CN105330700A - Tenofovir alafenamide fumarate impurity preparing method - Google Patents
Tenofovir alafenamide fumarate impurity preparing method Download PDFInfo
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- CN105330700A CN105330700A CN201510943798.8A CN201510943798A CN105330700A CN 105330700 A CN105330700 A CN 105330700A CN 201510943798 A CN201510943798 A CN 201510943798A CN 105330700 A CN105330700 A CN 105330700A
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- vitamin
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- propyl group
- tynofovir
- phosphinyl
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- 239000012535 impurity Substances 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims description 7
- 229960003560 tenofovir alafenamide fumarate Drugs 0.000 title abstract description 4
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 title abstract description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 60
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims abstract description 52
- -1 tenofovir alafenamide isopropyl ester Chemical class 0.000 claims abstract description 38
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000004305 biphenyl Substances 0.000 claims abstract description 14
- 235000010290 biphenyl Nutrition 0.000 claims abstract description 14
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 12
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 claims abstract description 10
- 239000011782 vitamin Substances 0.000 claims description 56
- 229940088594 vitamin Drugs 0.000 claims description 56
- 229930003231 vitamin Natural products 0.000 claims description 56
- 235000013343 vitamin Nutrition 0.000 claims description 56
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 56
- 235000010894 Artemisia argyi Nutrition 0.000 claims description 40
- 244000030166 artemisia Species 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 238000002360 preparation method Methods 0.000 claims description 35
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 25
- 239000003513 alkali Substances 0.000 claims description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 15
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 13
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- 239000001530 fumaric acid Substances 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 239000002994 raw material Substances 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 150000001263 acyl chlorides Chemical class 0.000 claims description 9
- 238000005886 esterification reaction Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012320 chlorinating reagent Substances 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- QDQVXVRZVCTVHE-YFKPBYRVSA-N propan-2-yl (2s)-2-aminopropanoate Chemical compound CC(C)OC(=O)[C@H](C)N QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 claims description 8
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 6
- 230000032050 esterification Effects 0.000 claims description 6
- 150000002460 imidazoles Chemical class 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- 238000005194 fractionation Methods 0.000 claims description 5
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 5
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 5
- 150000003053 piperidines Chemical class 0.000 claims description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 4
- 239000007791 liquid phase Substances 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 229940059260 amidate Drugs 0.000 claims description 2
- 230000009435 amidation Effects 0.000 claims description 2
- 238000007112 amidation reaction Methods 0.000 claims description 2
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 abstract description 5
- 229930024421 Adenine Natural products 0.000 abstract description 4
- 229960000643 adenine Drugs 0.000 abstract description 4
- 238000010189 synthetic method Methods 0.000 abstract description 3
- 229960004946 tenofovir alafenamide Drugs 0.000 abstract 3
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 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 2
- 238000010792 warming Methods 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
- 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 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel synthetic method of three tenofovir alafenamide fumarate impurities. The synthetic method has important significance in synthesis of high-quality tenofovir alafenamide fumarate. The invention mainly aims at studying synthesis of a tenofovir alafenamide isopropyl ester impurity 9-[(R)-2-[[(S)-[[(S)-1-isopropoxy phenoxyl phosphinyl] methoxyl] propyl] adenine (IV), a tenofovir alafenamide diphenyl ester impurity 9-[(R)-2-[[(S)-[bi-(phenoxyl) phosphinyl] methoxyl] propyl] adenine (VI) and a tenofovir alafenamide diamide impurity 9-[(R)-2-[[bi-[[(S)-1-(isopropoxy carbonyl) ethyl] amino] phosphinyl] methoxyl] propyl] adenine (VII), and their specific synthesis routes are shown in the description.
Description
Technical field
The present invention relates to the preparation method that fumaric acid tynofovir Chinese mugwort draws phenol amine impurity.
Background technology
Fumaric acid tynofovir Chinese mugwort draws phenol amine (tenofoviralafenamidefumarate), chemistry 9-by name [(R)-2-[[(S)-[[(S)-1-(isopropoxy carbonyl) ethyl] is amino] phenoxy group phosphinyl] methoxyl group] propyl group] adenine fumarate is a kind of novel nucleoside acids reverse transcriptase inhibitors.This compound is researched and developed by GileadSciences company of the U.S., within 2015, in U.S.'s listing, is used for the treatment of adult's HIV.This medicine is also used to treat hepatitis B, is in the III phase at present clinical.This product is oral changes tynofovir into rapidly afterwards, tynofovir diphosphate is phosphorylated under the effect of cell kinase, cause DNA chain extension to stop after suppressing varial polymerases by combining with natural ribodesose substrate competitively and being inserted into virus N DA, thus suppress HIV and HBV active.
