CN111116655B - Preparation method of high-optical-purity tenofovir benzyl ester phosphonamide prodrug - Google Patents
Preparation method of high-optical-purity tenofovir benzyl ester phosphonamide prodrug Download PDFInfo
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- CN111116655B CN111116655B CN201911399956.2A CN201911399956A CN111116655B CN 111116655 B CN111116655 B CN 111116655B CN 201911399956 A CN201911399956 A CN 201911399956A CN 111116655 B CN111116655 B CN 111116655B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 229960004556 tenofovir Drugs 0.000 title abstract description 30
- 229940002612 prodrug Drugs 0.000 title abstract description 17
- 239000000651 prodrug Substances 0.000 title abstract description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 249
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 89
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 43
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 35
- 238000010992 reflux Methods 0.000 claims abstract description 34
- 239000002904 solvent Substances 0.000 claims abstract description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 20
- 238000001035 drying Methods 0.000 claims abstract description 19
- YAQKNCSWDMGPOY-JEDNCBNOSA-N propan-2-yl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)OC(=O)[C@H](C)N YAQKNCSWDMGPOY-JEDNCBNOSA-N 0.000 claims abstract description 19
- 239000007787 solid Substances 0.000 claims abstract description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 49
- 238000003756 stirring Methods 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000012071 phase Substances 0.000 claims description 20
- 239000008346 aqueous phase Substances 0.000 claims description 19
- 230000008569 process Effects 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 18
- 238000009833 condensation Methods 0.000 claims description 18
- 230000005494 condensation Effects 0.000 claims description 18
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 229960001270 d- tartaric acid Drugs 0.000 claims description 12
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 10
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 10
- 150000007524 organic acids Chemical class 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 9
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 9
- LSPHULWDVZXLIL-LDWIPMOCSA-N (?)-Camphoric acid Chemical compound CC1(C)[C@@H](C(O)=O)CC[C@@]1(C)C(O)=O LSPHULWDVZXLIL-LDWIPMOCSA-N 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- 239000001530 fumaric acid Substances 0.000 claims description 7
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- 239000011976 maleic acid Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 4
- 230000003113 alkalizing effect Effects 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 3
- 239000002585 base Substances 0.000 claims 3
- 239000000243 solution Substances 0.000 claims 2
- 239000007864 aqueous solution Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 claims 1
- -1 tenofovir benzyl ester Chemical class 0.000 abstract description 15
- 230000003287 optical effect Effects 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 239000000203 mixture Substances 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 238000004519 manufacturing process Methods 0.000 description 15
- 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 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 12
- 238000001514 detection method Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 150000002688 maleic acid derivatives Chemical class 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 229960001355 tenofovir disoproxil Drugs 0.000 description 2
- RWOLDZZTBNYTMS-SSDOTTSWSA-N (2r)-2-(2-chlorophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1Cl RWOLDZZTBNYTMS-SSDOTTSWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 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 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- YTFJQDNGSQJFNA-UHFFFAOYSA-N benzyl dihydrogen phosphate Chemical compound OP(O)(=O)OCC1=CC=CC=C1 YTFJQDNGSQJFNA-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 1
- 229960004134 propofol Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 1
- IKRXSZUARJIXLZ-JTQLQIEISA-N tert-butyl n-[(2s)-1-[methoxy(methyl)amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C IKRXSZUARJIXLZ-JTQLQIEISA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of a tenofovir benzyl ester phosphonamide prodrug with high optical purity, which comprises the preparation of a compound III and the preparation of a compound I, wherein the preparation method of the compound III comprises the following steps: taking tenofovir benzyl ester as a starting material, carrying out condensation reaction with L-alanine isopropyl ester hydrochloride under the protection of nitrogen to obtain a compound III, wherein a condensing agent adopts a kat condensing agent. The preparation method of the compound I comprises the following steps: dissolving a compound III in a resolving solvent, heating and refluxing, adding a resolving agent in a refluxing state to form a salt, continuously refluxing, then cooling and crystallizing, filtering under reduced pressure, drying to obtain a solid, then adding water and dichloromethane, slowly adding sodium carbonate, adjusting the pH value to 7-8, extracting a water phase with dichloromethane, combining dichloromethane solutions obtained twice, drying and spin-drying to obtain a compound I.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a preparation method of a tenofovir disoproxil phosphonate amide prodrug with high optical purity.
Background
The structural formula of the Propofol tenofovir is shown in the specification
Can be used for treating chronic Hepatitis B (HBV) of adult and teenagers (12 years old or older and at least 35kg body weight).
The improved compound is
Described in chinese patent No. ICN106188139A (application No. 201610353768.6, entitled tenofovir monobenzyl phosphate prodrug, its preparation method and use), the preparation method is as follows:
the inventor of the present invention found through research that in the method of the above chinese patent CN106188139A, the yield of the compound III is low, and pyridine is used as a solvent, and due to its toxicity, it is not friendly to the environment in the process of scale-up production, and due to the high boiling point of pyridine, the energy consumption is large during spin-drying, and the product needs column chromatography purification, and is cumbersome to operate, consumes a large amount of solvent, and has a high cost, and is not suitable for industrial scale-up production.
Chinese patent 201510958434.7 (publication No. CN 105924369A) provides a preparation method of an N- (tert-butoxycarbonyl) -L-leucine-N '-methoxy-N' -methylamide intermediate, which comprises the following steps: the compound A and the compound B are reacted in dichloromethane under the action of a Kate condensing agent.
The kat condensation reagent is for peptide coupling reagents, the chinese name: benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), currently commonly used for the synthesis of carboxamides.
The invention finds that the use of a cal condensation agent in the reaction of monophosphoric acid (the other two positions of the phosphoric acid have been substituted) with the amino group of isopropyl L-alanine hydrochloride has a good technical effect.
Therefore, the invention uses the Kate condensing agent in the preparation of the intermediate compound III of the tenofovir single benzyl ester phosphoric acid amide prodrug disclosed in the Chinese patent CN106188139A, and the preparation method is simple and convenient and is suitable for industrial amplification production.
