底燒絲置在自動勝器上並放置 漏(1公升)。將燒瓶以氮氣充滿,加人3分氯苯)3_氧-丙酸 (275.5公克)!及二氯甲烧(2.2公升)。將一感溫棒浸入反 應液中’並將反應液冷;gp篆摄庆雪T^Leak a 12-liter 3-neck round bottom flask (1 liter). Fill the flask with nitrogen, and in the reaction solution, place -12 liters of 3-neck round-bottomed burner wire on the automatic winner and place the drain (1 liter). Fill the flask with nitrogen and add 3 minutes of chlorobenzene) 3-oxy-propionic acid (275.5 g)! And dichloromethane (2.2 liters). Immerse a temperature-sensitive rod in the reaction solution ’and cool the reaction solution; gp 篆 照 庆 雪 T ^
1 ·〇4公升)之二氣甲烷溶液加 加入三乙胺(211毫 硼烷化合物)(1.60莫耳濃度, 39 入漏斗,緩慢加入並攪拌使溫度維持在攝氏零下20度至零 下2S度間。待加入完畢後(約%分鐘),將溶液置於冰浴 (攝氏2-3度)中升溫並攪拌。經過四小時攪拌後,以核磁共 振儀分析顯示啟始物1含量小於4%。 將剩餘起始物I依下列方法以質子核磁共振儀測量: 取出0.5毫升的反應物樣品,加水(〇·5毫升)及3莫耳濃度 氫氧化鈉溶液終止反應。撹拌終止的反應液使其分層。水 相以2莫耳濃度鹽酸(1毫升)酸化並以醋酸(1毫升)萃 取。將有機相分離、以硫酸鎂栓塞過濾,並以氮氣濃縮。 將殘餘物溶解於二氣甲烷,並以氮氣將溶劑揮發。將殘餘 物/谷解於丙酮,並以磁振氳光譜分析儀(丙酮—氛6)進行分 析。 將水(L2公升)加入混濁的橘色反應混合物,接著再加 入3莫耳濃度氬氧化鈉水溶液(ι·44公升)。劇烈攪拌混合 物5分鐘,再移至一分液漏斗内。將不同的層分離,鹼性 水溶液相以乙酸乙醋(1公升)沖洗。水溶液相以濃縮的鹽酸 (300毫升)酸化,再以乙酸乙酯萃取(二次,每次13公升)。 將兩次酸性乙酸乙酯萃取物混合,以10%氯化鈉溶液(600 毫升)沖洗,以酸鎂(130克)乾燥、過濾、低壓濃縮,得 到328公克的黃色油。靜置使由產生結晶。將產生的結 晶加入乙酸乙酯(180毫升)中使成混濁狀,再移至裝置在自 動攪拌器的2公升三頸圓底燒瓶中。將攪拌的乙酸乙酯溶 液q卻至攝氏1〇度以下(冰浴),再以己烷(8⑻毫升)稀 釋。將混合物在冰浴的狀態下攪拌4小時,並過濾。收集 口體,以4:1己烧··乙酸乙酯沖洗(三次,每次5〇毫升), 再乾燥至重量穩定(-30忖汞柱,室溫,丨2小時)。 回收=207·5克 白色粉末2 (74.5%) 礤振氫光譜分析儀(丙酮氘&卜2.7(d,>6赫兹,2氫), 4·7 (d,J=4 赫兹,1 氫),5.1-5.2 (m,1 氫),7.2-7.5 (m,4 氫)。 例3:⑸七)_1·(3_氣苯基卜以丙二醇⑶的製備 將一 12公升3頸圓底燒瓶裝置在自動攪拌器,加上漏 斗(2公升)和溫度計。以氮氣充滿燒瓶,加入⑶各&氯苯 土)3 5工基丙酸2(2〇6·7克)和四氫喃(MO毫升),將攪拌 的溶液冷卻至攝氏5度(冰浴)。將溶於四氮喃的工莫耳濃 又爛燒(2.14公升)經由漏斗緩慢力口入並擾拌,使溫度維持 在攝氏10度以下。當完全加入後(大約需一小時),移開冰 浴唆溶液在室溫下娜—小時。小心且緩慢的加入水_ 毛升)以終止反應’再加人3莫耳濃度錄化鈉溶液卿 毛升)。將混合物授拌l0分鐘,觀察溫度上升至攝氏4〇度 日寸’將混合物移至分離漏斗。將不同的層分開,水溶液相 乂乙酉夂乙g曰(600毫升)萃取。混合的有機相以1〇%氮氧化 納/奋液(5〇〇宅升)沖洗,乾燥(硫酸鎂,322克),過濾,在 41 200425897 低壓狀態濃縮成189·0克淡黃色的油(101%)。以磁振氫光 譜分析儀(氘-三氣甲烧)對此油進行初步分析化驗。 將此油以真空分餾純化,收集攝氏125-155度/0.15 毫米汞柱之分液。 回收二180.9公克 無色油3 (94.0%)。 磁振氫光譜分析儀(CDCI3):占H3.1 (m,2氫),2.5 (bs, 2 氫),3·9 (t,J=5 赫茲,2 氫),4.9(dd,J二7.4, 4.8 赫茲,1 氫), 7.2-7.4 (m,4 氫)。 對掌異構物超出量之測定步驟 為進行光學異構物南效能液相層析分析,將二醇3以 下列方法衍生為二醋酸酯: 將二醇3 (5·〇毫克,〇·〇26毫莫耳)溶解於二氯甲烷 (2·〇 :升)。加入醋酸酐(15微升,〇15毫莫耳)和4_(二甲 基胺基)嘧啶(13毫克,〇.1〇毫莫耳),在室溫下攪拌15 刀釦。加入1莫耳濃度鹽酸溶液(3毫升)終止反應,將下層 的有機層分離出來’以硫酸鎂栓塞魏,再魏氣濃縮。 將剩餘物溶解切醇(1毫升),並以絲異構物高效能液相 層析進行分析。 令人驚訝的是,經測量二醇3的對掌異構物超出量>98%。 南效處液相層析條件: 42 200425897 層析管桎:博<共價(8,8)惠克-〇1〇/1〇〇克朗1^(::,25〇 X4.6亳米;移動相=70:30,甲醇:水,從頭到尾一致之比 例;流逮=1.5毫升/分鐘;注射體積=10微升,紫外光檢測 於220奈米。 π留時間:s-二醇(二醋酸酯)=12.1分鐘,二醇(二醋 酸酿)=8.6分鐘。 範例4 :二乙基-對-甲苯石黃醚基氧曱基石粦酸鹽⑷的製備 將一 12公升3頸圓底燒瓶裝置在自動攪拌器,接上冷 凝器、溫度計和加熱爐。將燒瓶以氮氣充滿,加入亞磷酸 二甲酯(554公克)、多聚曱醛(142公克)、曱苯(2公升) 和三乙胺(53毫升)。將混合物於攝氏85-90度攪拌2小 日守’再加熱回流1小時。將產生的黃色水溶液在冰浴中冷 卻至攝氏4度,再加入對曱苯磺醚氣(718公克)。將冷凝 為置換為漏斗’邊授拌邊緩慢加入三乙胺(750毫升),溫 度維持在攝氏1〇度以下。整個加入的過程完成後(需45分 鐘),繼續在室溫下攪拌14小時。將混合物過濾,以曱苯沖 洗濾紙上的物質(2次,每次250毫升)。將濾液及沖洗液 混合並以水沖洗(2次,每次1公升)、乾燥(硫酸鎂,200公 克),以碴藻土(矽萊特521,編號61790-53-2)過濾,並在 低壓下濃縮。 43 200425897 回收= 1004公克 混濁黃色油4(77.6%)。 磁振氫光譜分析儀(三氯氣烧)。△ = L3 (t,J=8氫,m, 3氫), 2.4(s,3 氫),4.0-4.2 (m,4 氫),7·2 (d, J=8 赫茲,2 氫),7·8 (d, J=8赫兹,2氫)。 範例5 : 9-(2-强乙基)腺嘌呤(5)的製備 將一 12公升3頸圓底燒瓶裝置在自動擾拌器,接上冷 凝器、溫度計和加熱爐。將燒瓶以氣氣充滿,再加入腺噪 呤(504公克)、碳酸乙烯(343公克)、二甲基曱醯胺(3β7 公升)和氳氧化鈉(7.80公克)。將此攪拌的混合物加熱到 回流(約需80分鐘達到回流,熱鍋溫度二攝氏145度),再 加熱回流2小時。將加熱爐移開,使黃色水溶液冷卻至攝 氏100度以下。將產生的混合物置於冰浴冷卻至攝氏5度 以下,並以曱苯(3.8公升)稀釋。將混合物在攝氏10度以 下攪拌2小時再過濾,收集固體並以曱苯(2次,每次0.5 公升)和冷的乙醇(1.5公升)沖洗,然後乾燥至重量穩定 (-30吋汞枉,攝氏50度,14小時)。 固體5以高效能液相層析及磁振氫光譜分析儀(二甲 基氧化硫-/Πα 6)分析。 高效能液相層析條件: 44 200425897 二氧化石夕管柱(顆粒大小,10微米)(費諾美邦德克隆)1() C18管检,300Χ3·9毫米;移動相:溶劑A二2〇毫莫耳濃 度石舞酸鉀,酸鹼值6·2;溶劑乙腈;梯度:0_60%B/15 为1里’60-〇%8/2分鐘’0%B/3分鐘·;以波長270奈米之紫 外光進行檢測。 滯留時間:產物二6.5分鐘,3-位向異構物(試驗性)二 5.6分鐘。 回收=624公克。 淡黃色固體5(93.3%)。 磁振氧光譜分析儀(二曱基氧化硫_氘6): ^ = 3.6-3.8 (m, 2 氫),4.1 (t,J=6 赫兹,況),5.0 (bs, 1 氫),7.2(bs,2 氫),8.〇5(s, 1 氫),8.10(s,1 氩)。 範例6: 9-(2-二乙基膦醯基曱氧基乙基)腺嘌呤⑹的製備 將一5公升3頸圓底燒瓶裝置在自動攪拌器,接上溫 度汁。燒槪以氮氣充滿後裝入9-(2-涇乙基)腺嘌呤5 (464 公克)和二曱基曱醯胺(1·4〇公升)。將攪拌的反應物置 入冰浴並降溫至攝氏1〇度,加入叔丁醇鈉(436公克),溫 度升南至攝氏29度。移開冰浴,反應物在室溫下擾摔1小 時並呈輕微混濁狀水溶液。將一漏斗(2公升)接在燒瓶上, 並置於冰浴中使其溫度冷卻至攝氏5度。將二乙基_對_甲苯 石兴鲢基氧曱基碟酸鹽(1130公克)溶於二甲基甲酿胺(7〇〇 45 200425897 毫升)的溶液巾,邊麟雜慢的加人,將溫度轉在攝氏 K)度以下。待全部加入完畢後(2小時),移開冰浴使之在 室溫下渺^ 1小時。以高效能液相層析測定反應完成的程 度。取〇.〇5毫升的反應物溶解在10毫升2〇毫莫耳濃越 酸鉀缓衝液,酸鹼值6.2。 高效能液相層析條件: 二氧化硫層析管柱(顆粒大小,K)微米)(f諾美邦德克隆) 10C18管柱’ 300X3.9毫米;移動相:溶劑a=2〇毫莫 耳濃度鱗酸鉀(酸鹼值6.2),溶劑B=乙猜;梯度: 0-60%B /15 分鐘 ’ 60_0%B / 2 分鐘,〇%β / 3 分鐘;以波 長270奈米之紫外光進行偵測;注射體積=ι〇微升。 滯留時間:產物6 = 9.2分鐘,起始反應物5 = 6 5分鐘。 將攪拌的混合物冷卻至攝氏丨〇度,並緩慢加入8〇%醋 酸(25〇毫升)。待加入完成後(約需ls分鐘),使混合物在 至溫下攪拌30分鐘,溫度逐漸增加至攝氏3〇度。在低壓 下使溶劑揮發(R_152旋轉蒸顧器、,5毫米汞柱),最後留下 2115公克的橘色泥狀物。此物質不需純化即可用於下一步 乾例7: 9-(2-膦醯甲氧基乙基)腺嘌呤⑺的製備 將~ 12公升3頸圓底燒瓶裝置在自動攪拌器。在燒瓶 内加入未純化過的9-(2-二乙基膦醯基甲氧基乙基)腺嘌呤 46 200425897 6,溶入乙腈(4·0公升)使成泥狀。混合物在室溫下攪拌如 分1里並過濾。以乙腈(2次,每次〇·5公升)沖洗濾紙上的 固體物質,將濾液和沖洗液混合,直接用於下一步驟。 將一 22公升3頸圓底燒瓶裝置在自動攪拌器,接上溫 度計、冷凝器和加熱爐。燒瓶以氮氣充滿後加入9-(2_二乙 基膦酸基甲氧基乙基)腺嗓呤6溶液(2.59莫耳)、氯三甲 基石夕烧(1·315公升)及破化_ (1/719公斤)。碟化卸加入 後,混合物溫度會逐漸升高至攝氏35度。將攪拌的混合物 加溫至攝氏55度,在攝氏50_55度間攪拌丨小時。