CN110092803A - Tenofovir Chinese mugwort draws the preparation and its application of phenol amine fumarate process impurity - Google Patents
Tenofovir Chinese mugwort draws the preparation and its application of phenol amine fumarate process impurity Download PDFInfo
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- CN110092803A CN110092803A CN201810099676.9A CN201810099676A CN110092803A CN 110092803 A CN110092803 A CN 110092803A CN 201810099676 A CN201810099676 A CN 201810099676A CN 110092803 A CN110092803 A CN 110092803A
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- Prior art keywords
- amino
- base
- compound
- methyl
- oxygen
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 64
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 52
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 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 claims abstract description 30
- 229960004556 tenofovir Drugs 0.000 title claims abstract description 27
- 235000010894 Artemisia argyi Nutrition 0.000 title claims description 21
- 244000030166 artemisia Species 0.000 title claims description 21
- 239000012535 impurity Substances 0.000 title abstract description 27
- 150000001412 amines Chemical class 0.000 title abstract description 13
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 238000000034 method Methods 0.000 title abstract description 10
- 230000008569 process Effects 0.000 title abstract description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 92
- 239000001301 oxygen Substances 0.000 claims abstract description 92
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 92
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 91
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims abstract description 64
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 58
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 claims abstract description 49
- ZENKESXKWBIZCV-UHFFFAOYSA-N 2,2,4,4-tetrafluoro-1,3-benzodioxin-6-amine Chemical group O1C(F)(F)OC(F)(F)C2=CC(N)=CC=C21 ZENKESXKWBIZCV-UHFFFAOYSA-N 0.000 claims abstract description 45
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims abstract description 44
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 41
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims abstract description 40
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229940126062 Compound A Drugs 0.000 claims abstract description 16
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229930024421 Adenine Natural products 0.000 claims abstract description 11
- 229960000643 adenine Drugs 0.000 claims abstract description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 11
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims abstract description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 9
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 102
- 150000001875 compounds Chemical class 0.000 claims description 60
- 239000001294 propane Substances 0.000 claims description 51
- WXGDDUWFYSTFJV-TYYBGVCCSA-N (e)-but-2-enedioic acid;phosphoric acid Chemical compound OP(O)(O)=O.OC(=O)\C=C\C(O)=O WXGDDUWFYSTFJV-TYYBGVCCSA-N 0.000 claims description 24
- 239000000126 substance Substances 0.000 claims description 23
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 12
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 10
- 238000001514 detection method Methods 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims description 8
- XDXFALYQLCMAQN-WLHGVMLRSA-N butanedioic acid;(e)-but-2-enedioic acid Chemical compound OC(=O)CCC(O)=O.OC(=O)\C=C\C(O)=O XDXFALYQLCMAQN-WLHGVMLRSA-N 0.000 claims description 7
- 239000013558 reference substance Substances 0.000 claims description 7
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 description 105
- 238000003756 stirring Methods 0.000 description 43
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- 239000007788 liquid Substances 0.000 description 24
- -1 phenol amine Chemical class 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
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- 239000002904 solvent Substances 0.000 description 19
- 238000005292 vacuum distillation Methods 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 238000000926 separation method Methods 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- 239000001530 fumaric acid Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 229910019142 PO4 Inorganic materials 0.000 description 11
- 239000010452 phosphate Substances 0.000 description 11
- 101100205892 Caenorhabditis elegans taf-2 gene Proteins 0.000 description 10
- 150000001793 charged compounds Chemical class 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 101100098709 Caenorhabditis elegans taf-1 gene Proteins 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
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- 241000432824 Asparagus densiflorus Species 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000007605 air drying Methods 0.000 description 5
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- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 230000004069 differentiation Effects 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- QDQVXVRZVCTVHE-YFKPBYRVSA-N propan-2-yl (2s)-2-aminopropanoate Chemical compound CC(C)OC(=O)[C@H](C)N QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000004808 supercritical fluid chromatography Methods 0.000 description 4
- QGZGYBRNOUQYJF-FVGYRXGTSA-N Cl.C(C)(C)OC([C@@H](NCCC)CCO)=O Chemical compound Cl.C(C)(C)OC([C@@H](NCCC)CCO)=O QGZGYBRNOUQYJF-FVGYRXGTSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- BZCGWAXQDLXLQM-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O.ClP(Cl)(Cl)=O BZCGWAXQDLXLQM-UHFFFAOYSA-N 0.000 description 3
- PZQSQRCNMZGWFT-QXMHVHEDSA-N propan-2-yl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC(C)C PZQSQRCNMZGWFT-QXMHVHEDSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
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- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
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- 238000010828 elution Methods 0.000 description 2
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- 150000002338 glycosides Chemical class 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
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- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
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- 229910052698 phosphorus Inorganic materials 0.000 description 2
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- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
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- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 description 1
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- 229910021529 ammonia Inorganic materials 0.000 description 1
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
It ends the present invention relates to a kind of tenofovir and draws the process impurity and preparation method thereof of phenol amine fumarate 9- [(R) -2- [[(S)-[[(S) -1- (isopropoxy carbonyl) ethyl] amino] phenoxy group phosphinyl] methoxyl group] propyl] adenine hemifumarate, wherein the impurity is selected from compound A, (S)-isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester fumarate etc..
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, are related to process impurity and its preparation during production of raw medicine, in particular to
Tenofovir Chinese mugwort draws phenol amine fumarate process impurity and preparation method thereof.
Background technique
Hepatitis B has become global public health problem.There are about 2,000,000,000 people to infect hepatitis B in the whole world
Malicious (HBV), has 500,000~700,000 people to die of hepatic failure caused by HBV infection, cirrhosis and hepatocellular carcinoma every year.China's chronic
The number about 1.3 hundred million of Hepatitis virus infection, there are a large amount of patients because of acute or chronic hepatitis B in studies have shown that China every year
Cause dead.
Treating the crucial of the disease at present is still antiviral therapy, and antiviral drugs is divided into two major classes, i.e. ucleosides and dry
Plain class is disturbed, wherein nucleoside medicine is more extensive in clinical treatment, and drug improves patient by the inhibition to virus replication
Liver function, help to improve life in patients.This kind of drug includes: 1998 by Food and Drug Adminstration of the US (FDA)
The cytosine nucleoside reverse transcriptase inhibitor Lamivudine of the GlaxoSmithKline PLC of approval;The granted adenine core of in September, 2002
Glycoside reverse transcriptase inhibitor Aldoforwe ester;Obtain within 2005 the guanosint glycoside reverse transcription of FDA approval Shi Guibao company
Enzyme inhibitor Entecavir;Granted tenofovir disoproxil fumarate in 2008.
It is the tenofovir disoproxil fumarate of a upgrade version that tenofovir Chinese mugwort, which draws phenol amine fumarate, and drug effect is replaced with fumaric acid
Nuo Fuwei ester is identical, but dosage and toxicity are far smaller than tenofovir disoproxil fumarate, and bioavilability is high.