Fumaric acid tynofovir Chinese mugwort draws phenol amine and tynofovir Chinese mugwort to draw the synthesis principal reaction route of phenol amine (VIII) as follows:
(1) with (R)-tynofovir for raw material, 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) is obtained through DCC condensation, through chloro, 9-[(R)-2-[[(R is reacted to obtain with ALANINE isopropyl ester, S)-[[(S)-1-(isopropoxy carbonyl) ethyl] is amino] phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4, 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxy carbonyl) ethyl] is amino] phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (VIII) is obtained after fractionation, obtain fumaric acid tynofovir Chinese mugwort finally by salify and draw phenol amine.
(2) with (R)-tynofovir for raw material, through chloro, 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) is obtained with the esterification of phenoxy trimethyl silicone alkane, again through chloro, react salify obtains 9-[(R)-2-[[(R with ALANINE isopropyl ester, S)-[[(S)-1-(isopropoxy carbonyl) ethyl] is amino] phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4, 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxy carbonyl) ethyl] is amino] phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (VIII) is obtained after fractionation, obtain fumaric acid tynofovir Chinese mugwort finally by salify and draw phenol amine.
(3) with (R)-tynofovir for raw material, 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) is reacted to obtain with triphenyl phosphite, through chloro, 9-[(R)-2-[[(R is reacted to obtain with ALANINE isopropyl ester, S)-[[(S)-1-(isopropoxy carbonyl) ethyl] is amino] phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4, 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxy carbonyl) ethyl] is amino] phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (VIII) is obtained after fractionation, tenofovir disoproxil fumarate is obtained finally by salify.
Wherein, fumaric acid tynofovir Chinese mugwort draws phenol amine to synthesize the crucial control being impurity, and therefore fumaric acid tynofovir Chinese mugwort draws the study on the synthesis of phenol amine impurity significant.Document points out that fumaric acid tynofovir Chinese mugwort draws phenol amine to need the impurity of research to comprise: tynofovir Chinese mugwort draws phenol amine isopropyl ester impurity, chemical name: 9-[(R)-2-[[(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV); Tynofovir Chinese mugwort draws phenol amine diphenyl ester impurity (VI), chemical name: 9-[(R)-2-[[(S)-[two-(phenoxy group) phosphinyls] methoxyl group] propyl group] VITAMIN B4; Tynofovir Chinese mugwort draws phenol amine diamide impurity (VII), chemical name: 9-[(R)-2-[[two-[[(S)-1-(isopropoxy carbonyl) ethyl] is amino] phosphinyls] methoxyl group] propyl group] VITAMIN B4 etc.Document is few to draw the synthesis of phenol amine impurity to report for fumaric acid tynofovir Chinese mugwort both at home and abroad.
Summary of the invention
The present invention relates to fumaric acid tynofovir Chinese mugwort and draw phenol amine three impurity: tynofovir Chinese mugwort draws phenol amine isopropyl ester impurity (IV), tynofovir Chinese mugwort draws phenol amine diphenyl ester impurity (VI), tynofovir Chinese mugwort draws the synthetic method of phenol amine diamide impurity (VII), and synthetic route of the present invention is as follows:
Impurity (VI) and (IV) with 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) for raw material, (VII) with (R)-tynofovir (I) for raw material.Wherein 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) is the intermediate that tynofovir Chinese mugwort draws in phenol amine (VIII) building-up process.
Impurity (IV), the preparation method of (VI) and (VII) has not yet to see bibliographical information so far.
Synthesis step of the present invention:
(1) 9-[(R)-2-[preparation of [(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV)
1. 9-[(R)-2-[and [(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV) with 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) for raw material, pass through chloro, with Virahol esterification under alkaline condition, esterification reaction temperature-5 ~ 0 DEG C, then split obtained through preparation liquid phase.