將混合 物繼續再攪拌3小時,同時緩慢降溫至攝氏38度以高效能 液相層析測定反應完成的程度。 南效能液相層析條件: . 二氧化硫管柱(顆粒大小,10微米)(費諾美邦德克隆)1〇 C18 ’ 300X3.9耄米管柱;移動相:溶劑A = 2〇毫莫耳濃 度鱗酸钟溶液,酸驗值6 2,溶劑B=乙腈;梯度:〇_6〇%b /15分鐘,60_0%B/2分鐘,〇%B/3分鐘;以波長27〇奈 米之紫外光進行偵測。。 滞留時間:產物7二5·2分鐘,起始反應物6 = 9.2分 鐘。 將反應燒瓶接上漏斗(2公升),緩慢加入3 5莫耳濃度 (4公升)’溫度祕氏32度升紅44度。將 兩液相的溶液移至直立式分液漏斗,並將兩層溶液分離。 47 200425897 驗丨生的液相以乙酸乙酯(2公升)萃取,再移至一裝置在自動 攪拌器上的12公升3頸燒瓶,並接上一漏斗(1公升)。邊 攪拌邊緩慢加入濃鹽酸,以標準實驗室的酸鹼值測量儀測 定酸鹼度,直至酸鹼值等於3。將產生的黃色溶液在室溫下 攪拌12小時,產生沈澱。將攪拌的混合物置於冰浴中冷卻 至攝氏7度,以濃鹽酸調整酸鹼度至酸鹼值等於3。將混合 物在冰浴中繼續攪拌5小時然後過濾。過濾需時約4小時。 收集固體物,以丙酮沖洗,並在過濾漏斗上風乾。 將一5公升3頸圓底燒瓶裝置在一自動攪拌器,並接 上一 250宅升的漏斗。在燒瓶内加入未經純化的固體和1 莫耳濃度氫氧化鈉溶液(L25公升)。攪拌混合物使固體完 全溶解(15分鐘)。緩慢加入濃鹽酸直至酸鹼值等於3。產 生的混合物在室溫下攪拌4小時後過濾。收集固體物並以 水(2次’每次250笔升)和丙酮(200毫升)沖洗,乾燥直至 重量不變(-30吋汞柱,攝氏60度,14小時)。 回收=292公克 白色固體(41.3%)。 磁振氧光譜分析儀(重水);5 =3.25 (d,J二8赫茲,2氫),3.70 (t,赫兹,2 氮),4.10 (t,J=4 赫兹,2 氮),4.60 (s,4 氮),7.80 (s,1 氫),7.90 (s,1 氫)。 乾例 8: 9· {2-[2,4-順-(S)_(+)-4-(3-氮笨基)-2-乳-1,3,2- 二歐索林酸磷南-2-基]甲氧基乙基}腺嘌呤曱烷磺酸鹽(9) 48 200425897 的製備(註:鱗南=ph〇sphorinan) 範例8.1:合成二氯化合物(8)1 · 04 liters) of digas methane solution was added with triethylamine (211 milliborane compound) (1.60 mole concentration, 39 into the funnel, slowly add and stir to maintain the temperature between minus 20 degrees Celsius and minus 2S degrees Celsius) After the addition is complete (approximately% minutes), the solution is placed in an ice bath (2-3 degrees Celsius) to warm up and stir. After four hours of stirring, analysis by nuclear magnetic resonance analysis shows that the content of the starter 1 is less than 4%. The remaining starting material I was measured by a proton nuclear magnetic resonance apparatus according to the following method: A 0.5 ml sample of the reactant was taken out, and the reaction was terminated by adding water (0.5 ml) and a 3 mol sodium hydroxide solution. Stir the terminated reaction solution to make it The layers were separated. The aqueous phase was acidified with 2 molar hydrochloric acid (1 mL) and extracted with acetic acid (1 mL). The organic phase was separated, filtered through a plug of magnesium sulfate, and concentrated with nitrogen. The residue was dissolved in methane, The solvent was evaporated with nitrogen. The residue / calcin was dissolved in acetone and analyzed with a magnetic resonance spectrometer (acetone-Atom 6). Water (L2 liter) was added to the cloudy orange reaction mixture, followed by 3 Molar Argon Oxygen Aqueous sodium solution (ι · 44 liters). The mixture was stirred vigorously for 5 minutes, and then transferred to a separatory funnel. The different layers were separated, and the basic aqueous phase was washed with ethyl acetate (1 liter). The aqueous phase was concentrated with hydrochloric acid. (300 ml) was acidified and extracted with ethyl acetate (twice, 13 liters each time). The two acidic ethyl acetate extracts were mixed, washed with 10% sodium chloride solution (600 ml), and washed with magnesium acid ( (130 g) dried, filtered, and concentrated under reduced pressure to obtain 328 g of yellow oil. Let stand to crystallize. The resulting crystals were added to ethyl acetate (180 ml) to make it cloudy, and then transferred to the device in an automatic stirrer In a 2-liter three-necked round-bottomed flask. The stirred ethyl acetate solution q was reduced to below 10 degrees Celsius (ice bath), and then diluted with hexane (8 ml). The mixture was stirred in the ice bath for 4 hours. Hours, and filter. Collect the mouth, rinse with 4: 1 hexane · ethyl acetate (three times, 50 ml each time), and then dry to a stable weight (-30 忖 Hg, room temperature, 2 hours) Recovered = 207.5 grams of white powder 2 (74.5%) oscillating hydrogen spectroscopic analysis (Acetone deuterium & Bu 2.7 (d, > 6 Hz, 2 hydrogen), 4 · 7 (d, J = 4 Hz, 1 hydrogen), 5.1-5.2 (m, 1 hydrogen), 7.2-7.5 (m (4 hydrogen). Example 3: Preparation of (3_) phenylene glycol propylene glycol 3) A 12 liter 3-necked round bottom flask was placed in an automatic stirrer, and a funnel (2 liter) and a thermometer were added. The flask was filled with nitrogen, and each of CD & chlorophenyl earth) 3 5 g of propanoic acid 2 (206.7 g) and tetrahydrofuran (MO ml) was added, and the stirred solution was cooled to 5 ° C (ice bath) ). Dissolve and burn the Kombulam (2.14 liters) dissolved in tetrazine slowly through the funnel and stir to keep the temperature below 10 degrees Celsius. When fully added (approximately one hour), remove the ice bath solution at room temperature for an hour. Carefully and slowly add water (Mao Sheng) to stop the reaction 'and add 3 Molar sodium chloride solution (Mao Sheng). The mixture was allowed to stir for 10 minutes, and the temperature was observed to rise to 40 degrees Celsius. The mixture was transferred to a separation funnel. The different layers were