Disclosure of Invention
The invention aims to provide a simple preparation method of tenofovir benzyl ester phosphonamide precursor with high optical purity, which is suitable for industrial production.
The preparation method comprises the preparation of a compound III and the preparation of a compound I, wherein the first purpose of the invention is to provide a preparation method of the compound III, and the compound III has the following structural formula:
the method comprises the following steps:
step 1) with tenofovir disoproxil (Compound II)
Is used as a starting material, is mixed with L-alanine isopropyl ester hydrochloride,
under the protection of nitrogen, carrying out condensation reaction to obtain a compound III, wherein a condensation reagent adopts a Cartesian condensation agent, the reaction is carried out in a condensation solvent under an alkaline condition, and after the reaction is finished, a reaction solution is sequentially washed by water and a monopotassium phosphate water solution, dried, filtered and separated to obtain a crude product of the compound III.
Wherein the molar ratio of the compound II, L-alanine isopropyl ester hydrochloride and the Kate condensing agent is 1:1.2-1.4:1.2-1.3, preferably, the molar ratio of the compound II, L-alanine isopropyl ester hydrochloride and the kat condensation agent is 1:1.25-1.35:1.20-1.25.
The condensation solvent is selected from: one or more of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, isopropyl ether or tert-butyl methyl ether, preferably dichloromethane, chloroform, ethyl acetate, acetonitrile or tetrahydrofuran, and more preferably dichloromethane, chloroform or ethyl acetate.
The amount of the condensation solvent to be used is 1 to 30 times by volume, preferably 5 to 16 times by weight (volume to weight ratio, e.g., g: ml) based on the weight of the compound II.
The base is selected from: triethylamine, diisopropylethylamine, N-dimethylaniline or 4-dimethylaminopyridine, preferably diisopropylethylamine, N-dimethylaniline or 4-dimethylaminopyridine. When the base to be added is a solid, it may be dissolved with the condensation solvent used in the present invention to a concentration of about 30 to 55% (the amount of the condensation solvent used herein is not included in the total amount of the condensation solvent).
The amount of the base is 2 to 5 times, preferably 2.5 to 4 times, and more preferably 2.5 to 3.5 times the amount of the compound II.
The reaction temperature is controlled at 20-60 ℃, preferably 20 ℃, 40 ℃ and 60 ℃. The holding time is 2 to 5 hours, preferably 2 to 3 hours.
In order to obtain the compound III with high relative purity, any purification method can be adopted optionally, such as recrystallization, chromatography column and the like, and the recrystallization method is preferred in the invention, namely, the crude product of the compound III is dissolved in isopropanol, organic acid is added, reflux stirring is carried out, and temperature reduction and filtration are carried out. Dissolving the filter cake with water and dichloromethane, then adding an alkalizing agent, adjusting the pH value to 7-8, extracting the water phase with dichloromethane after liquid separation, combining the organic phases, drying and spin-drying to obtain the compound III with high purity, wherein the yield of the compound III is up to more than 80%, and the purity is higher than 95%.
The recrystallization method comprises the following steps: the amount of isopropanol used is 3 to 4 times by volume, preferably 3.3 to 3.7 times by weight, based on the weight of compound III. The organic acid is selected from malonic acid, fumaric acid, succinic acid, propionic acid, acetic acid or maleic acid. The amount of the organic acid to be used is 0.5 to 2 times, preferably 1 to 1.2 times the amount of the substance of the compound III. The reflux time after the addition of the organic acid ranges from 1 to 2 hours. The volume ratio of water to dichloromethane is 1-3, and the total amount of the water to dichloromethane is 8-12 volumes of the weight of the compound III salt; the alkalizing agent is sodium carbonate which is commonly used. The amount of dichloromethane used in the aqueous phase is 2-4 times the volume of the salt of compound III.
A second object of the present invention is to provide a process for the preparation of compound i, which comprises the steps of: dissolving the intermediate compound III in a resolving solvent, heating and refluxing, adding a resolving agent in a refluxing state to form a salt, continuously refluxing, then cooling and crystallizing, filtering under reduced pressure, drying to obtain a solid, then adding water and dichloromethane, slowly adding sodium carbonate, adjusting the pH value to 7-8, extracting a water phase with dichloromethane, combining dichloromethane solutions obtained twice, drying and spin-drying to obtain a compound I. The reaction formula is as follows:
wherein the resolving solvent is selected from: ethanol, isopropanol, acetone, acetonitrile, 1, 4-dioxane, preferably isopropanol, ethanol or 1, 4-dioxane; the volume of the resolving solvent is 1 to 20 times, preferably 3 to 15 times, and more preferably 6.7 to 15 times (volume/weight unit such as mL, g) of the weight of the compound III.
Wherein the resolving agent is selected from: d-tartaric acid, R-mandelic acid, R-o-chloromandelic acid, D-malic acid, D-camphoric acid or D-camphorsulfonic acid, preferably D-tartaric acid, R-mandelic acid or D-camphoric acid.
The amount of the resolving agent is 0.5 to 4 times, preferably 0.5 to 2 times, and more preferably 0.53 to 1.62 times the amount of the compound III. When the resolving agent is D-tartaric acid or R-mandelic acid, the amount of the resolving agent is 1.07-1.62 times of that of the compound III, and when the resolving agent is D-camphoric acid, the amount of the resolving agent is 0.53-0.8 time of that of the compound III.
The reaction temperature is from room temperature to 120 ℃, preferably from 40 ℃ to 110 ℃ and the reaction time is from 0.5 to 5 hours.
The crystallization temperature is-20 deg.C-45 deg.C, preferably-10 deg.C-25 deg.C, and the time is 6-18 hr.
The proportion of water and dichloromethane is 1-3:1-3, the total amount of which is 10-15 times the volume of the compound III. When the aqueous phase is extracted with dichloromethane, the amount of dichloromethane used is 3 to 6 times by volume based on the weight of compound III.