2. [[in the preparation method of [(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV), solvent for use is selected from acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, ethyl acetate, Pyrrolidine, triethylamine, pyridine, piperidines, N-Methyl pyrrolidone, N to (R)-2-to 9-, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, the preferred acetonitrile of the present invention is as solvent.
[[in the preparation method of [(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV), 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) is 1: 10 ~ 20 with the weightmeasurement ratio of solvent to (R)-2-to 9-.
3. [(R)-2-is [in the preparation method of [(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV) for 9-, chlorinating agent used is selected from sulfur oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, the preferred sulfur oxychloride of the present invention is as chlorinating agent.
The mol ratio that 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) and sulfur oxychloride react is 1: 1 ~ 2, and the present invention preferably 1: 2.
4. 9-[(R)-2-[[(R that under alkaline condition, acyl chlorides and isopropanol reaction obtain, S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4, the kind of wherein said alkali and consumption all can be Conventional solvents and the consumption of this type of reaction of this area, the consumption of the preferred following alkali of the present invention and alkali: wherein, described alkali is preferably, sodium bicarbonate, saleratus, triethylamine, DIPEA, diethylamine, pyridine, imidazoles, 4-lutidine; The consumption of described alkali is preferably 1 ~ 1.5 equivalent, regulator solution pH to 7 ~ 9.
5. [[in the preparation method of [(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV), [[[(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV) adopts and prepares liquid phase process fractionation (R)-2-9-(R)-2-9-.
(2) 9-[preparation of (R)-2-[[(S)-[two-(phenoxy group) phosphinyls] methoxyl group] propyl group] VITAMIN B4 (VI)
1. tynofovir Chinese mugwort draws phenol amine diphenyl ester impurity (VI) with 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) for raw material, pass through chloro, obtain with phenol esterification under alkaline condition, esterification reaction temperature-5 ~ 0 DEG C.
2. tynofovir Chinese mugwort is drawn in the preparation method of phenol amine diphenyl ester impurity (VI), solvent for use is selected from acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, ethyl acetate, Pyrrolidine, pyridine, piperidines, N-Methyl pyrrolidone, DMF.
Tynofovir Chinese mugwort is drawn in the preparation method of phenol amine diphenyl ester impurity (VI), and 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) is 1: 10 ~ 20 with the weightmeasurement ratio of solvent.
3. tynofovir Chinese mugwort is drawn in the preparation method of phenol amine diphenyl ester impurity (VI), and chlorinating agent used is selected from sulfur oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, and the preferred sulfur oxychloride of the present invention is as chlorinating agent.
The mol ratio that 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) and sulfur oxychloride react is 1: 1 ~ 2, and the present invention preferably 1: 2.
4. the tynofovir that under alkaline condition, acyl chlorides and phenol reactant obtain ends and draws phenol amine diphenyl ester impurity (VI), wherein, the kind of described alkali and consumption all can be Conventional solvents and the consumption of this type of reaction of this area, the consumption of the preferred following alkali of the present invention and alkali: wherein, described alkali is preferably, sodium bicarbonate, saleratus, triethylamine, DIPEA, diethylamine, pyridine, imidazoles, 4-lutidine; The consumption of described alkali is preferably 1 ~ 1.5 equivalent, regulator solution pH to 7 ~ 9.
5. tynofovir Chinese mugwort is drawn in the preparation method of phenol amine diphenyl ester impurity (VI), tynofovir Chinese mugwort draws phenol amine diphenyl ester impurity (VI) refining employing silica gel column chromatography method, eluent adopts ethanol/methylene system, particular methanol: methylene dichloride=1: 20 ~ 30.
(3) preparation of 9-[(R)-2-[[two-[[(S)-1-(isopropoxy carbonyl) ethyl] is amino] phosphinyls] methoxyl group] propyl group] VITAMIN B4 (VII)
1. tynofovir Chinese mugwort draws phenol amine diamide impurity (VII) with 9-[(R)-2-(phosphonium mesitoyl methoxy) propyl group] VITAMIN B4 (I) for raw material; pass through chloro; obtain with the amidation of ALANINE isopropyl ester under alkaline condition, amidate action temperature-5 ~ 0 DEG C.
2. tynofovir Chinese mugwort is drawn in the preparation method of phenol amine diamide impurity (VII), solvent for use is selected from acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, ethyl acetate, Pyrrolidine, pyridine, piperidines, N-Methyl pyrrolidone, DMF.