Tenofovir Chinese mugwort draws the chemical name of phenol amine fumarate are as follows: 9- [(R) -2- [[(S)-[[(S) -1- (isopropoxy
Carbonyl) ethyl] amino] phenoxy group phosphinyl] methoxyl group] propyl] adenine hemifumarate, structural formula are as follows:
Tenofovir Chinese mugwort draws the synthetic route of phenol amine fumarate to report in patent CN103842366, the plan of the route
Slightly: with (R) -9- [2- (phosphate methoxy) propyl] adenine (SM1) and triphenyl phosphite (SM3) for starting material,
Under the action of triethylamine, esterification is carried out in acetonitrile, obtains intermediate ((((R) -1- (6- amino -9H- purine -9- base)
Propane -2- base) oxygroup) methyl) phosphoric acid monophenyl (TAF-1).The intermediate, with thionyl chloride heating stirring, obtains in toluene
Phosphinylidyne chlorization product (TAF-2).TAF-2 using with l-Alanine isopropyl ester (SM2) be condensed, obtain 9- [(R) -2- [[(R,
S)-[[(S) -1- (isopropoxy carbonyl) ethyl] amino] phenoxy group phosphinyl] methoxyl group] propyl] adenine fumarate, it should
Fumarate obtains 9- [(R) -2- [[(R, S)-[[(S) -1- (isopropoxy carbonyl) second at salt with fumaric acid again after free
Base] amino] phenoxy group phosphinyl] methoxyl group] propyl] adenine hemifumarate (TAF).
The route is the synthetic strategy with industrial production value.Currently, there is no to the technique generated in this route
The report of impurity.
Summary of the invention
Impurity research is that the important content of drug research and development always through drug research and development directly affects the safety of drug
Property, validity.Phenol amine fumarate and corresponding formulation products quality research is drawn to provide impurity control in order to end to tenofovir
Product improve tenofovir Chinese mugwort and draw phenol amine Related product quality standard, the safe medication of phenol amine fumarate is drawn for tenofovir Chinese mugwort
Important guidance is provided, present invention research synthesizes and confirmed that tenofovir Chinese mugwort draws the work in phenol amine fumarate production line
Skill impurity.
The tenofovir Chinese mugwort of patent CN103842366 report is drawn in the synthetic method of phenol amine fumarate, and a system can be generated
The process impurity of column, chemical name and structural formula see the table below:
The way of production of the above impurity is as follows:
Compound A, compound B: in step 1, last handling process needs to use methanol, under alkaline condition, with system
In intermediate TAF-1 ester exchange reaction occurs, generate impurity intermediate, and further across step 2 and step 3, transmitting
Into finished product, compound A, B are generated.The differentiation foundation of compound A, B: two compounds are by TAF-3 in methanol solution
Transesterification preparation, judges from mechanism, it should the overturning of phosphorus chirality occurs, therefore production quantity is more for compound A, it is less to be
Compound B.
Compound C, compound D: in step 1, treatment process also needs to use ethyl alcohol, and ester occurs with intermediate TAF-1 and hands over
Reaction is changed, impurity intermediate is generated, and then pass through step 2 and step 3, is transmitted in finished product, generate compound C, D.Change
Close the differentiation foundation of object C, D: by TAF-3 prepared by the transesterification in ethanol solution for two compounds, judges from mechanism, it should
The overturning of phosphorus chirality occurs, therefore production quantity is more for compound C, it is less for compound D.
Compound E, compound F: in intermediate TAF-1, methanol can occur as residual solvent with TAF-2 effect
Esterification generates impurity intermediate, and then passes through step 3, is transmitted in finished product, generates compound E, F;Compound E, F
Differentiation foundation: analogy tenofovir Chinese mugwort draws the phosphine chiral selectivity of phenol amine, and in compound E, F, phosphine chirality is based on S configuration
Product is wanted, therefore, production quantity is more for compound E, less for compound F.
Compound G, compound H: in intermediate TAF-1, ethyl alcohol can occur as residual solvent with TAF-2 effect
Esterification generates impurity intermediate, and then passes through step 3, is transmitted in finished product, generates compound G, H.Compound G, H
Differentiation foundation: analogy tenofovir Chinese mugwort draws the phosphine chiral selectivity of phenol amine, and in compound G, H, phosphine chirality is based on S configuration
Product is wanted, therefore, production quantity is more for compound G, less for compound H.
Compound I contains impurity asparagus fern door propylhomoserin isopropyl ester in starting material 2 (l-Alanine isopropyl ester), is transmitted to end
In product, compound I is generated.
As a result, on one side, the present invention relates to compound A, its chemical name is: (S)-isopropyl 2- (((R)-
((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester fumaric acid
Salt, structural formula are as follows:
On the other hand, the present invention relates to compound B, its chemical name is: (S)-isopropyl 2- (((S)-((((R) -1-
(6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester fumarate, structure
Formula is as follows:
On the other hand, the present invention relates to compound C, its chemical name is: (S)-isopropyl 2- (((R)-((((R) -1-
(6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester fumarate, structure
Formula is as follows:
On the other hand, the present invention relates to compound D, its chemical name is: (S)-isopropyl 2- (((S)-((((R) -1-
(6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester fumarate, structure
Formula is as follows:
On the other hand, the present invention relates to compound E, its chemical name is: (S)-aminomethyl phenyl ((((R) -1- (6- amino -
9H- purine -9- base) propane -2- base) oxygen) methyl) phosphate fumarate, structural formula is as follows:
On the other hand, the present invention relates to compound F, its chemical name is: (R)-aminomethyl phenyl ((((R) -1- (6- amino -
9H- purine -9- base) propane -2- base) oxygen) methyl) phosphate fumarate, structural formula is as follows:
On the other hand, the present invention relates to compound G, its chemical name is: (S)-ethylphenyl ((((R) -1- (6- amino -
9H- purine -9- base) propane -2- base) oxygen) methyl) phosphate fumarate, structural formula is as follows:
On the other hand, the present invention relates to compound H, its chemical name is: (R)-ethylphenyl ((((R) -1- (6- amino -
9H- purine -9- base) propane -2- base) oxygen) methyl) phosphate fumarate, structural formula is as follows:
On the other hand, the present invention relates to compound I, its chemical name is: diisopropyl 2- ((((((R) -1- (6- amino -
9H- purine -9- base) propane -2- base) oxygen) methyl) (phenoxy group) phosphinyl) amino) succinate fumarate, structural formula
It is as follows:
In specific embodiments, above compound A~I is unpack format, preferably substantially pure form, more preferably
With greater than about 95% purity.