separated and the aqueous phase was extracted with ethyl acetate (600 ml). The combined organic phases were rinsed with 10% sodium nitroxide / fen solution (500 liters), dried (magnesium sulfate, 322 g), filtered, and concentrated at a low pressure of 41 200425897 to 189.0 g of a light yellow oil ( 101%). A preliminary analysis was performed on this oil using a magneto-optical hydrogen spectrometer (deuterium-trifluoromethane). This oil was purified by vacuum fractionation, and a liquid separation of 125-155 ° C / 0.15 mm Hg was collected. Two 180.9 grams of colorless oil 3 (94.0%) was recovered. Magnetic vibrational hydrogen spectrum analyzer (CDCI3): Occupies H3.1 (m, 2 hydrogen), 2.5 (bs, 2 hydrogen), 3.9 (t, J = 5 Hz, 2 hydrogen), 4.9 (dd, J 2 7.4, 4.8 Hz, 1 hydrogen), 7.2-7.4 (m, 4 hydrogen). The determination of palm isomer excess was performed by performing optical performance isomer analysis of the liquid isomer. The diol 3 was derivatized into diacetate by the following method: Glycol 3 (5.0 mg, 0.00 26 mmol) was dissolved in dichloromethane (2.0: 1). Add acetic anhydride (15 μl, 0.15 mmol) and 4- (dimethylamino) pyrimidine (13 mg, 0.10 mmol) and stir at room temperature for 15 knives. The reaction was terminated by the addition of a 1 mol hydrochloric acid solution (3 ml), and the lower organic layer was separated ', and Wei was plugged with magnesium sulfate, and then Wei gas was concentrated. The residue was dissolved in ceranol (1 ml) and analyzed by high performance liquid chromatography with silk isomers. Surprisingly, the para-isomer excess of diol 3 was measured > 98%. Conditions for liquid chromatography at the South Effect Division: 42 200425897 Chromatography Tubes: Bo < Covalent (8,8) Wick-〇〇〇〇〇〇〇〇rone 0 ^ (::, 25〇X4.6mm) Mobile phase = 70:30, methanol: water, consistent ratio from beginning to end; flow rate = 1.5 ml / min; injection volume = 10 microliters, UV light detection at 220 nm. Π retention time: s-diol (Diacetate) = 12.1 minutes, diol (diacetic acid) = 8.6 minutes. Example 4: Preparation of diethyl-p-toluene yellow ether oxocarboxylate hydrazone A 12 liter 3-neck round bottom flask Installed in an automatic stirrer, connected to a condenser, thermometer and heating furnace. Fill the flask with nitrogen and add dimethyl phosphite (554 g), polyacetaldehyde (142 g), toluene (2 liters) and three Ethylamine (53 ml). Stir the mixture at 85-90 degrees Celsius for 2 hours and heat to reflux for 1 hour. The resulting yellow aqueous solution is cooled to 4 degrees Celsius in an ice bath, and p-toluenesulfonate is added. (718 g). Replace the condensate with a funnel and slowly add triethylamine (750 ml) while stirring, maintaining the temperature below 10 degrees Celsius. After the addition process is completed (takes 45 minutes), continue to stir at room temperature for 14 hours. The mixture is filtered, and the material on the filter paper is washed with toluene (twice, 250 ml each time). The filtrate and the washing solution are mixed and mixed with Rinse with water (2 times, 1 liter each time), dry (magnesium sulfate, 200 g), filter through diatomaceous earth (silicone 521, number 61790-53-2), and concentrate under low pressure. 43 200425897 Recovery = 1004 Gram turbid yellow oil 4 (77.6%). Magnetic resonance hydrogen spectrometer (trichloro gas burning). △ = L3 (t, J = 8 hydrogen, m, 3 hydrogen), 2.4 (s, 3 hydrogen), 4.0-4.2 (m, 4 hydrogen), 7.2 (d, J = 8 Hz, 2 hydrogen), 7.8 (d, J = 8 Hz, 2 hydrogen). Example 5: 9- (2-strongethyl) gland Preparation of Purine (5) A 12 liter 3-necked round bottom flask was placed in an automatic stirrer, connected with a condenser, a thermometer and a heating furnace. The flask was filled with gas, and then adenine (504 g) and carbonic acid were added. Ethylene (343 g), dimethylammonium (3β7 liters), and osmium sodium oxide (7.80 g). Heat this stirred mixture to reflux (it takes about 80 minutes to achieve reflux, hot pot temperature is two shots) 145 degrees), heat and reflux for another 2 hours. Remove the heating furnace to cool the yellow aqueous solution below 100 degrees Celsius. The resulting mixture is cooled in an ice bath to below 5 degrees Celsius, and diluted with toluene (3.8 liters) Stir the mixture for 2 hours at 10 degrees Celsius and then filter. Collect the solids and rinse with toluene (twice, 0.5 liters each) and cold ethanol (1.5 liters), then dry to a stable weight (-30 inches of mercury). , 50 degrees Celsius, 14 hours). Solid 5 was analyzed by high performance liquid chromatography and magnetic resonance hydrogen spectroscopy (dimethyl sulphur oxide- / Πα 6). High-performance liquid chromatography conditions: 44 200425897 Stone dioxide column (particle size, 10 