The invention has the advantages that:
1) The method uses a kat condensing agent to directly replace the combination of triphenylphosphine and 2,2' -dipyridyl disulfide, simultaneously rejects solvent pyridine with high toxicity, has small dosage of L-isopropyl alanine, reduces the difficulty of subsequent impurity removal, and simplifies the subsequent process.
2) The yield of the compound III prepared by the method is up to more than 80%, and the purity is also higher than 95%.
3) In the resolution process of the compound III, isopropanol is adopted for crystallization, and a mixed solvent of water and dichloromethane is used for extraction, so that the resolution yield can reach over 48 percent.
4) Generally, when the compound III is prepared, the method provided by the invention is environment-friendly, simple in post-treatment, convenient to purify and free of column chromatography, avoids energy consumption of a column chromatography elution solvent in distillation and concentration, saves cost and has high purity: when the compound I is prepared, the method provided by the invention avoids chiral column resolution, reduces solvent consumption, avoids distillation and concentration for preparing elution solution by a large amount of chromatography, reduces energy consumption, saves cost, and has high yield and high purity. Therefore, the method is suitable for industrial large-scale production.
Drawings
FIG. 1: an HPLC (high performance liquid chromatography) spectrum obtained by detecting the content of the compound III prepared by the method of the comparative example 1; FIG. 2 is a schematic diagram: an HPLC (high performance liquid chromatography) spectrum obtained by detecting the content of the compound III prepared by the method in the embodiment 1; FIG. 3: HPLC chromatogram obtained by content detection of the compound I prepared by the method of example 20.
Detailed Description
The following examples are intended to further illustrate the invention and are not to be construed as limiting the invention in any way.
Comparative example 1:
referring to embodiment 3 of CN106188139A, the specific operation steps are as follows:
tenofovir benzyl ester (5 mmol) was dissolved in pyridine (20 mL), triethylamine (5 mL) and L-alanine isopropyl ester hydrochloride (10 mmol) were added sequentially, and after stirring at 50 ℃ for 30 min triphenylphosphine (15 mmol) and 2,2' -dithiodipyridine (15 mmol) were added, and after stirring at 50 ℃ for 3 h, the crude HPLC was spin-dried under reduced pressure as shown in FIG. 1. After column chromatography, 1.57g of compound III is obtained, with a yield of 64% and an HPLC (detection method see Experimental example 1, the same below) content of 93%.
Example 1: process for preparing compounds III
Dichloromethane (250 mL), tenofovir benzyl ester (compound II,50g, 0.13mol), L-alanine isopropyl ester hydrochloride (29g, 0.17mol) and Cartesian condensing agent (70g, 0.11mol) were added to the reaction flask in this order under a dry nitrogen blanket, and the mixture was stirred and cooled. After the temperature of the system was reduced to 0 ℃, triethylamine (50.5 g,0.5 mol) was added dropwise under controlled temperature. After the dropwise addition, the temperature was raised to 45 ℃ and kept for 2 hours. The reaction solution was washed successively with water (250 mL), an aqueous potassium dihydrogen phosphate solution (10% in concentration, 250mL,5 times). The organic phase was dried over anhydrous sodium sulfate (15 g), filtered, concentrated under reduced pressure to remove all solvents and yield 85g of crude intermediate compound III.
Intermediate compound III (85 g crude, 0.13 mol) was dissolved in isopropanol (300 mL), malonic acid (14.6 g, 0.14mol) was added, and the mixture was refluxed with stirring for 2 hours and then cooled naturally. After stirring at 0 ℃ for 5 hours, the mixture was filtered under reduced pressure. The cake was dried under vacuum at 50 ℃ for 5 hours to give 66.6g of the malonate compound III as a near-white product, water (300 mL) and dichloromethane (300 mL) were added to the malonate compound of intermediate compound III and stirred, sodium carbonate was slowly added, the pH was adjusted to 7-8, the layers were separated, the aqueous phase was extracted once with dichloromethane (200 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and dried by rotary drying to give intermediate compound III as a clear oil, 54.5g, yield 85.5%, HPLC content 98.9% (see FIG. 2).
Example 2: process for preparing compounds III
Acetonitrile (500 mL), tenofovir benzyl ester (II, 50g, 0.13mol), L-alanine isopropyl ester hydrochloride (29g, 0.17mol) and a Carbocondensing agent (70g, 0.111mol) were added to a reaction flask in this order under the protection of dry nitrogen, and the mixture was stirred and cooled. After the temperature of the system was lowered to 0 ℃, triethylamine (65.7g, 0.65mol) was added dropwise under controlled temperature. After the dropwise addition, the temperature was raised to 60 ℃ and kept for 2 hours. The solvent was dried by spinning, and the reaction mixture was dissolved in methylene chloride (400 mL), and washed successively with water (250 mL) and an aqueous potassium dihydrogen phosphate solution (10%, 250mL,5 times). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all the solvent and yield 83g of crude intermediate compound III.
The intermediate compound III (83 g crude, 0.13 mol) was dissolved in isopropanol (300 mL), fumaric acid (16.6 g, 0.143mol) was added, and the mixture was refluxed with stirring for 2 hours and then cooled naturally. After stirring at 0 ℃ for 5 hours, the mixture was filtered under reduced pressure. The cake was dried under vacuum at 50 ℃ for 5 hours to give 68.1g of fumarate salt of off-white product III, to the fumarate salt of intermediate III was added water (300 mL) and dichloromethane (300 mL) and stirred, sodium carbonate was slowly added, pH was adjusted to 7-8, the layers were separated, the aqueous phase was extracted once with dichloromethane (200 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and dried by rotary drying to give intermediate compound III as a clear oil, 53.0g, yield 83.2%, HPLC content 97.2%.