On the other hand, the present invention relates to the one or more of above compound A~I to draw phenol amine rich in detection tenofovir Chinese mugwort
Application in horse hydrochlorate or the sample purity for drawing the pharmaceutical preparation of phenol amine fumarate that ends containing tenofovir as reference substance,
Middle tenofovir Chinese mugwort draws the chemical name of phenol amine fumarate are as follows: 9- [(R) -2- [[(R, S)-[[(S) -1- (isopropoxy carbonyl
Base) ethyl] amino] phenoxy group phosphinyl] methoxyl group] propyl] adenine hemifumarate, structural formula are as follows:
Detailed description of the invention
Fig. 1: compound A:(S)-isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl)
Oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester fumarate1H-NMR;
Fig. 2: compound A:(S)-isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl)
Oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester fumarate high resolution mass spectrum;
Fig. 3: compound A:(S)-isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl)
Oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester fumarate31P-NMR;
Fig. 4: compound B:(S)-isopropyl 2- (((S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl)
Oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester fumarate1H-NMR;
Fig. 5: compound B:(S)-isopropyl 2- (((S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl)
Oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester fumarate high resolution mass spectrum;
Fig. 6: compound B:(S)-isopropyl 2- (((S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl)
Oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester fumarate31P-NMR;
Fig. 7: compound C:(S)-isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl)
Oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester fumarate1H-NMR;
Fig. 8: compound C:(S)-isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl)
Oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester fumarate high resolution mass spectrum;
Fig. 9: compound C:(S)-isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl)
Oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester fumarate31P-NMR;
Figure 10: compound D:(S)-isopropyl 2- (((S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl)
Oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester fumarate1H-NMR;
Figure 11: compound D:(S)-isopropyl 2- (((S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl)
Oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester fumarate high resolution mass spectrum;
Figure 12: compound D:(S)-isopropyl 2- (((S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl)
Oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester fumarate31P-NMR;
Figure 13: compound E:(S)-aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) phosphate fumarate1H-NMR;
Figure 14: compound E:(S)-aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) phosphate fumarate high resolution mass spectrum;
Figure 15: compound E:(S)-aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) phosphate fumarate31P-NMR;
Figure 16: compound F:(R)-aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) phosphate fumarate1H-NMR;
Figure 17: compound F:(R)-aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) phosphate fumarate high resolution mass spectrum;
Figure 18: compound F:(R)-aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) phosphate fumarate31P-NMR;
Figure 19: compound G:(S)-ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) phosphate fumarate1H-NMR;
Figure 20: compound G:(S)-ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) phosphate fumarate high resolution mass spectrum;
Figure 21: compound G:(S)-ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) phosphate fumarate31P-NMR;
Figure 22: compound H:(R)-ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) phosphate fumarate1H-NMR;
Figure 23: compound H:(R)-ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) phosphate fumarate high resolution mass spectrum;
Figure 24: compound H:(R)-ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) phosphate fumarate31P-NMR;
Figure 25: asparagus fern door propylhomoserin isopropyl ester hydrochloride1H-NMR;
Figure 26: compound I: diisopropyl 2- ((((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) (phenoxy group) phosphinyl) amino) succinate fumarate1H-NMR;
Figure 27: compound I: diisopropyl 2- ((((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) (phenoxy group) phosphinyl) amino) and succinate fumarate high resolution mass spectrum;
Figure 28: compound I: diisopropyl 2- ((((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen)
Methyl) (phenoxy group) phosphinyl) amino) succinate fumarate31P-NMR;
Figure 29: l-Alanine, N- [(S)-[[(1R) -2- (6- amino -9H-9- purine radicals) -1- methyl ethoxy] methyl]
Phenoxy group phosphinyl] -, 1- Methylethyl ester, (2E) -2- butylene diester (2: 1)1H-NMR
Figure 30: l-Alanine, N- [(S)-[[(1R) -2- (6- amino -9H-9- purine radicals) -1- methyl ethoxy] methyl]
Phenoxy group phosphinyl] -, 1- Methylethyl ester, the high resolution mass spectrum of (2E) -2- butylene diester (2: 1).
Figure 31: l-Alanine, N- [(S)-[[(1R) -2- (6- amino -9H-9- purine radicals) -1- methyl ethoxy] methyl]
Phenoxy group phosphinyl] -, 1- Methylethyl ester, (2E) -2- butylene diester (2: 1)31P-NMR
Figure 32: impurity reference substance solution HPLC map
Figure 33: TAF test solution HPLC map
Specific embodiment
In order to which further the present invention will be described, will be illustrated below by specific embodiment, but reality below
Example is applied to be not limited in any way protection scope of the present invention.
Embodiment 1:(S)-isopropyl 2- (((R, S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen)
Methyl) (methoxyl group) phosphinyl) amino) and propionic ester synthesis.
50ml methanol and 10ml purified water are added into the there-necked flask of 250ml, is added with stirring 5.92g9- [(R) -2-
[[(R, S)-[[(S) -1- (isopropoxy carbonyl) ethyl] amino] phenoxy group phosphinyl] methoxyl group] propyl] adenine fumaric acid
Salt (TAF-3), nitrogen protection are cooled to 10~20 DEG C, and 1.20g NaOH is added, finishes, is stirred overnight.Methylene chloride is added
Organic phase is collected in 100ml, pure water 50ml, liquid separation, and vacuum distillation obtains solid crude product, and it is pure will to obtain crude product progress column chromatography
Change, elute ratio are as follows: methanol: methylene chloride=1: 20, collect the total 230ml of eluent, 30~40 DEG C of temperature control, vacuum degree :-
0.08MPa, vacuum distillation, is evaporated off solvent to no fraction and steams, obtain yellow oil 0.67g, as (S)-isopropyl 2- (((R,
S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester, it receives
Rate: 16.16%.
Embodiment 2:(S)-isopropyl 2- (((R, S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen)
Methyl) (methoxyl group) phosphinyl) amino) and propionic ester separation
By 0.67g (S)-isopropyl 2- (((R, S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) first
Base) (methoxyl group) phosphinyl) amino) propionic ester is added in 50ml ethyl alcohol and dissolves, with supercritical fluid chromatography (model: MD-
2018Plus) separate sample.Column model: DAICEL CHIRALCEL AS-H (0.46cm I.D.x 25cm L), column temperature
35 DEG C, Detection wavelength: 220nm, sample introduction concentration: 20mg/ml, CO2/ EtOH=70/30, flow velocity 2.0ml/min, time 10 divide
Clock.Merge collection liquid after separation, 30~40 DEG C of temperature control, vacuum degree: -0.08MPa, vacuum distillation are evaporated off solvent to no fraction and steam
Out, 300.3mg (S)-isopropyl 2- (((S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) is obtained
(methoxyl group) phosphinyl) amino) propionic ester (compound B free alkali), oily liquids, yield 44.78% obtains 12.2mg (S)-
Isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (methoxyl group) phosphinyl) ammonia
Base) propionic ester (compound A free alkali), oily liquids, yield 1.82%.