microns) (Fernomex Bond clone) 1 () C18 tube inspection, 300 × 3 · 9 mm; Mobile phase: Solvent A 22 Millimolar concentration of potassium stone dance acid, pH 6.2; solvent acetonitrile; gradient: 0_60% B / 15 for 1 mile '60 -〇% 8/2 minutes' 0% B / 3 minutes ·; at a wavelength of 270 Nanometer UV detection. Retention time: 6.5 minutes for product 2 and 5.6 minutes for 3-position isomer (experimental). Recovery = 624 grams. Light yellow solid 5 (93.3%). Magnetic Oscillation Oxygen Spectral Analyzer (Difluorenyl Sulfur Oxide_Deuterium 6): ^ = 3.6-3.8 (m, 2 hydrogen), 4.1 (t, J = 6 Hz, condition), 5.0 (bs, 1 hydrogen), 7.2 (bs, 2 hydrogen), 8.05 (s, 1 hydrogen), 8.10 (s, 1 argon). Example 6: Preparation of 9- (2-diethylphosphinofluorenyloxyethyl) adenine hydrazone A 5 liter 3-necked round bottom flask was placed in an automatic stirrer and warmed with juice. Fill the burner with nitrogen and fill with 9- (2-fluorethyl) adenine 5 (464 g) and diamidinofluoramine (1.40 liters). The stirred reaction was placed in an ice bath and cooled to 10 ° C. Sodium tert-butoxide (436 g) was added and the temperature was raised to 29 ° C. The ice bath was removed and the reaction was shaken at room temperature for 1 hour and became a slightly cloudy aqueous solution. A funnel (2 liters) was attached to the flask, and the temperature was cooled to 5 ° C in an ice bath. A solution of diethyl-p-tolysinoxoyloxanyl diacetate (1130 g) in dimethyl methylamine (70045 200425897 ml) was added slowly. Turn the temperature below K ° C. After the addition is complete (2 hours), remove the ice bath and let it stand at room temperature for 1 hour. The degree of completion of the reaction was determined by high performance liquid chromatography. Take 0.55 ml of the reaction and dissolve it in 10 ml of 20 millimolar potassium potassium hydroxide buffer, pH 6.2. High-performance liquid chromatography conditions: Sulfur dioxide chromatography column (particle size, K) microns) (f Nomebond clone) 10C18 column '300X3.9 mm; mobile phase: solvent a = 20 millimolar concentration scale Potassium acid (pH 6.2), solvent B = ethoxy; gradient: 0-60% B / 15 minutes' 60_0% B / 2 minutes, 0% β / 3 minutes; detection with ultraviolet light with a wavelength of 270 nm Measure; injection volume = μ0 μl. Residence time: product 6 = 9.2 minutes, starting reactant 5 = 65 minutes. The stirred mixture was cooled to 0 ° C and 80% acetic acid (250 ml) was slowly added. After the addition is complete (approximately ls minutes), the mixture is stirred at room temperature for 30 minutes, and the temperature is gradually increased to 30 degrees Celsius. The solvent was evaporated under reduced pressure (R_152 rotary evaporator, 5 mmHg), leaving 2115 grams of orange mud. This material was used in the next step without purification. Example 7: Preparation of 9- (2-phosphinofluorenylmethoxyethyl) adenine pyrene. A ~ 12 liter 3-neck round bottom flask was placed in an automatic stirrer. An unpurified 9- (2-diethylphosphinomethylmethoxyethyl) adenine 46 200425897 6 was added to the flask, and the mixture was dissolved in acetonitrile (4.0 liters) to make a mud. The mixture was stirred at room temperature for 1 minute and filtered. The solid matter on the filter paper was washed with acetonitrile (twice, 0.5 liter each time), and the filtrate and the washing solution were mixed and used directly in the next step. A 22-liter 3-necked round bottom flask was placed in an automatic stirrer, connected to a thermometer, a condenser, and a heating furnace. After the flask was filled with nitrogen, 9- (2-diethylphosphonomethoxyethyl) adenosine 6 solution (2.59 moles), chlorotrimethyllithium sulfite (1.315 liters), and degraded _ ( 1/719 kg). After adding the dish, the temperature of the mixture will gradually rise to 35 degrees Celsius. Warm the stirred mixture to 55 degrees Celsius, and stir it for 50 hours at a temperature between 50 and 55 degrees Celsius. The mixture was stirred for another 3 hours while slowly cooling down to 38 degrees Celsius to determine the degree of completion of the reaction by high performance liquid chromatography. Conditions for high performance liquid chromatography:. Sulfur dioxide column (particle size, 10 microns) (Fernomex Bond clone) 10C18 '300X3.9mm rice column; mobile phase: solvent A = 20 mmoles Scale acid bell solution, acid test value 6, 2, solvent B = acetonitrile; gradient: 0-60% b / 15 minutes, 60_0% B / 2 minutes, 0% B / 3 minutes; UV at a wavelength of 27 nm Light for detection. . Retention time: product 7-25.2 minutes, starting reactant 6 = 9.2 minutes. The reaction flask was attached to a funnel (2 liters), and a 35 mol concentration (4 liters) 'temperature was slowly added to 32 degrees liters and 44 degrees red. The two-phase solution was transferred to a vertical separatory funnel, and the two layers of solution were separated. 