CN1618795A - Process of preparing slereo iosmer of 1,3-oxapantane kind nucleotide - Google Patents
Process of preparing slereo iosmer of 1,3-oxapantane kind nucleotide Download PDFInfo
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- CN1618795A CN1618795A CNA2003101086783A CN200310108678A CN1618795A CN 1618795 A CN1618795 A CN 1618795A CN A2003101086783 A CNA2003101086783 A CN A2003101086783A CN 200310108678 A CN200310108678 A CN 200310108678A CN 1618795 A CN1618795 A CN 1618795A
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- 238000000034 method Methods 0.000 title claims abstract description 42
- 230000008569 process Effects 0.000 title claims abstract description 7
- 239000002773 nucleotide Substances 0.000 title abstract 2
- 125000003729 nucleotide group Chemical group 0.000 title abstract 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims abstract description 88
- 239000000203 mixture Substances 0.000 claims abstract description 39
- 239000002777 nucleoside Substances 0.000 claims abstract description 28
- 239000001301 oxygen Substances 0.000 claims description 114
- 229910052760 oxygen Inorganic materials 0.000 claims description 114
- 241000534944 Thia Species 0.000 claims description 80
- 239000003153 chemical reaction reagent Substances 0.000 claims description 35
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 26
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 22
- 229940104302 cytosine Drugs 0.000 claims description 10
- WGCNASOHLSPBMP-UHFFFAOYSA-N Glycolaldehyde Chemical class OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 9
- 238000001640 fractional crystallisation Methods 0.000 claims description 9
- 238000009833 condensation Methods 0.000 claims description 8
- 230000005494 condensation Effects 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 7
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 5
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims description 5
- 229960002510 mandelic acid Drugs 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 5
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 2
- 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 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 229940041616 menthol Drugs 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 125000003835 nucleoside group Chemical group 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 80
- 238000006243 chemical reaction Methods 0.000 description 59
- 239000007787 solid Substances 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 16
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 229960003328 benzoyl peroxide Drugs 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 12
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 238000006555 catalytic reaction Methods 0.000 description 10
- 229960001627 lamivudine Drugs 0.000 description 10
- -1 methylols Chemical class 0.000 description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 8
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 229940075963 (-)- camphor Drugs 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- 150000005690 diesters Chemical class 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229960001866 silicon dioxide Drugs 0.000 description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 4
- NOOLISFMXDJSKH-AEJSXWLSSA-N (+)-menthol Chemical compound CC(C)[C@H]1CC[C@H](C)C[C@@H]1O NOOLISFMXDJSKH-AEJSXWLSSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000010268 HPLC based assay Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 3
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 3
- 235000011130 ammonium sulphate Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 3
- WCYAALZQFZMMOM-UHFFFAOYSA-N methanol;sulfuric acid Chemical compound OC.OS(O)(=O)=O WCYAALZQFZMMOM-UHFFFAOYSA-N 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- DSSYKIVIOFKYAU-OIBJUYFYSA-N (S)-camphor Natural products C1C[C@]2(C)C(=O)C[C@H]1C2(C)C DSSYKIVIOFKYAU-OIBJUYFYSA-N 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000006385 ozonation reaction Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- UOYSNVURWVNNQA-UHFFFAOYSA-N CCCCC.[S].[O] Chemical compound CCCCC.[S].[O] UOYSNVURWVNNQA-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- 102000010722 N-Glycosyl Hydrolases Human genes 0.000 description 1
- 108010063372 N-Glycosyl Hydrolases Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- NEXSMEBSBIABKL-UHFFFAOYSA-N hexamethyldisilane Chemical compound C[Si](C)(C)[Si](C)(C)C NEXSMEBSBIABKL-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- GXZLBUYKJFLNLF-UHFFFAOYSA-N prop-2-ene-1,1-diol Chemical compound OC(O)C=C GXZLBUYKJFLNLF-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
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- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A process for preparing the stereoisomer of 1,3-sulfenyl pentane kind of nucleotides features that the mixture of said stereoisomers is decomposed of chiral assistant to obtain cis-2-L-1,3-sulfenylpentane kind of nucleosides. A novel intermediate for said process is also disclosed.
Description
The present invention relates to utilize chiral auxiliary(reagent) to split 1, the mixture of the steric isomer of 3-oxygen thia pentane class nucleosides prepares cis-2-L-1, the method for 3-oxygen thia pentane class nucleosides.The invention still further relates to the new intermediate that is used for above-mentioned preparation method.
1, the 3-oxathiolane nucleosides is the newfound in recent years active and active nucleoside analog of anti-hepatitis B virus (HBV) of excellent anti AIDS virus (HIV) that has.Suitable-L-2-methylol-5-(cytosine(Cyt)-1 '-)-1,3-oxygen thia pentane (lamivudine) and suitable-L-2-methylol-5-(5 '-flucytosine-1 '-)-1,3-oxygen thia pentane (FTC) be in this compounds two ratified to go on the market and be used for the medicine of antiviral therapy.