Embodiment 3:(S)-isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) first
Base) (methoxyl group) phosphinyl) amino) and propionic ester fumarate (compound A) synthesis.
10ml acetonitrile is added into the there-necked flask of 50ml, 300.3mg (S)-isopropyl 2- (((R)-is sequentially added under stirring
((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester,
84.1mg fumaric acid, nitrogen protection are heated to flowing back, and insulated and stirred 2 hours.30~40 DEG C of temperature control, vacuum degree: -0.08MPa,
Vacuum distillation, is evaporated off solvent to no fraction and steams, obtain compound A, 345.7mg white powder, yield: 89.94%.1H-NMR
(400Mz, DMSO-d6) δ: 13.146 (br, s, 2H), 8.141 (s, 1H), 8.097 (s, 1H), 7.201 (br, s, 2H), 6.638
(s, 2H), 5.092 (dd, J=10.4Hz, J=21.6Hz, 1H), 4.890~4.874 (m, 1H), 4.249~4.184 (m,
2H), 3.949~3.908 (m, 1H), 3.783~3.728 (m, 2H), 3.672~3.645 (m, 1H), 3.461 (d, J=
10.8Hz, 3H), 1.209 (d, J=7.2Hz, 3H), 1.170 (d, J=6.0Hz, 6H), 1.051 (d, J=6.0Hz, 3H).(in detail
See attached drawing 1) ESI-HRMS spectrogram display molecular ion peak m/z=415.18585 [M+H]+, corresponding molecular weight and offer
Structural formula calculated value (415.17805) is consistent.Absolute error is 1.26ppm, within high resolution mass spectrum error range.
(being detailed in attached drawing 2);31P-NMR (162Mz, DMSO-d6) δ: 25.502 (being detailed in attached drawing 3).
Embodiment 4:(S)-isopropyl 2- (((S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) first
Base) (methoxyl group) phosphinyl) amino) and propionic ester fumarate (compound B) synthesis.
2ml acetonitrile is added into the there-necked flask of 25ml, 12.2mg (S)-isopropyl 2- (((S)-is sequentially added under stirring
((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester, 3.4mg
Fumaric acid, nitrogen protection are heated to flowing back, and insulated and stirred 2 hours.30~40 DEG C of temperature control, vacuum degree: -0.08MPa, decompression are steamed
It evaporates, solvent to no fraction is evaporated off and steams, obtains impurity B, 12.8mg white powder, yield: 81.96%.1H-NMR (400Mz,
DMSO-d6) δ: 8.141 (br, s, 1H), 8.091 (br, s, 1H), 7.196 (br, s, 2H), 6.619 (s, 4H), 5.118 (dd, J
=10.4Hz, J=22.0Hz, 1H), 4.911~4.880 (m, 1H), 4.275~4.110 (m, 2H), 3.907 (m, 1H),
3.794~3.700 (m, 1H), 3.688~3.639 (m, 2H), 3.459 (d, J=11.2Hz, 3H), 1.244~1.187 (m,
9H), 1.042 (d, J=6.0Hz, 3H).(being detailed in attached drawing 4) ESI-HRMS spectrogram shows molecular ion peak m/z=415.18579
[M+H]+, corresponding molecular weight is consistent with the structural formula calculated value (415.17805) of offer.Absolute error is
1.11ppm, within high resolution mass spectrum error range.(being detailed in attached drawing 5)31P-NMR (162Mz, DMSO-d6) δ: 25.116 (in detail
See attached drawing 6).
Embodiment 5:(S)-isopropyl 2- (((R, S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen)
Methyl) (ethyoxyl) phosphinyl) amino) and propionic ester synthesis.
50ml ethyl alcohol and 10ml purified water are added into the there-necked flask of 250ml, is added with stirring 5.92g 9- [(R) -2-
[[(R, S)-[[(S) -1- (isopropoxy carbonyl) ethyl] amino] phenoxy group phosphinyl] methoxyl group] propyl] adenine fumaric acid
Salt (TAF-3), nitrogen protection are cooled to 10~20 DEG C, and 1.20g NaOH is added, finishes, is stirred overnight.Methylene chloride is added
Organic phase is collected in 100ml, pure water 50ml, liquid separation, and vacuum distillation obtains solid crude product, and it is pure will to obtain crude product progress column chromatography
Change, elute ratio are as follows: methanol: methylene chloride=1: 20, collect the total 290ml of eluent, 30~40 DEG C of temperature control, vacuum degree :-
0.08MPa, vacuum distillation, is evaporated off solvent to no fraction and steams, obtain yellow oil 1.06g, as (S)-isopropyl 2- (((R,
S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester, it receives
Rate: 19.91%.
Embodiment 6:(S)-isopropyl 2- (((R, S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen)
Methyl) (ethyoxyl) phosphinyl) amino) and propionic ester separation
By 1.00g (S)-isopropyl 2- (((R, S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) first
Base) (ethyoxyl) phosphinyl) amino) propionic ester is added in 50ml ethyl alcohol and dissolves, with supercritical fluid chromatography (model: MD-
2018Plus) separate sample.Column model: DAICEL CHIRALCEL AS-H (0.46cm I.D.x 25cm L), column temperature
35 DEG C, Detection wavelength: 220nm, sample introduction concentration: 20mg/ml, CO2/ EtOH=70/30, flow velocity 2.0ml/min, time 10 divide
Clock.Merge collection liquid after separation, 30~40 DEG C of temperature control, vacuum degree: -0.08MPa, vacuum distillation are evaporated off solvent to no fraction and steam
Out, 468.0mg (S)-isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) is obtained
(ethyoxyl) phosphinyl) amino) propionic ester, oily liquids, yield 46.80%.Obtain 90.0mg (S)-isopropyl 2- (((S)-
((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester, oily
Liquid, yield 9.00%.
Embodiment 7:(S)-isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) first
Base) (ethyoxyl) phosphinyl) amino) and propionic ester fumarate (compound C) synthesis.
10ml acetonitrile is added into the there-necked flask of 50ml, 468.0mg (S)-isopropyl 2- (((R)-is sequentially added under stirring
((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester, 128mg
Fumaric acid, nitrogen protection are heated to flowing back, and insulated and stirred 2 hours.30~40 DEG C of temperature control, vacuum degree: -0.08MPa, decompression are steamed
It evaporates, solvent to no fraction is evaporated off and steams, obtains compound C, 581.1mg white powder, yield: 97.70%.1H-NMR
(400Mz, DMSO-d6) δ: 13.128 (br, s, 2H), 8.142 (s, 1H), 8.102 (s, 1H), 7.192 (br, s, 2H), 6.638
(s, 2H), 5.033 (dd, J=10.4Hz, J=21.6Hz, 1H), 4.891~4.860 (m, 1H), 4.292~4.149 (m,
2H), 3.940~3.713 (m, 5H), 3.654~3.631 (m, 1H), 1.225~1.138 (m, 12H), 1.055 (d, J=
6.4Hz, 3H).(being detailed in attached drawing 7) ESI-HRMS spectrogram shows molecular ion peak m/z=429.20253 [M+H]+, corresponding
Molecular weight is consistent with the structural formula calculated value (429.19370) of offer.Absolute error is 3.61ppm, in high resolution mass spectrum
Within error range.(being detailed in attached drawing 8)31P-NMR (162Mz, DMSO-d6) δ: 24.004 (being detailed in attached drawing 9).