47 200425897 The extracted liquid phase was extracted with ethyl acetate (2 liters), transferred to a 12 liter 3-neck flask equipped with an automatic stirrer, and connected to a funnel (1 liter). Slowly add concentrated hydrochloric acid while stirring, and measure the pH with a standard laboratory pH meter until the pH is equal to 3. The resulting yellow solution was stirred at room temperature for 12 hours, causing precipitation. The stirred mixture was cooled in an ice bath to 7 degrees Celsius, and the pH was adjusted to pH 3 with concentrated hydrochloric acid. The mixture was stirred for another 5 hours in an ice bath and then filtered. Filtration takes about 4 hours. The solids were collected, rinsed with acetone, and air-dried on a filter funnel. A 5 liter 3-neck round bottom flask was set in an automatic stirrer and connected to a 250-litre funnel. The flask was charged with unpurified solids and a 1 molar sodium hydroxide solution (L 25 liters). The mixture was stirred to completely dissolve the solids (15 minutes). Slowly add concentrated hydrochloric acid until the pH value is equal to 3. The resulting mixture was stirred at room temperature for 4 hours and then filtered. The solids were collected and rinsed with water (twice '250 strokes each time) and acetone (200 ml) and dried until the weight remained constant (-30 inches Hg, 60 ° C, 14 hours). Recovered = 292 g of white solid (41.3%). Magnetic resonance oxygen spectrometer (heavy water); 5 = 3.25 (d, J 2 8 Hz, 2 hydrogen), 3.70 (t, Hertz, 2 nitrogen), 4.10 (t, J = 4 Hz, 2 nitrogen), 4.60 ( s, 4 nitrogen), 7.80 (s, 1 hydrogen), 7.90 (s, 1 hydrogen). Dry case 8: 9 · {2- [2,4-cis- (S) _ (+)-4- (3-azabenzyl) -2-milk-1,3,2-dioxoline phosphate South-2-yl] methoxyethyl} adenine pinane sulfonate (9) 48 200425897 Preparation (Note: Southern = phosphorinan) Example 8.1: Synthesis of dichloro compound (8)
NEt2 Ο 8 PCI2 將一2公升3頸圓底燒瓶裝置在一自動攪拌器,接上 冷凝裔、漏斗(125耄升)和加熱爐。燒瓶以氮氣充滿後加入 9-(2-膦酿曱氧基乙基腺嘌呤7 (50 0公克)、二氯甲烷(650 宅升)和氮,氮-二乙基甲醯胺(22.5毫升)。自漏斗緩慢將 乙二隨二氯(58.0毫升)加入攪拌中的反應混合物,這時會 劇烈產生氣體,將氮氣的入口移開以幫助氣體排出,全部 加入後(15分鐘),移開漏斗,將劇烈攪拌的混合物加熱回 w 2小時。溶液在此過程呈泥漿狀。待反應混合物稍微冷 部後加入乙二酿二氯(1·〇毫升)及氮,氮-二乙基曱驢胺。 一乙基曱酿胺的加入會劇烈地產生氣體。將最後的混合物 力Λ、、回机’直至所有的固體均已溶解(需另外2.5小時,總 反應π間約為4·5 *時)。以高效能液相層析分析反應液, ’、、、頁示產m2 8約佔83%。反應的進行是觀察二氯化合物的形 49 200425897 成。從反應混合物取出樣品(約50微升),以含1滴三甲 胺的脫水甲醇(1毫升)終止反應。利用高效能液相層析分 析產生的甲基鱗酸化合物。 高效能液相層析條件: YMC-派克 R&D,R-33-5 S-5 120A,250X4.6 毫米;移動 相·浴劑A= 20宅莫耳濃度構酸舒,酸驗值6.2;溶劑 乙腈;梯度:10-60%B/15 分鐘,60-10%B/2 分鐘,1〇%Β/3 分鐘;1·4毫升/分鐘;注射體積=10微升;以波長27〇奈米 之紫外光進行偵測。 滯留時間:二曱基磷酸鹽11 = 8.5分鐘,單甲基鱗酸 鹽12二5.8分鐘。NEt2 0 8 PCI2 A 2 liter 3-necked round bottom flask was installed in an automatic stirrer, and the condenser, funnel (125 liters) and heating furnace were connected. After the flask was filled with nitrogen, 9- (2-phosphinophenoxyethyl adenine 7 (50 g)), dichloromethane (650 liters), and nitrogen, nitrogen-diethylformamide (22.5 ml) were added. Slowly add ethylene dichloride (58.0 ml) from the funnel to the stirred reaction mixture. At this time, gas will be generated violently. Remove the nitrogen inlet to help the gas to escape. After all the addition (15 minutes), remove the funnel. The vigorously stirred mixture was heated back to w for 2 hours. The solution was in the form of a slurry during this process. After the reaction mixture was slightly cold, ethylenedichloride (1.0 ml) and nitrogen, nitrogen-diethylstilamine were added. The addition of monoethylpyrene amine will generate gas violently. Force the final mixture Λ, and return to the machine until all the solids have been dissolved (requires another 2.5 hours, the total reaction π interval is about 4 · 5 * hours) The reaction liquid was analyzed by high performance liquid chromatography. The yield of m 2 8 accounts for about 83%. The progress of the reaction is to observe the shape of the dichloro compound 49 200425897. The sample (about 50 microliters) is taken from the reaction mixture. ), Terminated with 1 drop of trimethylamine in dehydrated methanol (1 ml) Yes. Analysis of the methylphosphonic acid compounds produced by high performance liquid chromatography. Conditions for high performance liquid chromatography: YMC-Parker R & D, R-33-5 S-5 120A, 250X4.6 mm; mobile phase Bath A = 20 molar concentration of acid acid, acid value 6.2; solvent acetonitrile; gradient: 10-60% B / 15 minutes, 60-10% B / 2 minutes, 10% B / 3 minutes; 1.4 ml / min; injection volume = 10 microliters; detection with ultraviolet light at a wavelength of 27 nm. Retention time: diphosphonium phosphate 11 = 8.5 minutes, monomethyl phosphonate 12 to 5.8 minutes .