Example 3: process for preparing compounds III
Chloroform (600 mL), tenofovir benzyl ester (II, 50g, 0.13mol), L-alanine isopropyl ester hydrochloride (29g, 0.17mol) and a Carbocondensing agent (70g, 0.111mol) were added to a reaction flask in this order under the protection of dry nitrogen, and the mixture was stirred and cooled. After the temperature of the system is reduced to 0 ℃, diisopropylethylamine (51.6g, 0.4mol) is dropwise added at controlled temperature. After the dropwise addition, the temperature was raised to 20 ℃ and kept for 2 hours. The reaction solution was washed successively with water (250 mL), an aqueous potassium dihydrogen phosphate solution (10%, 250mL,5 times). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all the solvent and to obtain 82g of crude intermediate compound III.
Intermediate compound III (82 g crude, 0.13 mol) was dissolved in isopropanol (300 mL), succinic acid (16.9 g, 0.143mol) was added, and after stirring and refluxing for 2 hours, the temperature was naturally reduced. After stirring at 0 ℃ for 5 hours, the mixture was filtered under reduced pressure. The cake was dried under vacuum at 50 ℃ for 5 hours to give 64.5g of succinate as an off-white product III, water (300 mL) and methylene chloride (300 mL) were added to the succinate as an intermediate compound III, followed by stirring, sodium carbonate was slowly added, the pH was adjusted to 7-8, the aqueous phase was separated, extracted once with methylene chloride (200 mL), and the methylene chloride phases were combined, dried over anhydrous sodium sulfate and dried by rotary drying to give intermediate compound III as a clear oil, 51.2g, yield 80.4%, HPLC content 98.6%.
Example 4: process for preparing compounds III
Dichloromethane (800 mL), tenofovir benzyl ester (II, 50g, 0.13mol), L-alanine isopropyl ester hydrochloride (29g, 0.17mol) and a Carbocondensing agent (70g, 0.111mol) were added to the reaction flask in this order under a dry nitrogen blanket, and the mixture was stirred and cooled. After the temperature of the system is reduced to 0 ℃, diisopropylethylamine (51.6g, 0.4mol) is dropwise added at controlled temperature. After the dropwise addition, the temperature was raised to 50 ℃ and kept for 2 hours. The reaction solution was washed successively with water (250 mL), an aqueous potassium dihydrogen phosphate solution (10%, 250mL,5 times). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all the solvent, and the solvent was used to obtain 86g of crude intermediate compound III.
Intermediate compound III (86 g crude, 0.13 mol) was dissolved in isopropanol (300 mL), propionic acid (10.6 g, 0.143mol) was added, and the mixture was refluxed with stirring for 2 hours and then cooled naturally. After stirring at 0 ℃ for 5 hours, the mixture was filtered under reduced pressure. The cake was dried under vacuum at 50 ℃ for 5 hours to give 66.1g of propionate of off-white product III, water (300 mL) and dichloromethane (300 mL) were added to the propionate of intermediate compound III and stirred, sodium carbonate was slowly added, pH was adjusted to 7-8, the layers were separated, the aqueous phase was extracted once with dichloromethane (200 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and spun dry to give intermediate compound III as a clear oil, 55.6g, yield 87.3%, HPLC content 98.6%.
Example 5: process for preparing compounds III
Under the protection of dry nitrogen, ethyl acetate (400 mL), tenofovir benzyl ester (II, 50g, 0.13mol), L-alanine isopropyl ester hydrochloride (29g, 0.17mol) and a Cart's condensing agent (70g, 0.111mol) are added into a reaction bottle in sequence, and the mixture is stirred and cooled. After the temperature of the system was lowered to 0 ℃, a solution of 4-dimethylaminopyridine (40.3 g, 0.33mol) in ethyl acetate (200 mL) was added dropwise at a controlled temperature. After the dropwise addition, the temperature was raised to 20 ℃ and maintained for 3 hours. The reaction solution was washed successively with water (250 mL), an aqueous potassium dihydrogen phosphate solution (10%, 250mL,5 times). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all the solvent and yield 87g of crude intermediate compound III.
Intermediate compound III (87 g crude, 0.13 mol) was dissolved in isopropanol (300 mL), maleic acid (16.6 g, 0.143mol) was added, and the mixture was refluxed with stirring for 2 hours and then cooled naturally. After stirring at 0 ℃ for 5 hours, the mixture was filtered under reduced pressure. The cake was dried under vacuum at 50 ℃ for 5 hours to give 69.9g of the maleate salt of off-white product III, water (300 mL) and dichloromethane (300 mL) were added to the maleate salt of intermediate compound III and stirred, sodium carbonate was added slowly, the pH was adjusted to 7-8, the layers were separated, the aqueous phase was extracted once with dichloromethane (200 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and spun dry to give intermediate compound III as a clear oil, 54.9g, 86.2% yield, 98.2% HPLC content.
Example 6: process for preparing compounds III
Tetrahydrofuran (250 mL), tenofovir benzyl ester (II, 50g, 0.13mol), L-alanine isopropyl ester hydrochloride (29g, 0.17mol) and a Carbocondensing agent (70g, 0.111mol) were added to the reaction flask in this order under the protection of dry nitrogen, and the mixture was stirred and cooled. After the temperature of the system was lowered to 0 ℃, a tetrahydrofuran (150 mL) solution of N, N-dimethylaniline (50.5 g,0.5 mol) was added dropwise under controlled temperature. After the dropwise addition, the temperature was raised to 50 ℃ and kept for 2 hours. The solvent was dried by spinning, the reaction mixture was dissolved in methylene chloride (400 mL), and the reaction mixture was washed with water (250 mL) and an aqueous potassium dihydrogen phosphate solution (10%, 250mL,5 times). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all solvents and yield 85g of crude intermediate compound III.
Intermediate compound III (85 g crude, 0.13 mol) was dissolved in isopropanol (300 mL), acetic acid (8.4g, 0.14mol) was added, and after stirring and refluxing for 2 hours, the temperature was naturally decreased. After stirring at 0 ℃ for 5 hours, the mixture was filtered under reduced pressure. The cake was dried under vacuum at 50 ℃ for 5 hours to give 60.2g of the acetate of the off-white product III, water (300 mL) and methylene chloride (300 mL) were added to the acetate of the intermediate compound III and stirred, sodium carbonate was slowly added to adjust the pH to 7-8, the layers were separated, the aqueous phase was extracted once with methylene chloride (200 mL), the methylene chloride phases were combined, dried over anhydrous sodium sulfate and dried by rotary drying to give the intermediate compound III as a clear oil, 51.8g, yield 81.3%, HPLC content 97.0%.