Embodiment 8:(S)-isopropyl 2- (((S)-((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) first
Base) (ethyoxyl) phosphinyl) amino) and propionic ester fumarate (compound D) synthesis.
2ml acetonitrile is added into the there-necked flask of 25ml, 90.0mg (S)-isopropyl 2- (((S)-is sequentially added under stirring
((((R) -1- (6- amino -9H-9- purine radicals) -2- propyl) oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester, 25mg
Fumaric acid, nitrogen protection are heated to flowing back, and insulated and stirred 2 hours.30~40 DEG C of temperature control, vacuum degree: -0.08MPa, decompression are steamed
It evaporates, solvent to no fraction is evaporated off and steams, obtains compound D, 100.0mg white powder, yield: 87.42%.1H-NMR
(400Mz, DMSO-d6) δ: 13.127 (br, s, 2H), 8.142 (s, 1H), 8.099 (s, 1H), 7.194 (br, s, 2H), 6.639
(s, 2H), 5.064 (dd, J=10.4Hz, J=22.0Hz, 1H), 4.911~4.879 (m, 1H), 4.249~4.145 (m,
2H), 3.895~3.707 (m, 4H), 3.674~3.627 (m, 2H), 1.223~1.139 (m, 12H), 1.045 (d, J=
6.4Hz, 3H).(being detailed in attached drawing 10) ESI-HRMS spectrogram display molecular ion peak m/z=429.20118 [M+H]+, it is corresponding
Molecular weight is consistent with the structural formula calculated value (429.19370) of offer.Absolute error is 0.46ppm, in high resolution mass spectrum
Within error range.(being detailed in attached drawing 11)31P-NMR (162Mz, DMSO-d6) δ: 23.690 (being detailed in attached drawing 12).
Embodiment 9: aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphoric acid
The synthesis of ester.
50ml methanol is added into the there-necked flask of 250ml, is added with stirring 5.00g phenyl ((((R) -1- (6- amino -9H-
Purine -9- base) propane -2- base) oxygen) methyl) phosphoryl chloride phosphorus oxychloride (TAF-2), nitrogen protection is cooled to 10~20 DEG C, and stirring 2~3 is small
When.30~40 DEG C of temperature control, vacuum degree: -0.08MPa, vacuum distillation are evaporated off solvent to no fraction and steam, obtain brown oil liquid
The crude product liquid is carried out HPLC separation, obtains 0.45g aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) third by body
Alkane -2- base) oxygen) methyl) phosphate crude product, yield: 9.11%.
Embodiment 10: aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphoric acid
The separation of ester crude product;
By 0.45g aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphate
Crude product, which is added in 50ml methanol, to be dissolved, and separates sample with supercritical fluid chromatography (model: MD-2018Plus).Chromatography column type
Number: DAICEL CHIRALCEL AS-H (0.46cm I.D.x 25cm L), 35 DEG C of column temperature, Detection wavelength: 220nm, sample introduction are dense
Degree: 20mg/ml, CO2/ MeOH=70/30, flow velocity 2.0ml/min, the time 10 minutes.Merge collection liquid after separation, temperature control 30~
40 DEG C, vacuum degree: -0.08MPa, vacuum distillation are evaporated off solvent to no fraction and steam, obtain 110.0mg (R)-aminomethyl phenyl
((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphate, oily liquids, yield: 24.44%;
Obtain 316.2mg (S)-aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphoric acid
Ester, oily liquids, yield: 70.26%.
Embodiment 11:(S)-aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl)
The synthesis of phosphate fumarate (compound E).
10ml acetonitrile is added into the there-necked flask of 50ml, 316.2mg (S)-aminomethyl phenyl ((((R)-is sequentially added under stirring
1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphate, 88.21mg fumaric acid, nitrogen protection is heated to
Reflux, insulated and stirred 2 hours.30~40 DEG C of temperature control, vacuum degree: -0.08MPa, vacuum distillation are evaporated off solvent to no fraction and steam
Out, compound E, 370mg, white powder, yield: 98.85% are obtained.1H-NMR (400Mz, DMSO-d6) δ: 8.145 (s, 1H),
8.056 (s, 1H), 7.342 (t, J=8.0Hz, 2H), 7.226~7.194 (m, 3H), 7.056 (d, J=7.6Hz, 2H),
6.640 (s, 2H), 4.271~4.099 (m, 2H), 4.077~3.964 (m, 3H), 3.729 (d, J=10.8Hz, 3H), 1.135
(d, J=6.4Hz, 3H).(being detailed in attached drawing 13) ESI-HRMS spectrogram display molecular ion peak m/z=378.13339 [M+H]+, institute
Corresponding molecular weight is consistent with the structural formula calculated value (378.12529) of offer.Absolute error is 2.18ppm, in high score
It distinguishes within mass spectrum error range.(being detailed in attached drawing 14)31P-NMR (162Mz, DMSO-d6) δ: 19.886 (being detailed in attached drawing 15).
Embodiment 12:(R)-aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl)
The synthesis of phosphate fumarate (compound F).
10ml acetonitrile is added into the there-necked flask of 50ml, is sequentially added under stirring, 110.0mg (R)-aminomethyl phenyl
((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphate, 33.8mg fumaric acid, nitrogen protection,
It is heated to flowing back, insulated and stirred 2 hours.30~40 DEG C of temperature control, vacuum degree: -0.08MPa, vacuum distillation are evaporated off solvent to nothing and evaporate
Divide and steam, obtains compound F, 140.4mg white powder, yield: 97.61%.1H-NMR (400Mz, DMSO-d6) δ: 8.150
(s, 1H), 8.058 (s, 1H), 7.372 (t, J=8.0Hz, 2H), 7.229~7.189 (m, 3H), 7.127 (d, J=8.4Hz,
2H), 6.640 (s, 2H), 4.274~4.167 (m, 2H), 4.062~4.003 (m, 3H), 3.675 (d, J=10.8Hz, 3H),
1.113 (d, J=6.0Hz, 3H).(being detailed in attached drawing 16) ESI-HRMS spectrogram shows molecular ion peak m/z=378.13294 [M+
H]+, corresponding molecular weight is consistent with the structural formula calculated value (378.12529) of offer.Absolute error is 1ppm, in height
Within Resolution Mass Spectrometry error range.(being detailed in attached drawing 17)31P-NMR (162Mz, DMSO-d6) δ: 20.019 (being detailed in attached drawing 18).