將反應溶液稍微冷卻,移開冷凝器,改加裝有溫度計 的蒸餾器、冷凝器和收集燒杯(25〇毫升)。將反應溶液加熱 至回流,收集250毫升的蒸餾液,在反應溶液中加入二氣 曱烧(25〇冑升),另外收集25〇毫升蒸館液。移開蒸餘器, 將反應的燒瓶置於氮氣下。加入二氣曱烷(1〇〇毫升)稀 50 200425897 釋,並置於冰浴中冷卻。以高效能液相層析分析反應液, 顯示產品約佔89%。 高效能液相層析分析條件: YMC-派克 R&D’R-33_5S_5 120A,250X4.6 毫米;移動 相:溶劑A=20毫莫耳濃度磷酸鉀溶液,酸鹼值6.2;溶劑 B-乙腈,梯度:1〇-60%Β/ 15 分鐘,6〇_l〇%B/ 2 分鐘, 10%B/3分鐘;I·4毫升/分鐘;注射體積二1〇微升;以波 長270奈米之紫外光進行偵測。 滯留時間:產品8 = 8·5分鐘,起始反應物7 = 5·9分 鐘 緩慢加入錢(18毫升)至娜巾液。待完全加入 後(5分鐘),將產生的淡橘色溶液放置在冰浴中直到被使用 (30分鐘)。 範例8.2:偶合反應 將-2公升3頸圓底燒瓶裳置在一自動勝器,接上 漏斗(1公升)。將燒瓶以氮氣充滿,加入⑻+)_(3_氯苯 基)-u-丙二醇3(341公克)’以二氯甲烧(5〇〇毫升)和三 乙胺(125毫升)做為溶劑。將熱電偶針浸入反應液中,並將 娜物冷卻至攝氏零下71度(乾冰/異丙醇)。將二氣化合物 1 由漏斗緩慢加人,在加人的同時攪拌,使溫度保持在攝氏 零下67度以下。當加人的過程完畢(1.25小時),將冰浴移 51 200425897 開’將攪拌物在30分鐘的時間回溫至攝氏〇度。以水(55〇 毫升)沖洗反應物,獻將不同層分開。二氯技相以乙酸 乙醋(500毫升)稀釋,並以5%氯化納溶液(_毫升)沖洗。 有機相以硫麵(5〇公克)乾操,以賴土(残特52i)過 濾、’並在低驗態以觸公克之深紅污泥濃縮。將樣品溶 解在甲醇。 高效能液相層析條件: YMC_派克 R&D,R_33_5S_5 蠢,25GX46 毫米;移動 相· /合剤A-20耄莫耳濃度磷酸鉀,酸鹼值6 2;溶劑B = 乙腈;梯度:10_60%B/ 15 分鐘,60_10%b/2 分鐘,1〇%b/3 刀名里,1.4笔升/分鐘;注射體積=1〇微升;以波長奈米 之紫外光進行偵測。 滯留時間: I 13 = 12.5 分鐘,反 14 = 13.0 分鐘The reaction solution was cooled slightly, and the condenser was removed, and a distillation apparatus equipped with a thermometer, a condenser, and a collection beaker (250 ml) were replaced. The reaction solution was heated to reflux, and 250 ml of a distillate was collected. To the reaction solution was added dioxane (250,000 liters), and another 250 ml of a distillate was collected. The vaporizer was removed and the reaction flask was placed under nitrogen. Dioxane (100 ml) was added to dilute 50 200425897 and the solution was cooled in an ice bath. Analysis of the reaction liquid by high performance liquid chromatography showed that the product accounted for about 89%. HPLC analysis conditions: YMC-Parker R & D'R-33_5S_5 120A, 250X4.6 mm; mobile phase: solvent A = 20 millimolar potassium phosphate solution, pH 6.2; solvent B-acetonitrile Gradient: 10-60% B / 15 minutes, 60-10% B / 2 minutes, 10% B / 3 minutes; 1.4 ml / min; injection volume 20 microliters; at a wavelength of 270 nanometers Detect by ultraviolet light of meters. Retention time: Product 8 = 8.5 minutes, starting reactant 7 = 5.9 minutes. Slowly add money (18 ml) to the Na towel solution. After the addition is complete (5 minutes), the resulting light orange solution is placed in an ice bath until used (30 minutes). Example 8.2: Coupling reaction Place a 2-liter 3-necked round-bottom flask in an automatic winner and attach the funnel (1 liter). The flask was filled with nitrogen, and ⑻ +) _ (3-chlorophenyl) -u-propanediol 3 (341 g) was added. Dichloromethane (500 ml) and triethylamine (125 ml) were used as solvents. . Immerse the thermocouple needle in the reaction solution, and cool the substrate to minus 71 ° C (dry ice / isopropanol). Add the digas compound 1 slowly from the funnel, and while stirring, keep the temperature below 67 degrees Celsius. When the addition process is complete (1.25 hours), move the ice bath 51 200425897 to open the temperature of the stirrer to 0 ° C in 30 minutes. The reaction was rinsed with water (55 ml) and the different layers were separated. The dichloro phase was diluted with ethyl acetate (500 ml) and rinsed with a 5% sodium chloride solution (_ml). The organic phase was dried over sulfur (50 g), filtered through soil (Residential 52i), and concentrated in a low-red state to touch gram of dark red sludge. The sample was dissolved in methanol. High performance liquid chromatography conditions: YMC_Parker R & D, R_33_5S_5 Stupid, 25GX46 mm; Mobile phase · / A 剤 A-20 耄 Molar concentration potassium phosphate, pH 6 2; Solvent B = Acetonitrile; Gradient: 10_60% B / 15 minutes, 60_10% b / 2 minutes, 10% b / 3 in the name of the knife, 1.4 liters / minute; injection volume = 10 microliters; detection with ultraviolet light with a wavelength of nanometers. Residence time: I 13 = 12.5 minutes, inverse 14 = 13.0 minutes
CI 將物質溶解在乙醇(毫升)並敍—裝置在磁授摔 器、冷凝器和加熱爐的2公升圓底燒瓶。將醋酸(55毫升) 加入’亚將此紅色液體加熱至回流8 ]、時。由高效能液相 層析確疋反應已完成。將樣品溶解在甲醇。 52 4 200425897 4 高效能液相層析條件: R & D ^ R.33>5 S-5 120A ^ 250 X 4.6 ^ 相· /谷?1] A 20宅莫耳濃度鱗酸鉀,酸驗值6 2;溶劑b 〜乙腈;梯度:10-60%B/ 15 分鐘,6〇_1〇%B/ 2 分鐘,l〇%B/ 3分鐘·; 14耄升/分鐘·;注射體積=10微升;以波長270奈 米之紫外光進行偵測。 滯留時間:廢15 = 9·5分鐘,及16 = 9.8分鐘CI Dissolve the substance in ethanol (ml) and re-install it in a 2-liter round-bottom flask equipped with a magnetic shaker, condenser, and heating furnace. Acetic acid (55 ml) was added to the sub-heated red liquid to reflux 8]. The completion of the reaction was confirmed by high performance liquid chromatography. The sample was dissolved in methanol. 52 4 200425897 4 Conditions for high performance liquid chromatography: R & D ^ R.33 > 5 S-5 120A ^ 250 X 4.6 ^ phase · / valley? 1] A 20 molole potassium potassium scale acid, acid test Value 62; solvent b ~ acetonitrile; gradient: 10-60% B / 15 minutes, 60-10% B / 2 minutes, 10% B / 3 minutes · 14 l / min ·; injection volume = 10 microliters; detection with ultraviolet light at a wavelength of 270 nm. Detention time: scrap 15 = 9 · 5 minutes, and 16 = 9.8 minutes