Tynofovir Chinese mugwort is drawn in the preparation method of phenol amine diamide impurity (VII), and 9-[(R)-2-(phosphonium mesitoyl methoxy) propyl group] VITAMIN B4 (I) is 1: 10 ~ 20 with the weightmeasurement ratio of solvent.
3. tynofovir Chinese mugwort is drawn in the preparation method of phenol amine diamide impurity (VII), and chlorinating agent used is selected from sulfur oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, and the preferred sulfur oxychloride of the present invention is as chlorinating agent.
The mol ratio that 9-[(R)-2-(phosphonium mesitoyl methoxy) propyl group] VITAMIN B4 (I) and sulfur oxychloride react is 1: 1 ~ 2, and the present invention preferably 1: 2.
4. the tynofovir that under alkaline condition, acyl chlorides and ALANINE isopropyl ester react obtained ends and draws phenol amine diamide impurity (VII), wherein, the kind of described alkali and consumption all can be Conventional solvents and the consumption of this type of reaction of this area, the consumption of the preferred following alkali of the present invention and alkali: wherein, described alkali is preferably sodium bicarbonate, saleratus, triethylamine, DIPEA, diethylamine, pyridine, imidazoles, 4-lutidine; The consumption of described alkali is preferably 1 ~ 3 equivalent, regulator solution pH to 7 ~ 9.
5. tynofovir Chinese mugwort is drawn in the preparation method of phenol amine diamide impurity (VII), tynofovir Chinese mugwort draws phenol amine diamide impurity (VII) refining employing silica gel column chromatography method, eluent adopts ethanol/methylene system, particular methanol: methylene dichloride=1: 20 ~ 30.
Embodiment
Following Examples further illustrates the present invention, but the present invention is not limited.
Embodiment:
Embodiment 19-[(R)-2-[preparation of [(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV)
1g9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 is placed in 50mL three-necked bottle, 15ml acetonitrile and 0.64g sulfur oxychloride is added under room temperature, be warming up to 70 DEG C and stir 2 ~ 3h, after reacting completely, concentrated, be chilled to-5 DEG C, add Virahol 10ml, stir 1h, concentrated, enriched material obtains pale yellow oil 0.89g through column chromatography for separation, yield 80.1%.
0.89 above-mentioned gained yellow oil is split through preparation liquid phase and obtains 0.44g white solid, yield 49.4%.
Its Structural Identification data are as follows:
1H-NMR(400Mz，DMSO-d
6)δ：1.07～1.12(d，3H，CH
3)，1.14～1.21(m，6H，2×CH
3)，3.90～3.93(m，1H，OCH)，3.94～4.03(m，2H，CH
2N)，4.14～4.30(m，2H，OCH)，4.59～4.66(m，1H，OCH(CH
3)
2)，6.62(s，2H，NH
2)，7.02-7.38(m，5H，C
6H
5)，8.04(s，1H，H-2)，8.14(s，1H，H-8)。
ESI-MS(m/z)：406.10[M+H]
+。
Embodiment 29-[the preparation of (R)-2-[[(S)-[two-(phenoxy group) phosphinyls] methoxyl group] propyl group] VITAMIN B4 (VI)
1g9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 is placed in 50mL three-necked bottle, 15ml acetonitrile and 0.64g sulfur oxychloride is added under room temperature, be warming up to 70 DEG C and stir 2 ~ 3h, after reacting completely, concentrated, be chilled to-5 DEG C, add 15mL acetonitrile and 0.26g phenol, stir 1h, concentrated, enriched material obtains white solid 0.85g through column chromatography for separation.Yield 70.3%.
Its Structural Identification data are as follows:
1H-NMR(400Mz，DMSO-d
6)δ：1.26～1.28(d，3H，CH
3)，3.86～3.94(m，1H，CH
2CHO)，4.11～4.20(m，2H，OCH
2P)，4.35～4.39(m，2H，CH
2N)5.86(s，2H，NH
2)，7.06～7.36(m，10H，2×C
6H
5)，7.89(s，1H，H-2)，8.34(s，1H，H-8)。
ESI-MS(m/z)：442.10[M+H]
+。
The preparation of embodiment 39-[(R)-2-[[two-[[(S)-1-(isopropoxy carbonyl) ethyl] is amino] phosphinyls] methoxyl group] propyl group] VITAMIN B4 (VII)
1g9-[(R)-2-(phosphonium mesitoyl methoxy) propyl group] VITAMIN B4 is placed in 50mL three-necked bottle; 15ml acetonitrile and 0.64g sulfur oxychloride is added under room temperature; 70 DEG C of heated and stirred reaction 2 ~ 3h; concentrated, be chilled to-5 DEG C, add 15mL acetonitrile and 1.45gL-alanine isopropyl ester; stir 1h; concentrated, enriched material obtains white solid 0.85g through column chromatography for separation, yield 60.1%.