Embodiment 13: ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphoric acid
The synthesis of ester.
50ml ethyl alcohol is added into the there-necked flask of 250ml, is added with stirring 5.00g phenyl ((((R) -1- (6- amino -9H-
Purine -9- base) propane -2- base) oxygen) methyl) phosphoryl chloride phosphorus oxychloride (TAF-2), nitrogen protection is cooled to 10~20 DEG C, and stirring 2~3 is small
When.30~40 DEG C of temperature control, vacuum degree: -0.08MPa, vacuum distillation are evaporated off solvent to no fraction and steam, obtain brown oil liquid
The crude product liquid is carried out HPLC separation, obtains 0.69g ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) third by body
Alkane -2- base) oxygen) methyl) phosphate crude product, yield: 13.46%.
Embodiment 14: ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphoric acid
The separation of ester crude product;
By 0.69g ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphate
Crude product, which is added in 50ml methanol, to be dissolved, and separates sample with supercritical fluid chromatography (model: MD-2018Plus).Chromatography column type
Number: DAICEL CHIRALCEL AS-H (0.46cm I.D.x 25cm L), 35 DEG C of column temperature, Detection wavelength: 220nm, sample introduction are dense
Degree: 20mg/ml, CO2/ MeOH=70/30, flow velocity 2.0ml/min, the time 10 minutes.Merge collection liquid after separation, temperature control 30~
40 DEG C, vacuum degree: -0.08MPa, vacuum distillation are evaporated off solvent to no fraction and steam, obtain 144.6mg (R)-ethylphenyl
((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphate, oily liquids, yield: 20.96%;
Obtain 305.1mg (S)-ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphoric acid
Ester, oily liquids, yield: 44.22%.
Embodiment 15:(S)-ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl)
The synthesis of phosphate fumarate (compound G).
10ml acetonitrile is added into the there-necked flask of 50ml, 305.1mg (S)-ethylphenyl ((((R)-is sequentially added under stirring
1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphate, 42.9mg fumaric acid, nitrogen protection is heated to
Reflux, insulated and stirred 2 hours.30~40 DEG C of temperature control, vacuum degree: -0.08MPa, vacuum distillation are evaporated off solvent to no fraction and steam
Out, compound G, 389.4mg white powder, yield: 98.32% are obtained.1H-NMR (400Mz, DMSO-d6) δ: 13.162 (br,
1H), 8.141 (s, 1H), 8.055 (s, 1H), 7.345 (t, J=8.0Hz, 2H), 7.219~7.174 (m, 3H), 7.061 (d, J
=8.8Hz, 2H), 6.637 (s, 2H), 4.260~4.091 (m, 2H), 4.074~3.939 (m, 5H), 1.203~1.168 (m,
3H), 1.134 (d, J=6.4Hz, 3H).(being detailed in attached drawing 19) ESI-HRMS spectrogram shows molecular ion peak m/z=392.14867
[M+H]+, corresponding molecular weight is consistent with the structural formula calculated value (392.14094) of offer.Absolute error is
1.16ppm, within high resolution mass spectrum error range.(being detailed in attached drawing 20)31P-NMR (162Mz, DMSO-d6) δ: 18.558 (in detail
See attached drawing 21).
Embodiment 16:(R)-ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl)
The synthesis of phosphate fumarate (compound H).
10ml acetonitrile is added into the there-necked flask of 50ml, 144.6mg (R)-ethylphenyl ((((R)-is sequentially added under stirring
1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) phosphate, 42.9mg fumaric acid, nitrogen protection is heated to
Reflux, insulated and stirred 2 hours.30~40 DEG C of temperature control, vacuum degree: -0.08MPa, vacuum distillation are evaporated off solvent to no fraction and steam
Out, impurity H, 183.3mg, white powder, yield: 97.76% are obtained.1H-NMR (400Mz, DMSO-d6) δ: 13.139 (br,
1H), 8.145 (s, 1H), 8.057 (s, 1H), 7.375 (t, J=8.0Hz, 2H), 7.226~7.191 (m, 3H), 7.134 (d, J
=8.8Hz, 2H), 6.635 (s, 2H), 4.273~4.200 (m, 2H), 4.043~3.986 (m, 5H), 1.168~1.099 (m,
6H).(being detailed in attached drawing 22) ESI-HRMS spectrogram display molecular ion peak m/z=392.14863 [M+H]+, corresponding molecular weight
It is consistent with the structural formula calculated value (392.14094) of offer.Absolute error is 1.04ppm, in high resolution mass spectrum error model
Within enclosing.(being detailed in attached drawing 23)31P-NMR (162Mz, DMSO-d6) δ: 18.654 (being detailed in attached drawing 24).
Embodiment 17: the synthesis of asparagus fern door propylhomoserin isopropyl ester hydrochloride
100ml isopropanol is added into the there-necked flask of 250ml, opens stirring, 10.00g asparagus fern door propylhomoserin is added, adds
89.42g thionyl chloride, is warming up to reflux, and insulated and stirred 6~8 hours.Vacuum distillation, 30~40 DEG C of temperature control, vacuum degree :-
0.08MPa is evaporated off solvent to no fraction and steams, and the mashing of 100ml methyl tertiary butyl ether(MTBE), filtering, by filter cake are added into residue
It is dried under reduced pressure in case, is dried under reduced pressure 2~3 hours as 50 DEG C, obtain 18.49g asparagus fern door propylhomoserin salt isopropyl ester hydrochlorate, canescence
Powder, yield: 97.31%.1H-NMR (400Mz, DMSO-d6) δ: 8.706 (br, 2H), 5.018~4.909 (m, 2H), 4.229
(t, J=6.0Hz, 1H), 3.004~2.895 (m, 2H), 1.238~1.192 (m, 12H) (being detailed in attached drawing 25).
Embodiment 18: diisopropyl 2- ((((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl)
(phenoxy group) phosphinyl) amino) succinate fumarate (compound I) synthesis
100ml methylene chloride is added into the there-necked flask of 250ml, opens stirring, sequentially adds 16.57g asparagus fern door propylhomoserin
Isopropyl ester hydrochloride and 13.11g saleratus are stirred at room temperature 3~4 hours, and filtering collects filtrate, is transferred to 250ml there-necked flask
In, nitrogen protection, 5.00g phenyl ((((R) -1- (6- amino -9H- purine-is slowly added dropwise into system for temperature control -10~-20 DEG C
9- yl) propane -2- base) oxygen) methyl) phosphoryl chloride phosphorus oxychloride (TAF-2) toluene (50ml) solution, drop finish, be stirred overnight.It is pure that 50ml is added
Change water, extract liquid separation, collects organic phase, 30~40 DEG C of temperature control, vacuum degree: -0.08MPa, vacuum distillation are evaporated off solvent to nothing and evaporate
Divide and steam, obtains 4.62g brownish black oily liquids.It takes the 1.00g oily liquids to carry out HPLC separation, obtains 0.55g diisopropyl
Base 2- ((((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) (phenoxy group) phosphinyl) amino) amber
Amber acid esters, pale yellow oily liquid, yield 34.48%.