範例 8·3: 9·{2_【2,4_餐(S)_(+)-4-(3_氯苯基)_2_氧_1,3,2·二歐 索林酸phosphorinan-2-yl】甲氧基乙基}腺嘌呤腺嘌呤甲烷 磺酸鹽(9)之結晶 加入曱烧〜酸(21·5宅升)15分鐘後會產生沈殿物。將 混合物以乙醇(400 ¾升)稀釋,加熱直到固體溶解(反應锅 溫度=攝氏70度)。將溶液冷卻同時攪拌,沈澱物在攝氏46 度時形成。將混合物繼續攪拌2小時,冷卻至室溫,再置 入冰浴2·5小時。過濾混合物並收集固體,以乙醇(2次, 每次15毫升)沖洗,再乾燥至重量不變(-30吋汞柱,攝氏 53 200425897 55度’ 14小時”回收’·4公克之白色粉末9(519%)。 固體含約6.5%之反位幾何異構物。 光學異構物高效能液相層析:博可共價(s,s)惠克_〇 110/100克朗FEC250X4.6毫米;移動相=55 45,曱醇 (U %醋酸溶於水;移動相前後-致;1〇毫升/分鐘;注 射體積=10微升;以波長260奈米之紫外光進行綱。樣品 配製=2.0毫克/毫升於水。滞留時間:餐⑻5 = 246分 鐘,及-⑻6 = 27.5分鐘,賡(S) 7二ΐ8·〇分鐘 以磁振氧光谱分析儀(重水)確認組成之結構。Example 8 · 3: 9 · {2_ [2,4_Meals (S) _ (+)-4- (3_chlorophenyl) _2_oxy_1,3,2 · diosolinic acid phosphorinan-2 -yl] Methoxyethyl} Adenine Adenine Methane Sulfonate (9) Crystals will be added after 15 minutes of simmering to acid (21.5 liters). The mixture was diluted with ethanol (400 ¾ liters) and heated until the solids were dissolved (reactor temperature = 70 ° C). The solution was cooled and stirred, and a precipitate formed at 46 ° C. The mixture was further stirred for 2 hours, cooled to room temperature, and placed in an ice bath for 2.5 hours. Filter the mixture and collect the solids, rinse with ethanol (twice, 15 ml each time), and dry to the same weight (-30 inches Hg, 53 2004 25897 55 degrees '14 hours "recovered 4 grams of white powder 9 (519%). The solid contains about 6.5% of inverse geometric isomers. Optical isomers High performance liquid chromatography: Boke covalent (s, s) Wick_〇110 / 100 crowns FEC250X4.6 mm Mobile phase = 55 45, methanol (U% acetic acid dissolved in water; before and after mobile phase; 10 ml / min; injection volume = 10 microliters; outline by UV light with a wavelength of 260 nm. Sample preparation = 2.0 mg / ml in water. Retention time: meals ⑻5 = 246 minutes, and -⑻6 = 27.5 minutes, 赓 (S) 7 ΐ 8 · 0 minutes. The structure of the composition was confirmed with a magnetic resonance oxygen spectrometer (heavy water).
NH9 . MsOHNH9. MsOH
範例 8·4: 9_{2-丨2,4-順-(S)-(+)-4-(3-氯苯基)-2氧· 1,3,2__歐索林酸麟南_2·基]甲氧基乙基}腺嗓吟甲烧碍酸鹽 (9)之再結晶(註:填南=phosporinan) 將一3公升3頸圓底燒瓶裝置於自動攪拌器上,並接 上冷凝器、加熱爐和溫度計。將兩批次的未純化曱石黃酿鹽9 和乙醇(1.4公升)置入燒瓶内。將攪拌的混合物加熱至回流 (反應鍋溫度為攝氏78度)直到固體溶解(約10分鐘)。再慢 f艾冷卻至室溫,需15小時(沈殿物在攝氏56度時形成)。混 54 200425897 合物在室溫下再擾拌2小時,然後過濾、。將收集之固體以 乙醇(2次,每次15毫升)沖洗,再乾燥至重量不變(-3〇忖 汞柱,攝氏65度,60小時)。 顏色:白色固體粉末 純度=97% (高效能液相層析) 光學純度(光學異構物高效能液相層析)>99.5%. 熔點(攝氏度):186.5-188 單位旋轉(甲醇,攝氏25度,589奈米):+16.429 組成:碳,41.58;氫,4.56;氮,13.37 [理論值:碳,41.5〇; 氫,4.53;氮,13.35] 磁振氩光譜分析儀(重水):5 = 1.30-1.60(m,1氫), 1.80-1.95 (m,1 氫),2.60 (s,3 氫),3.70-3.90 (m,4 氫),4·10_4·50 (m,2 氩),4·60 (s,3 氫),5·15_5·40 (m,1 氫), 6.70-6.80 (m,2 氩),7·00_7·10 (m,2 氳),8·00 (s,1 氫),8·10 (s, 1氫)。 範例9··經由鹽交換製備鹽酸鹽類 在這個發明中,亦會形成以磷酸為基礎前趨藥物的草 酸鹽類。這前趨藥物的鹽類也可被換成其他醫藥界接受的 其他鹽類。草酸鹽是溶解在含有高酸解離常數值酸的溶液 中。 55 200425897 將一3頸圓底燒瓶裝置在一自動攪拌器上,接上冷凝 為、加熱爐和溫度計。在燒瓶内加入未純化的草酸鹽和乙 醇(5-10%溶液,依重量)。將攪拌的混合物加熱至回流(反 應鍋溫度為攝氏78度)直到所有固體溶解。將溶液以鹽酸酸 化,並將溫度緩慢降至室溫(沈澱物在冷卻過程中形成)。 在室溫攪拌混合物,然後過濾。將含有鹽酸鹽類之固體收 集,以乙醇沖洗,並以烤箱乾燥至溫度不變(烤箱溫度=攝 氏65度)。 範例10:經鹽類交換形成硫酸鹽 將一 3頸圓底燒瓶裝置在一自動攪拌器上,接上冷凝 器、加熱爐和溫度計在燒瓶内加入未純化的甲磺醯鹽9和 乙醇(5-10%溶液,依重量)。將攪拌的混合物加熱至回流 (反應鍋溫度為攝氏78度)直至所有固體溶解。將溶液以硫 酸酸化,並逐漸冷卻至室溫(沈澱在降溫過程中形成”在 至溫下攪拌混合物,接著過濾得到期待的產物。將收集到 的含有硫酸鹽的固體以乙醇沖洗,並在真空烤箱中乾燥至 重量不變(烤箱溫度=攝氏65度)。 範例11:經游離鹼反應形成硫酸鹽類 將一3頸圓底燒瓶裝置在一自動攪拌器上,接上冷凝 為、加熱爐和溫度计。在燒瓶内加入未純化的甲石黃酿鹽9和 56 200425897 碳酸氫納鎌。加_拌混合物直至所有的_溶解。將 溶液以硫酸酸化,並逐漸降溫至室溫(沈殿物在降溫過程中 形成)。混合物在室溫後過濾。收集含硫酸鹽的固體, 以乙醇沖洗’並在真空烤箱中乾燥至重量不變(烤箱溫度= 攝氏65度)。 範例12··經陰離子樹脂反應形成順丁烯二酸鹽 將一 3頸圓底燒瓶裝置在一自動攪拌器上,接上冷凝 為、加熱爐和溫度計在燒瓶内加入未純化的甲磺醯鹽9。 加熱授拌混合物直至固體全部溶解。將含有曱績酿鹽 9的溶液通過陰離子樹脂。得到的溶液含有結構式丨以順丁 烯二酸酸化的游離鹼,將攪拌的混合物逐漸冷卻至室溫(沈 /属又物在降溫過程中形成)。將混合物在室溫下攪拌後過減, 收集含有順丁烯二酸鹽固體,以乙醇沖洗,並在真空烤箱 中乾燥至重量不變(烤箱溫度=攝氏65度)。 【圖式簡單說明】 益。 57Example 8 · 4: 9_ {2- 丨 2,4-cis- (S)-(+)-4- (3-chlorophenyl) -2ox · 1,3,2__Osulin acid Linnan_ 2 · yl] methoxyethyl} Adenophylline (9) Recrystallization (Note: Fill South = phosporinan) A 3 liter 3-necked round bottom flask was placed on an automatic stirrer and connected Install condenser, heating furnace and thermometer. Two batches of unpurified vermiculite yellow stuffed salt 9 and ethanol (1.4 liters) were placed in the flask. The stirred mixture was heated to reflux (reaction pot temperature was 78 degrees Celsius) until the solids dissolved (about 10 minutes). Slowly, it takes 15 hours to cool to room temperature (Shen Dianwu formed at 56 degrees Celsius). 