Example 7: process for preparing compounds III
Chloroform (300 mL), tenofovir benzyl ester (II, 50g, 0.13mol), L-alanine isopropyl ester hydrochloride (29g, 0.17mol) and a Cart's condensing agent (70g, 0.11mol) were added to a reaction flask in this order under the protection of dry nitrogen, and the temperature was lowered with stirring. After the temperature of the system was lowered to 0 ℃, a chloroform (100 mL) solution of N, N-dimethylaniline (54.5g, 0.45mol) was added dropwise under controlled temperature. After the dropwise addition, the temperature was raised to 60 ℃ and kept for 2 hours. The reaction solution was washed successively with water (250 mL), an aqueous potassium dihydrogen phosphate solution (10%, 250mL,5 times). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all the solvent and yield 87g of crude intermediate III.
Intermediate compound III (87 g crude, 0.13 mol) was dissolved in isopropanol (300 mL), maleic acid (16.6 g, 0.143mol) was added, and the mixture was refluxed with stirring for 2 hours and then cooled naturally. After stirring at 0 ℃ for 5 hours, the mixture was filtered under reduced pressure. The cake was dried under vacuum at 50 ℃ for 5 hours to give 69.9g of maleate salt of near-white product III, water (300 mL) and dichloromethane (300 mL) were added to the maleate salt of intermediate compound III and stirred, sodium carbonate was slowly added, pH was adjusted to 7-8, the layers were separated, the aqueous phase was extracted once with dichloromethane (200 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and spun dry to give intermediate compound III as a clear oil, 54.9g, yield 86.2%, HPLC content 98.7%.
Example 8: process for preparing compounds III
Dichloromethane (500 mL), tenofovir benzyl ester (II, 50g, 0.13mol), L-alanine isopropyl ester hydrochloride (29g, 0.17mol) and a catide (70g, 0.111mol) were added to a reaction flask in this order under the protection of dry nitrogen, and the temperature was lowered with stirring. After the temperature of the system was reduced to 0 ℃, diisopropylethylamine (64.5g, 0.5mol) was added dropwise under controlled temperature. After the dropwise addition, the temperature was raised to 40 ℃ and kept for 2 hours. The reaction solution was washed with water (250 mL), an aqueous potassium dihydrogen phosphate solution (10%, 250mL,5 times) in this order (without spin-drying). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all the solvent and yield 83g of crude intermediate compound III.
The intermediate compound III (83 g crude, 0.13 mol) was dissolved in isopropanol (300 mL), fumaric acid (16.6 g, 0.143mol) was added, and the mixture was refluxed with stirring for 2 hours and then cooled naturally. After stirring at 0 ℃ for 5 hours, the mixture was filtered under reduced pressure. The cake was dried under vacuum at 50 ℃ for 5 hours to give 65.5g of fumarate salt of off-white product III, water (300 mL) and dichloromethane (300 mL) were added to the fumarate salt of intermediate compound III and stirred, sodium carbonate was slowly added, pH =7-8 was adjusted, the layers were separated, the aqueous phase was extracted once with dichloromethane (200 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and dried by rotary drying to give intermediate compound III as a clear oil, 51.3g, yield 80.6%, HPLC content 97.1%.
Example 9: process for preparing compounds III
The same protocol as in example 1 was followed except that dichloromethane (350 mL), tenofovir benzyl ester (Compound II,50g, 0.13mol), and L-alanine isopropyl ester hydrochloride (27.3g, 0.111mol) were used. The yield was 87.0%, and the HPLC content was 99.2%.
Example 10: process for preparing compounds III
The same as in the example 1 protocol, except that dichloromethane (500 mL), tenofovir benzyl ester (Compound II,50g, 0.13mol), L-alanine isopropyl ester hydrochloride (37.5g, 0.22mol). The yield was 86.3%, and the HPLC content was 98.1%.
Example 11: process for preparing compounds III
The same procedure as in example 1 was followed, except that the intermediate compound III (83 g of crude product, 0.13 mol) was dissolved in isopropanol (283 mL), and fumaric acid (15.10 g,0.13 mol) was added. Yield 83.4%, HPLC content 97.8%.
Example 12: process for preparing compounds III
The same procedure as in example 1, except that the intermediate compound III (83 g crude, 0.13 mol) was dissolved in isopropanol (308 mL), and fumaric acid (18.1 g, 0.156mol) was added. Yield 84.2%, HPLC content 98.5%.
Experimental example 1: comparison of the methods
1. The experimental method comprises the following steps: examples 1-12, comparative example 1.
2. The investigation indexes are as follows:
and (3) content detection: the specific method is shown in table 1:
table 1: content detection condition of compound III
3. The experimental results are as follows: see FIG. 1, FIG. 2 and Table 2
Table 2: detection result of Compound III
As can be seen from table 2: the yield of the method provided by comparative example 1 is about 64% and the purity is 93%, the yield of the method provided by the invention is higher than 80%, the purity is higher than 97%, and the yield is obviously better than that of comparative example 1.
Example 13: process for the preparation of tenofovir benzyl ester phosphoramide prodrugs
Dissolving intermediate compound III (64g, 0.13mol) in isopropanol (430 mL), heating to reflux, adding D-camphoric acid (14g, 0.07mol) under reflux, stirring and refluxing for 3 hours, cooling to-10 ℃, stirring for 6 hours, and filtering under reduced pressure. The filter cake was dried in vacuo at 60 ℃ for 12 h to give a near white solid, which was stirred into water (400 mL) and dichloromethane (400 mL), sodium carbonate was added slowly, pH =7-8 was adjusted, the layers were separated, the aqueous phase was extracted once with dichloromethane (300 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and spun dry to give compound I as a clear oil, 28.2g. The yield is 46 percent, and the chiral purity is 99.7 percent.