10mL acetonitrile is added into the there-necked flask of 50ml, opens stirring, sequentially adds 0.55g diisopropyl 2-
((((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygen) methyl) (phenoxy group) phosphinyl) amino) succinic acid
Ester and 0.11g fumaric acid, are heated to flowing back, and insulated and stirred 2 hours.Vacuum distillation, 30~40 DEG C of temperature control, vacuum degree :-
0.08MPa is evaporated off solvent to no fraction and steams to get compound I, 0.64g, off-white powder, yield: 96.55% is arrived.1H-
NMR (400Mz, DMSO-d6) δ: 13.098 (br, 1H) 8.143 (s, 1H), 8.100 (s, 1H), 7.296 (t, J=7.6Hz,
2H), 7.161~7.143 (m, 3H), 7.080 (d, J=7.6Hz, 2H), 6.634 (s, 2H), 5.689 (m, 1H), 4.867~
4.831 (m, 2H), 4.339~4.169 (m, 3H), 3.795~3.761 (m, 5H), 1.176~1.062 (m, 15H).It (is detailed in attached
Figure 26) ESI-HRMS spectrogram show molecular ion peak m/z=563.24049 [M+H]+, the knot of corresponding molecular weight and offer
Structure formula calculated value (563.23048) is consistent.Absolute error is 4.86ppm, within high resolution mass spectrum error range.(in detail
See attached drawing 27)31P-NMR (162Mz, DMSO-d6) δ: 22.674,22.601 (being detailed in attached drawing 28).
Embodiment 19:((((R) -1- (6- amino -9H- purine -9- base) propane -2- base) oxygroup) methyl) phosphoric acid monophenyl
(TAF-1)
Under nitrogen protection, into the reaction flask of 5L, 950g acetonitrile is added, opens stirring, sequentially adds 150g tenofovir
(SM1), 106g triethylamine, 96g 4-dimethylaminopyridine and 90 grams of triphenyl phosphites (SM3).Charging finishes, and is warming up to 60
DEG C, insulated and stirred to TLC detection raw material SM1 fundamental reaction finishes.The lower vacuum distillation of stirring, is added 400g methanol to residue.
20~25 DEG C of temperature control, under stirring condition, 150g concentrated hydrochloric acid is added dropwise, time for adding 0.5~1 hour, is added dropwise, stirring 0.5 is small
It is precipitated up to a large amount of solids, 2.0Kg ethyl acetate is added, stirred 12~16 hours, filtering, under the conditions of 60 DEG C, forced air drying 4
~6 hours, obtain intermediate TAF-1 crude product about 125g.
750g water is added into 1L reaction flask, opens stirring, adds 125g TAF-1 crude product, 10~20 DEG C of temperature control, stir
Mix 0.5~1 hour, filter, with 237g ethanol rinse, under the conditions of 55~65 DEG C, forced air drying 6~8 hours, obtain for class it is white
Color powder 102g.Yield: 55.0%.
Embodiment 20:9- [(R) -2- [[(R, S)-[[(S) -1- (isopropoxy carbonyl) ethyl] amino] phenoxy group phosphine oxide
Base] methoxyl group] propyl] adenine (TAF-3)
600g toluene is added to the reaction flask of 5L, opens stirring, sequentially adds 100g TAF-1 and 300g thionyl chloride.
It 70 DEG C of temperature control, stirs 24 hours.After reaction, it is evaporated under reduced pressure, 600g normal heptane is added to residue, stirring 0.5~1 is small
When, filtering, filter cake is eluted with 300g normal heptane, and forced air drying 8~12 hours under the conditions of 40 DEG C obtain TAF-2 94g, for Huang
Color powder.
1.8Kg methylene chloride is added into 5L reaction flask, opens stirring, sequentially adds 180g l-Alanine isopropyl ester
(SM2), with 60g eluent methylene chloride, mother liquor is transferred in 5L reaction flask with 400g saleratus, stirring 2 hours, filtering,
Stirring is opened, 180g anhydrous sodium sulfate is added, is stirred 0.5~1 hour, with 60g eluent methylene chloride, mother liquor is shifted for filtering
Into 5L reaction flask, under nitrogen gas stirring, opens stirring and be added dropwise under conditions of control reaction temperature is 0~10 DEG C into system
The toluene mixed serum (90g TAF-2 being added in 610g toluene, stir 1 hour for use) of 700g TAF-2, time for adding 1~2
Hour, it is added dropwise, continues insulated and stirred 1~2 hour.900g water, stirring are added into reaction system, liquid separation is collected organic
Phase, then successively purify water washing with 15% sodium dihydrogen phosphate of 450g (W/W) aqueous solution and 900g respectively, collect organic phase.To have
Machine phase transfer opens stirring into 5L reaction flask, and 100g anhydrous sodium sulfate is added, and stirs 0.5~1 hour, filtering, with 60g bis-
Chloromethanes elution.Mother liquor is transferred in 5L reaction flask, is evaporated under reduced pressure.
1100g acetonitrile is added to residue, opens stirring, stirs 2~3 hours under the conditions of 40 DEG C of temperature control, filter while hot, receive
Collect filtrate.40 DEG C of temperature control, stirring continues stirring 0.5 hour to system dissolved clarification, and slow cooling is to 0~5 DEG C, temperature fall time 2~3
Hour, insulated and stirred 2~3 hours.Filtering, forced air drying 12 hours under the conditions of 40 DEG C obtain off-white powder (TAF-3)
53.8g, yield: 41.1%.