Its Structural Identification data are as follows:
1H-NMR(400Mz，DMSO-d
6)δ：1.14～1.15(d，3H，CH
3)，1.16～1.26(d，6H，2×CH
3)，1.28～1.41(d，12H，4×CH
3)，3.09(t，1H，CH
2CHO)，3.48～3.53(d，2H，NH)，3.78～3.85(m，2H，OCH
2P)，3.89～3.97(m，2H，CH
2N)，4.83～4.87(m，1H，CH(CH
3)
2)，5.05～5.09(m，1H，CH(CH
3)
2)，6.06(s，2H，NH
2)，8.09(s，1H，H-2)，8.32(s，1H，H-8)。
ESI-MS(m/z)：514.20[M+H]
+。
Claims (7)
1. fumaric acid tynofovir Chinese mugwort draws the preparation method of phenol amine impurity, it is characterized in that 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) is by chloro, under alkaline condition, obtain 9-[(R)-2-[[(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV) (be called for short tynofovir end draw phenol amine isopropyl ester impurity) with Virahol esterification; 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II), by chloro, obtains 9-[(R)-2-[[(S)-[two-(phenoxy group) phosphinyls] methoxyl group] propyl group] VITAMIN B4 (VI) (be called for short tynofovir end draw phenol amine diphenyl ester impurity) with phenol esterification under alkaline condition; 9-[(R)-2-(phosphonium mesitoyl methoxy) propyl group] VITAMIN B4 (I), by chloro, reacts to obtain 9-[(R)-2-[[two-[[(S)-1-(isopropoxy carbonyl) ethyl] is amino] phosphinyls] methoxyl group] propyl group] VITAMIN B4 (VII) (being called for short for Nuo Fuaila phenol amine diamide impurity) again with ALANINE isopropyl ester under alkaline condition.
2. 9-according to claim 1 [(R)-2-[preparation method of [(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV), [[preparation of [(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV) is for raw material with 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) to (R)-2-to 9-, acyl chlorides is obtained by chloro, temperature of reaction 70 ~ 80 DEG C, then with isopropanol reaction, temperature of reaction-5 ~ 0 DEG C, and obtain 9-[(R)-2-[[(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV) by the fractionation of preparation liquid phase.
3. according to claim 2, the preparation of acyl chlorides can use sulfur oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, and the preferred sulfur oxychloride of the present invention is as chlorinating agent; The mol ratio that 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) and sulfur oxychloride react is 1: 1 ~ 2; Solvent for use is selected from acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, ethyl acetate, Pyrrolidine, triethylamine, pyridine, piperidines, N-Methyl pyrrolidone, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, the preferred acetonitrile of the present invention is as solvent; [[in the preparation method of [(S)-[[(S)-1-isopropoxy phenoxy group phosphinyl] methoxyl group] propyl group] VITAMIN B4 (IV), 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) is 1: 10 ~ 20 with the weightmeasurement ratio of solvent to (R)-2-to 9-; Acyl chlorides and isopropanol reaction need to control pH value of solution: scope 7 ~ 9, and alkali used is selected from sodium bicarbonate, saleratus, triethylamine, DIPEA, diethylamine, pyridine, imidazoles, 4-lutidine, and the preferred triethylamine of the present invention is as alkali; The consumption of described alkali is preferably 1 ~ 1.5 equivalent.
4. tynofovir Chinese mugwort according to claim 1 draws the preparation method of phenol amine diphenyl ester impurity (VI), tynofovir Chinese mugwort draws the preparation of phenol amine diphenyl ester impurity (VI) with 9-[(R)-2-[[(phenoxy group phosphinyl) methoxyl group] propyl group]] VITAMIN B4 (II) for raw material, pass through chloro, esterification is obtained in the basic conditions with phenol again, esterification reaction temperature-5 ~ 0 DEG C.