Example 14: process for the preparation of tenofovir benzyl ester phosphoramide prodrugs
Dissolving intermediate compound III (64g, 0.13mol) in acetone (430 mL), heating to reflux, adding D-camphoric acid (28g, 0.14mol) under reflux, stirring and refluxing for 3 hours, cooling to-10 ℃, stirring for 6 hours, and filtering under reduced pressure. The filter cake was dried in vacuo at 60 ℃ for 12 h to give a near white solid, which was added to water (400 mL) and dichloromethane (400 mL) and stirred, sodium carbonate was slowly added, pH =7-8 was adjusted, the layers were separated, the aqueous phase was extracted once with dichloromethane (300 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and spun dry to give compound I as a clear oil, 25.6g. The yield is 40 percent, and the chiral purity is 96.8 percent.
Example 15: process for the preparation of tenofovir benzyl ester phosphoramide prodrugs
The intermediate compound III (64g, 0.13mol) was dissolved in ethanol (430 mL), heated to reflux, and R-mandelic acid (21.3g, 0.14mol) was added under reflux, stirred under reflux for 3 hours, then cooled to-10 ℃, stirred for 6 hours, and filtered under reduced pressure. The filter cake was dried under vacuum at 60 ℃ for 12 hours to give a near white solid, the solid was added to water (400 mL) and dichloromethane (400 mL) and stirred, sodium carbonate was slowly added, pH =7-8 was adjusted, the layers were separated, the aqueous phase was extracted once with dichloromethane (300 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and spun dry to give compound I as a clear oil, 27.5g. The yield is 43 percent, and the chiral purity is 99.5 percent.
Example 16: process for the preparation of tenofovir benzyl ester phosphoramide prodrugs
The intermediate compound III (64g, 0.13mol) was dissolved in isopropanol (650 mL), heated to 90 ℃ and refluxed, D-camphoric acid (14g, 0.07mol) was added, and after 5 hours of reflux with stirring, the temperature was reduced to-10 ℃, and after 18 hours of stirring at-10 ℃, the mixture was filtered under reduced pressure. The filter cake was dried under vacuum at 60 ℃ for 12 hours to give a near white solid, the solid was added to water (400 mL) and dichloromethane (400 mL) and stirred, sodium carbonate was slowly added, pH =7-8 was adjusted, the layers were separated, the aqueous phase was extracted once with dichloromethane (300 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and spun dry to give compound I as a clear oil, 23.7g. The yield is 37 percent, and the chiral purity is 99.0 percent.
Example 17: process for the preparation of tenofovir benzyl ester phosphoramide prodrugs
The intermediate compound III (64g, 0.13mol) was dissolved in isopropanol (700 mL), heated to 90 ℃ and refluxed, D-tartaric acid (42g, 0.28mol) was added, and the mixture was refluxed for 5 hours under stirring, then cooled to-10 ℃, stirred at-10 ℃ for 18 hours, and then filtered under reduced pressure. The filter cake was dried in vacuo at 60 ℃ for 12 h to give a near white solid, which was stirred in water (400 mL) and dichloromethane (400 mL), sodium carbonate was slowly added, pH =7-8 was adjusted, the layers were separated, the aqueous phase was extracted once with dichloromethane (300 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and spun to give compound I as a clear oil, 24.3g. The yield is 38 percent, and the chiral purity is 99.3 percent.
Example 18: process for the preparation of tenofovir benzyl ester phosphoramide prodrugs
The intermediate compound III (64g, 0.13mol) was dissolved in acetone (250 mL), heated to 56 ℃ and refluxed, D-tartaric acid (21g, 0.14mol) was added thereto, and the mixture was refluxed for 0.5 hour under stirring, then cooled to-10 ℃, stirred at-10 ℃ for 10 hours, and then filtered under reduced pressure. The filter cake was dried under vacuum at 60 ℃ for 12 hours to give a near white solid, the solid was added to water (400 mL) and dichloromethane (400 mL) and stirred, sodium carbonate was slowly added, pH =7-8 was adjusted, the layers were separated, the aqueous phase was extracted once with dichloromethane (300 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and spun dry to give compound I as a clear oil, 22.4g. The yield is 35 percent, and the chiral purity is 98.0 percent.
Example 19: process for the preparation of tenofovir benzyl ester phosphoramide prodrugs
The intermediate compound III (64g, 0.13mol) was dissolved in 1, 4-dioxane (960 mL), heated to 100 ℃ under reflux, D-tartaric acid (21g, 0.14mol) was added thereto, and the mixture was refluxed with stirring for 1 hour, then cooled to 45 ℃ under reflux, stirred at 45 ℃ for 14 hours, and then filtered under reduced pressure. The filter cake was dried under vacuum at 60 ℃ for 12 hours to give a near white solid, the solid was added to water (400 mL) and dichloromethane (400 mL) and stirred, sodium carbonate was slowly added, pH =7-8 was adjusted, the layers were separated, the aqueous phase was extracted once with dichloromethane (300 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and spun dry to give compound I as a clear oil, 26.9g. The yield is 42 percent, and the chiral purity is 99.3 percent.
Example 20: process for the preparation of tenofovir benzyl ester phosphoramide prodrugs
The intermediate compound III (64g, 0.13mol) was dissolved in 1, 4-dioxane (640 mL), heated to 100 ℃ and refluxed, D-tartaric acid (21g, 0.14mol) was added, and after 2 hours of reflux with stirring, the temperature was lowered by program, and after 6 hours the temperature was lowered to 20 ℃ and at that temperature, after 10 hours of stirring, filtration was carried out under reduced pressure. The filter cake was dried in vacuo at 60 ℃ for 12 h to give a near white solid, which was added to water (400 mL) and dichloromethane (400 mL) and stirred, sodium carbonate was slowly added, pH =7-8 was adjusted, the layers were separated, the aqueous phase was extracted once with dichloromethane (300 mL), the dichloromethane phases were combined, dried over anhydrous sodium sulfate and spun dry to give compound I as a clear oil, 30.7g. The yield is 48 percent, and the chiral purity is 99.9 percent.