Embodiment 21:9- [(R) -2- [[(S)-[[(S) -1- (isopropoxy carbonyl) ethyl] amino] phenoxy group phosphinyl]
Methoxyl group] propyl] adenine hemifumarate (TAF)
Under nitrogen protection, 200g isopropanol, 9 grams of fumaric acid, 50 grams of TAF-3 are sequentially added into 2L reaction flask.Unlatching is stirred
It mixes, under the conditions of 40~50 DEG C of temperature control, stirs dissolved clarification, filter while hot, collect mother liquor.Mother liquor is transferred in 2L reaction flask, is opened
Stirring under the conditions of 40~50 DEG C of temperature control, stirs dissolved clarification, and slow cooling is to 0~5 DEG C, temperature fall time 2~3 hours, insulated and stirred 10
Hour.Filtering forced air drying 12~16 hours, obtains tenofovir Chinese mugwort and draws phenol amine hemifumarate under the conditions of 60~65 DEG C
Finished product 37.5g is white powder, yield 75.0%.1H-NMR (400Mz, DMSO-d6) δ: 13.140 (br, 1H), 8.158 (s,
1H), 8.117 (s, 1H), 7.303 (t, J=7.6Hz, 2H), 7.303 (t, J=7.6Hz, 2H), 7.123 (t, J=7.2Hz,
1H), 7.077 (d, J=7.6Hz, 2H), 6.648 (s, 1H), 5.613 (t, J=12.0Hz, 1H), 4.860 (m, 1H), 4.276
(m, 1H), 4.153 (dd, J=6.4,14.4Hz, 1H), 3.948 (m, 1H), 3.856~3.909 (m, 2H), 3.77 (dd, J=
9.6,13.6Hz, 1H), 1.155~1.170 (m, 6H), 1.141~1.155 (m, 3H), 1.058 (d, J=6.4Hz, 3H).(in detail
See attached drawing 29) ESI-HRMS spectrogram display molecular ion peak m/z=477.20187 [M+H]+, corresponding molecular weight and offer
Structural formula calculated value (477.20098) be consistent.Absolute error is 1.87ppm, within high resolution mass spectrum error range.
(being detailed in attached drawing 30)31P-NMR (162Mz, DMSO-d6) δ: 22.120 (being detailed in attached drawing 31).
Embodiment 22: impurity A-I ends in tenofovir as impurity reference substance and draws phenol amine hemifumarate bulk pharmaceutical chemicals impurity
Application in detection
(1) preparation of impurity A-I reference substance solution:
Take the impurity A-I of above-mentioned preparation appropriate, it is accurately weighed, add appropriate 80% acetonitrile-water ultrasound to make to dissolve, with 80% second
Nitrile-water quantitatively dilute be made in every 1ml be respectively containing about compound A~I 1 μ g mixed solution, mixed as impurity reference substance
Solution.
(2) preparation of test solution:
The tenofovir Chinese mugwort of above-mentioned preparation draws the preparation of the test solution of phenol amine hemifumarate: taking according to above-mentioned implementation
Tenofovir Chinese mugwort prepared by the step of example 19~21 draws phenol amine hemifumarate appropriate (Chinese mugwort containing tenofovir draws phenol amine about 10mg),
It is accurately weighed, it sets in 10ml volumetric flask, adds 80% acetonitrile-water to dissolve and be diluted to scale, shake up, every 1ml is made and contains for promise good fortune
The solution of Wei Aila phenol amine about 1mg, as test solution.
(3) chromatographic condition is as follows:
It is filler with octadecylsilane chemically bonded silica chromatographic column (4.6 × 150mm, 2.7 μm), with water (0.1% first
Acid) it is mobile phase A, with methanol (contain 0.1% formic acid) for Mobile phase B, gradient elution is carried out according to following table, flow velocity 1.0ml/min,
Detection wavelength 260nm, 40 DEG C of column temperature, 10 μ l of sampling volume.
Gradient elution program:
Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
0 | 95 | 5 |
10 | 85 | 15 |
40 | 55 | 45 |
50 | 10 | 90 |
55 | 10 | 90 |
55.01 | 95 | 5 |
60 | 95 | 5 |
(4) test procedure: 10 μ l of above-mentioned impurity reference substance solution and test solution is taken, liquid chromatograph is injected separately into
(being purchased from U.S. Agilent company, model: 1260 HPLC of Agilent) or LC-MS instrument (Agilent company, the U.S.,
Agilent 6120), chromatogram is recorded, calculates each impurity A-according to external standard method (four general rules 0512 of Chinese Pharmacopoeia version in 2015)
The content of I (referring to Figure 32,33).
(5) test result:
The tenofovir Chinese mugwort prepared according to embodiment 19~21 draws the impurity spectrum analysis of phenol amine hemifumarate
It should be noted that all documents referred in the present invention are incorporated as referring in this application, just as each
Piece document is individually recited as with reference to such.In addition, it should also be understood that, above-described is that specific implementation of the invention is arranged and transported
Technical principle, after having read the contents of the present invention, those skilled in the art can do various changes or be repaired to the present invention
Change without departing from spirit and scope of the invention, such equivalent forms are also fallen in the scope of the present invention.
Claims (11)
1. compound A, its chemical name is: (S)-isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2-
Propyl) oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester fumarate (17-A), structural formula is as follows:
2. compound B, its chemical name is: (S)-isopropyl 2- (((S)-((((R) -1- (6- amino -9H-9- purine radicals) -2-
Propyl) oxygen) methyl) (methoxyl group) phosphinyl) amino) propionic ester fumarate (17-B), structural formula is as follows:
3. compound C, its chemical name is: (S)-isopropyl 2- (((R)-((((R) -1- (6- amino -9H-9- purine radicals) -2-
Propyl) oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester fumarate (19-A), structural formula is as follows:
4. compound D, its chemical name is: (S)-isopropyl 2- (((S)-((((R) -1- (6- amino -9H-9- purine radicals) -2-
Propyl) oxygen) methyl) (ethyoxyl) phosphinyl) amino) propionic ester fumarate (19-B), structural formula is as follows:
5. compound E, its chemical name is: (S)-aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2-
Base) oxygen) methyl) phosphate fumarate (18-A), structural formula is as follows:
6. compound F, its chemical name is: (R)-aminomethyl phenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2-
Base) oxygen) methyl) phosphate fumarate (18-B), structural formula is as follows:
7. compound G, its chemical name is: (S)-ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2-
Base) oxygen) methyl) phosphate fumarate (4-A), structural formula is as follows:
8. compound H, its chemical name is: (R)-ethylphenyl ((((R) -1- (6- amino -9H- purine -9- base) propane -2-
Base) oxygen) methyl) phosphate fumarate (4-B), structural formula is as follows:
9. compound I, its chemical name is: diisopropyl 2- ((((((R) -1- (6- amino -9H- purine -9- base) propane -2-
Base) oxygen) methyl) (phenoxy group) phosphinyl) amino) succinate fumarate (23) its structural formula is as follows:
It is unpack format, preferably substantially pure form 10. compound described according to claim 1~any one of 9, more
It is preferred that having greater than about 95% purity.
11. the one or more of compound described according to claim 1~any one of 9 draw phenol half in detection tenofovir Chinese mugwort
Application in fumarate or the sample purity for drawing the pharmaceutical preparation of phenol hemifumarate that ends containing tenofovir as reference substance,
Wherein tenofovir Chinese mugwort draws the chemical name of phenol hemifumarate are as follows: (9- [(R) -2- [[(S)-[[(S) -1- (isopropoxy carbonyl
Base) ethyl] amino] phenoxy group phosphinyl] methoxyl group] propyl] adenine hemifumarate, structural formula are as follows:
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