5. according to claim 4, acyl chlorides and phenol reactant need to control pH value of solution: scope 7 ~ 9, and alkali used is selected from sodium bicarbonate, saleratus, triethylamine, DIPEA, diethylamine, pyridine, imidazoles, 4-lutidine, the preferred triethylamine of the present invention is as alkali; The consumption of described alkali is preferably 1 ~ 1.5 equivalent; Obtained tynofovir Chinese mugwort draws phenol amine diphenyl ester impurity (VI) refining employing silica gel column chromatography method, and eluent adopts ethanol/methylene system, particular methanol: methylene dichloride=1: 20 ~ 30.
6. tynofovir Chinese mugwort according to claim 1 draws the preparation method of phenol amine diamide impurity (VII); tynofovir Chinese mugwort draws phenol amine diamide impurity (VI) with 9-[(R)-2-(phosphonium mesitoyl methoxy) propyl group] VITAMIN B4 (I) for raw material; pass through chloro; add the amidation of ALANINE isopropyl ester under alkaline condition to obtain, amidate action temperature-25 ~-10 DEG C.
7. tynofovir Chinese mugwort according to claim 6 draws the preparation method of phenol amine diamide impurity (VII), and the preparation of acyl chlorides can use sulfur oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, the preferred sulfur oxychloride of the present invention is as chlorinating agent; 9-[(R)-2-(phosphonium mesitoyl methoxy) propyl group] VITAMIN B4 (I) is 1: 1 ~ 2 with the mol ratio of sulfur oxychloride; Solvent for use is selected from acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, ethyl acetate, Pyrrolidine, triethylamine, pyridine, piperidines, N-Methyl pyrrolidone, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, the preferred acetonitrile of the present invention is as solvent.Tynofovir Chinese mugwort is drawn in the preparation method of phenol amine diamide impurity (VI), and 9-[(R)-2-(phosphonium mesitoyl methoxy) propyl group] VITAMIN B4 (I) is 1: 10 ~ 20 with the weightmeasurement ratio of solvent; Acyl chlorides and ALANINE isopropyl ester reaction needed control pH value of solution: scope 7 ~ 9, alkali used is selected from sodium bicarbonate, saleratus, triethylamine, N, N-diisopropylethylamine, diethylamine, pyridine, imidazoles, 4-lutidine, the preferred triethylamine of the present invention is as alkali; The consumption of described alkali is preferably 1 ~ 1.5 equivalent; Obtained tynofovir Chinese mugwort draws phenol amine diamide impurity (VI) refining employing silica gel column chromatography method, and eluent adopts ethanol/methylene system, particular methanol: methylene dichloride=1: 20 ~ 30.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013115916A1 (en) * | 2012-02-03 | 2013-08-08 | Gilead Sciences, Inc. | Combination therapy comprising gs-7340 and cobicistat for use in the treatment of viral infections |
| CN103842366A (en) * | 2011-10-07 | 2014-06-04 | 吉联亚科学公司 | Methods for preparing anti-viral nucleotide analogs |
| WO2015161781A1 (en) * | 2014-04-21 | 2015-10-29 | 四川海思科制药有限公司 | Method for preparing nucleoside analogue and intermediate thereof |
-
2015
- 2015-12-17 CN CN201510943798.8A patent/CN105330700A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103842366A (en) * | 2011-10-07 | 2014-06-04 | 吉联亚科学公司 | Methods for preparing anti-viral nucleotide analogs |
| WO2013115916A1 (en) * | 2012-02-03 | 2013-08-08 | Gilead Sciences, Inc. | Combination therapy comprising gs-7340 and cobicistat for use in the treatment of viral infections |
| WO2015161781A1 (en) * | 2014-04-21 | 2015-10-29 | 四川海思科制药有限公司 | Method for preparing nucleoside analogue and intermediate thereof |
Cited By (10)
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|---|---|---|---|---|
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| CN107698621A (en) * | 2016-06-20 | 2018-02-16 | 杭州和泽医药科技有限公司 | A kind of phosphonate prodrugs of adenine derivative and its application in medicine |
| CN107021984A (en) * | 2017-04-28 | 2017-08-08 | 福建广生堂药业股份有限公司 | A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates |
| CN107021984B (en) * | 2017-04-28 | 2019-05-10 | 福建广生堂药业股份有限公司 | A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates |
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