Example 21: process for the preparation of tenofovir benzyl ester phosphoramide prodrugs
The same as in example 13 except that intermediate III (64g, 0.13mol) was dissolved in isopropanol (600 mL), heated to reflux and D-tartaric acid (24g, 0.11mol) was added under reflux. The yield is 43 percent, and the chiral purity is 99.1 percent.
Example 22: process for the preparation of tenofovir benzyl ester phosphoramide prodrugs
The same as in example 13 except that intermediate III (64g, 0.13mol) was dissolved in isopropanol (520 mL), heated to reflux and D-tartaric acid (27g, 0.18mol) was added under reflux. The yield is 45 percent, and the chiral purity is 99.2 percent.
Example 23: process for the preparation of tenofovir benzyl ester phosphoramide prodrugs
The same as in example 13 except that intermediate III (64g, 0.13mol) was dissolved in isopropanol (560 mL), heated to reflux, and D-tartaric acid (31.5g, 0.21mol) was added under reflux. The yield is 42 percent, and the chiral purity is 99.5 percent.
Experimental example 2: purity detection of compound I
1. The detection method comprises the following steps: for High Performance Liquid Chromatography (HPLC), the isomers of compound I (retention time t = 8.847) and compound I (retention time t = 12.737) were well separated using the following chiral column conditions (table 3), in particular. The chiral purity can reach more than 99.8 percent through detection.
Table 3: chromatographic conditions
2. Detecting a sample: examples 13-23, comparative example 2 was a procedure for the preparation of compound I according to example 7 with reference to CN 106188139A.
3. As a result:
the HPLC profile of the more typical example 20 is shown in FIG. 3.
Specific results are shown in Table 4
Table 4: the result of the detection
Table 4 the results show that: although the method of comparative example 2 provides compound i with low yield and purity, the isolation and purification of the method requires the use of preparative HPLC chromatography and is not suitable for industrial production. The invention provides a method for preparing a compound I, the yield is more than 35%, the purity is more than 96.8%, and the scheme is suitable for industrial production.
Claims (14)
1. A process for the preparation of compound i, comprising the steps of:
dissolving the intermediate compound III in a resolving solvent, heating and refluxing, adding a resolving agent in a refluxing state to form a salt, continuously refluxing, then cooling and crystallizing, filtering under reduced pressure, drying to obtain a solid, then adding water and dichloromethane, slowly adding sodium carbonate, adjusting the pH value to 7-8, extracting a water phase with dichloromethane, combining dichloromethane solutions obtained twice, drying and spin-drying to obtain a compound I,
the preparation method of the compound III comprises the following steps:
step 1): taking a compound II as an initial raw material, carrying out condensation reaction with L-alanine isopropyl ester hydrochloride under the protection of nitrogen to obtain a compound III, wherein a condensation reagent adopts a Kate condensation agent, the reaction is carried out in a condensation solvent under an alkaline condition, after the reaction is finished, a reaction solution is washed by water and a potassium dihydrogen phosphate aqueous solution in sequence, and a crude product of the compound III is obtained by filtering and separating; the mol ratio of the compound II, L-alanine isopropyl ester hydrochloride and the kat condensing agent is 1:1.2-1.4:1.2-1.3;
and 2) dissolving the crude product of the compound III in isopropanol, adding organic acid, refluxing and stirring, cooling and filtering, dissolving a filter cake with water and dichloromethane, then adding an alkalizing agent, adjusting the pH value to 7-8, extracting a water phase with dichloromethane after liquid separation, combining organic phases, and drying to obtain the compound III with high purity.
2. The method according to claim 1, wherein the molar ratio of compound II, L-alanine isopropyl ester hydrochloride and the kat condensation agent in step 1) is 1:1.25-1.35:1.20-1.25.
3. The method according to claim 1, wherein in step 1), the condensation solvent is selected from the group consisting of: one or more of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, isopropyl ether or tert-butyl methyl ether,
the dosage of the condensation solvent is 1 to 30 times of the weight of the compound II, and the unit is ml/g.
4. The process according to claim 1, wherein the condensation solvent is used in an amount of 5 to 16 times by volume in ml/g based on the weight of the compound II in the step 1).
5. The method according to claim 1, wherein in step 1), the base is selected from the group consisting of: triethylamine, diisopropylethylamine, N-dimethylaniline or 4-dimethylaminopyridine;
the dosage of the alkali is 2 to 5 times of the dosage of the compound II.
6. The method according to claim 1, wherein in step 1), the base is selected from the group consisting of: triethylamine, diisopropylethylamine, N-dimethylaniline or 4-dimethylaminopyridine;
the dosage of the alkali is 2.5 to 4 times of the dosage of the compound II.
7. The method according to claim 1, wherein in step 1), the base is selected from the group consisting of: triethylamine, diisopropylethylamine, N-dimethylaniline or 4-dimethylaminopyridine;
the dosage of the alkali is 2.5 to 3.5 times of the dosage of the compound II.
8. The preparation method of claim 1, wherein the reaction temperature in step 1) is controlled to be 20-60 ℃ and the holding time is 2-5 hours.
9. The process according to claim 1, wherein in step 2), the amount of isopropanol is 3 to 4 times the weight of compound iii in ml/g;
the organic acid is selected from malonic acid, fumaric acid, succinic acid, propionic acid, acetic acid or maleic acid, and the dosage of the organic acid is 0.5-2 times of that of the compound III;
adding organic acid and refluxing for 1-2 hr;
the volume ratio of water to dichloromethane is 1-3, and the total amount of the water to dichloromethane is 8-12 times of the weight of the compound III salt, and the unit is ml/g;
the amount of dichloromethane used in the extraction of the aqueous phase is 2-4 times the weight of the salt of compound III in ml/g.