54 200425897 The mixture was stirred at room temperature for another 2 hours, and then filtered. The collected solid was washed with ethanol (twice, 15 ml each time), and dried to the same weight (-3 ° C Hg, 65 ° C, 60 hours). Color: white solid powder purity = 97% (high performance liquid chromatography) optical purity (high performance liquid chromatography for optical isomers) > 99.5%. Melting point (degrees Celsius): 186.5-188 unit rotation (methanol, Celsius) 25 degrees, 589 nanometers): +16.429 Composition: carbon, 41.58; hydrogen, 4.56; nitrogen, 13.37 [theoretical value: carbon, 41.5〇; hydrogen, 4.53; nitrogen, 13.35] Magnetic vibration argon spectrometer (heavy water): 5 = 1.30-1.60 (m, 1 hydrogen), 1.80-1.95 (m, 1 hydrogen), 2.60 (s, 3 hydrogen), 3.70-3.90 (m, 4 hydrogen), 4.10-4.50 (m, 2 argon ), 4.60 (s, 3 hydrogen), 5.15_5 · 40 (m, 1 hydrogen), 6.70-6.80 (m, 2 argon), 7.00_7 · 10 (m, 2 氲), 8.00 ( s, 1 hydrogen), 8 · 10 (s, 1 hydrogen). Example 9: Preparation of hydrochloride salts through salt exchange In this invention, oxalate salts of prodrugs based on phosphoric acid are also formed. The salts of this prodrug can also be replaced with other salts accepted by other medical communities. Oxalate is dissolved in a solution containing a high acid dissociation constant. 55 200425897 A 3-necked round-bottomed flask was mounted on an automatic stirrer and connected to a condenser, a heating furnace and a thermometer. Add unpurified oxalate and ethanol (5-10% solution by weight) to the flask. Heat the stirred mixture to reflux (reaction pot temperature is 78 ° C) until all solids are dissolved. The solution was acidified with hydrochloric acid and the temperature was slowly dropped to room temperature (a precipitate formed during cooling). The mixture was stirred at room temperature and then filtered. The hydrochloride-containing solids were collected, rinsed with ethanol, and dried in the oven to the same temperature (oven temperature = 65 ° C). Example 10: Sulfate formation through salt exchange. A 3-necked round bottom flask was set on an automatic stirrer, connected to a condenser, a heating furnace and a thermometer. The flask was charged with unpurified mesylate 9 and ethanol (5 -10% solution, by weight). The stirred mixture was heated to reflux (reaction pot temperature was 78 degrees Celsius) until all solids were dissolved. The solution was acidified with sulfuric acid and gradually cooled to room temperature (precipitation was formed during the cooling process. "The mixture was stirred at room temperature, followed by filtration to obtain the desired product. The collected sulfate-containing solids were rinsed with ethanol and dried in vacuo. Dry in the oven until the weight remains unchanged (oven temperature = 65 degrees Celsius). Example 11: Formation of sulfates by free base reaction. A 3-necked round bottom flask is mounted on an automatic stirrer, connected to a condensing furnace, a heating furnace and Thermometer. Add the unpurified formazan yellow stuffed salt 9 and 56 200425897 sodium bicarbonate. Add the mixture until all _ are dissolved. The solution is acidified with sulfuric acid and gradually cooled to room temperature (Shen Dianwu cooling down Formed during the process). The mixture was filtered at room temperature. The sulfate-containing solids were collected, rinsed with ethanol, and dried in a vacuum oven to the same weight (oven temperature = 65 degrees Celsius). Example 12 · Reaction with anionic resin A maleate was formed. A 3-necked round bottom flask was mounted on an automatic stirrer. The condensate was heated, a heating furnace and a thermometer. Unpurified methanesulfonate was added to the flask.醯 Salt 9. Heat the mixture until all the solids are dissolved. Pass the solution containing 曱 酿 Brine Salt 9 through the anion resin. The resulting solution contains the free base of the formula 丨 acidified with maleic acid, and the stirred mixture is gradually cooled To room temperature (sink / genus is formed during cooling). Stir the mixture at room temperature and reduce it. Collect the maleate containing solids, rinse with ethanol, and dry in a vacuum oven to the weight (Oven temperature = 65 degrees Celsius). [Simple illustration of the diagram] Yi. 57
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