10. The process according to claim 1, wherein in step 2), the amount of isopropyl alcohol is 3.3 to 3.7 times by volume, in ml/g, based on the weight of compound iii;
the organic acid is selected from malonic acid, fumaric acid, succinic acid, propionic acid, acetic acid or maleic acid, and the amount of the organic acid is 1-1.2 times of that of the compound III.
11. The method of claim 1, wherein:
the resolving solvent is selected from: ethanol, isopropanol, acetone, acetonitrile and 1, 4-dioxane, wherein the volume consumption of the resolution solvent is 1-20 times of the weight of the compound III, and the unit is ml/g.
12. The method of claim 1, wherein:
the resolution solvent is selected from: isopropanol, ethanol or 1, 4-dioxane; the volume dosage of the resolution solvent is 3-15 times of the weight of the compound III, and the unit is ml/g.
13. The preparation method according to claim 1, wherein the resolving agent is selected from the group consisting of: d-tartaric acid, R-mandelic acid or D-camphoric acid, and resolving agent is 0.5-4 times of compound III.
14. The preparation method according to claim 1, wherein the resolving agent is selected from the group consisting of: d-tartaric acid, R-mandelic acid or D-camphoric acid, and resolving agent is 0.5-2 times of compound III.
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Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230992A (en) * | 2014-08-27 | 2014-12-24 | 太仓运通生物化工有限公司 | Preparation method of high-purity fumaric acid tenofovir disoproxil fumarate |
| CN104262397A (en) * | 2014-09-30 | 2015-01-07 | 浙江省天台县奥锐特药业有限公司 | Preparation method of high-purity tenofovir |
| CN105924369A (en) * | 2015-12-18 | 2016-09-07 | 重庆两江药物研发中心有限公司 | Preparation method of N-(t-butoxy carbonyl)-L-leucine-N'-methoxy-N'-methylformamide intermediate |
| CN106188139A (en) * | 2015-05-29 | 2016-12-07 | 江苏天士力帝益药业有限公司 | Tenofovir list benzyl ester phosphoamide prodrug, its preparation method and application |
| CN106699812A (en) * | 2015-11-12 | 2017-05-24 | 江苏豪森药业集团有限公司 | Method for preparation and purification of tenofovir prodrug |
| CN106749396A (en) * | 2016-12-12 | 2017-05-31 | 湖南理工学院 | A kind of method to prepare organophosphorus ester compound containing P (O) OH classes compound and the efficient esterification of alcohol |
| CN107011382A (en) * | 2016-01-28 | 2017-08-04 | 单爱莲 | A kind of tenofovir prodrug and preparation method thereof |
| CN108484672A (en) * | 2018-05-23 | 2018-09-04 | 中国药科大学制药有限公司 | The chiral separation method of the third tenofovir of phosphorus |
| CN108779133A (en) * | 2016-03-17 | 2018-11-09 | 赞蒂瓦有限合伙公司 | The tenofovir Chinese mugwort of diastereisomericallypure pure draws phenol amine or the preparation method of its salt |
| WO2019015640A1 (en) * | 2017-07-21 | 2019-01-24 | 四川海思科制药有限公司 | Salt of azacyclic amide derivative, crystal form thereof and preparation method therefor and use thereof |
| CN110283208A (en) * | 2018-06-22 | 2019-09-27 | 南京济群医药科技股份有限公司 | A kind of tenofovir Chinese mugwort draws the chiral separation method of phenol amine |
| CN110372750A (en) * | 2019-07-12 | 2019-10-25 | 苏利制药科技江阴有限公司 | A kind of synthetic method of tenofovir disoproxil fumarate impurity |
-
2019
- 2019-12-30 CN CN201911399956.2A patent/CN111116655B/en active Active
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230992A (en) * | 2014-08-27 | 2014-12-24 | 太仓运通生物化工有限公司 | Preparation method of high-purity fumaric acid tenofovir disoproxil fumarate |
| CN104262397A (en) * | 2014-09-30 | 2015-01-07 | 浙江省天台县奥锐特药业有限公司 | Preparation method of high-purity tenofovir |
| CN106188139A (en) * | 2015-05-29 | 2016-12-07 | 江苏天士力帝益药业有限公司 | Tenofovir list benzyl ester phosphoamide prodrug, its preparation method and application |
| CN106699812A (en) * | 2015-11-12 | 2017-05-24 | 江苏豪森药业集团有限公司 | Method for preparation and purification of tenofovir prodrug |
| CN105924369A (en) * | 2015-12-18 | 2016-09-07 | 重庆两江药物研发中心有限公司 | Preparation method of N-(t-butoxy carbonyl)-L-leucine-N'-methoxy-N'-methylformamide intermediate |
| CN107011382A (en) * | 2016-01-28 | 2017-08-04 | 单爱莲 | A kind of tenofovir prodrug and preparation method thereof |
| CN108779133A (en) * | 2016-03-17 | 2018-11-09 | 赞蒂瓦有限合伙公司 | The tenofovir Chinese mugwort of diastereisomericallypure pure draws phenol amine or the preparation method of its salt |
| CN106749396A (en) * | 2016-12-12 | 2017-05-31 | 湖南理工学院 | A kind of method to prepare organophosphorus ester compound containing P (O) OH classes compound and the efficient esterification of alcohol |
| WO2019015640A1 (en) * | 2017-07-21 | 2019-01-24 | 四川海思科制药有限公司 | Salt of azacyclic amide derivative, crystal form thereof and preparation method therefor and use thereof |
| CN108484672A (en) * | 2018-05-23 | 2018-09-04 | 中国药科大学制药有限公司 | The chiral separation method of the third tenofovir of phosphorus |
| CN110283208A (en) * | 2018-06-22 | 2019-09-27 | 南京济群医药科技股份有限公司 | A kind of tenofovir Chinese mugwort draws the chiral separation method of phenol amine |
| CN110372750A (en) * | 2019-07-12 | 2019-10-25 | 苏利制药科技江阴有限公司 | A kind of synthetic method of tenofovir disoproxil fumarate impurity |
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