1, the structure of 3-oxygen thia pentane class nucleosides and the numbering of ring atom are suc as formula shown in (A), and wherein B represents purine or miazines base and their analogue.1,3-oxygen thia pentane class nucleosides contains two chiral centres in C2 position and C5 position on ring, if the base of the methylol of C2 position and C5 position is in 1 in the ring, the homonymy of 3-oxygen thia penta ring promptly constitutes cis-isomeride, be in 1, the heteropleural of 3-oxygen thia penta ring promptly constitutes trans-isomer(ide).Above-mentioned cis and trans-isomer(ide) all exist with the form of a pair of enantiomer again, so 1,3-oxygen thia pentane class nucleosides has four steric isomers altogether, can be respectively with suitable-L, and suitable-D, anti--L, anti--D represents.
Usually have only 1 of cis, 3-oxygen thia pentane class nucleosides has effective biological activity, and the different enantiomorphs of cis nucleosides often have different physiological actions.Though for example the D type enantiomorph of lamivudine has the antiviral activity similar with lamivudine, its cytotoxicity is higher than lamivudine far away, though the antiviral activity of the D type enantiomorph of FTC is more similar than low both toxic characteristic of the order of magnitude of FTC.At present ratified to go on the market 1, the activeconstituents of 3-oxygen thia pentane class nucleosides antiviral all be single-steric isomer, therefore prepare 1, the method for the medicinal single stereoisomers of 3-oxygen thia pentane class nucleosides has very high practical value.
Chinese patent 92103921.2 has disclosed and has utilized 6 to be 1 of carbonyl or carbonyl derivative, again 6 carbonyls or carbonyl derivative is reduced into methylol after 3-oxygen thia pentane and the base condensation and prepares 1, the method for 3-oxygen thia pentane class nucleosides.If utilize 6 carbonyl derivatives that have chiral auxiliary(reagent) can obtain 1, the single stereoisomers of 3-oxygen thia pentane class nucleosides in the method.
Chinese patent 92108995.3 has disclosed 1, and the racemic mixture of 3-oxygen thia pentane class nucleosides is by chiral column or utilize the method for nucleosidase selective hydrolysis to split to obtain 1, the single stereoisomers of 3-oxygen thia pentane class nucleosides.
Chinese patent 92101981.5 has also disclosed and has utilized the method for chirality HPLC separation or lipase selective hydrolysis to obtain 1, the method for the single stereoisomers of 3-oxygen thia pentane class nucleosides.
The invention provides a kind of preparation structural formula (I) and be 1 of representative, the method for the steric isomer of the cis-L configuration of 3-oxygen thia pentane class nucleosides or the isomer mixture of this steric isomer enrichment.
The key feature of the inventive method is to have 1 of chiral auxiliary(reagent) on 2 methylols with structural formula (II) representative; 3-oxygen thia pentane obtains 1 of structural formula (III) representative with the pyrimidine base and the analogue condensation thereof of protection arbitrarily; the mixture of the steric isomer of 3-oxygen thia pentane class nucleosides; this mixture can contain two to four 1, the possible steric isomer of 3-oxygen thia pentane class nucleosides (III).The method of utilizing fractional crystallization is from separating the individual isomer that obtains the cis that the has chiral auxiliary(reagent)-2-L-configuration shown in structural formula (IV) the said mixture, remove chiral auxiliary(reagent) at last and obtain required cis-2-L-1, the single optical isomer (I) of 3-oxygen thia pentane class nucleosides.
Wherein, R* represents chiral auxiliary(reagent), and L represents leavings group, and B represents pyrimidine base and analogue thereof.
In first preferable methods of the present invention; use 2-position configuration different 1; the mixture of the steric isomer of 3-oxygen thia pentane (II ') obtain 1 with pyrimidine base and the analogue condensation under the catalysis of Iodotrimethylsilane or Iodotrimethylsilane base triflate thereof protected arbitrarily, the mixture of all four steric isomers of 3-oxygen thia pentane nucleosides (III) (III ').We find because the existence of chiral auxiliary(reagent), two cis-isomerides can separate by recrystallization with two trans-isomer(ide)s easily, select appropriate solvent two cis-isomerides can be separated by fractional crystallization then and obtain single steric isomer (IV) with temperature condition, remove at last chiral auxiliary(reagent) obtain required 1, the single optical isomer (I) of the cis-L configuration of 3-oxygen thia pentane class nucleosides.
The stereoisomer mixture of 1, the 3 oxygen sulphur pentane that the 2-position configuration that uses in the aforesaid method is different (II ') can obtain by following three kinds of methods:
One). with general formula is R*OCH
2The hydroxy-acetaldehyde derivative that has chiral auxiliary(reagent) of CHO and Thiovanic acid have 1 of chiral auxiliary(reagent) synthesizing on the methylol of 2-position under protonic acid or the lewis acidic catalysis; 3-oxygen thia pentane-5-ketone (V); then with this compound with the intermediate shown in the suitable reductive agent reduction accepted way of doing sth (VI), use suitable reagent such as acylating agent or halogenating agent etc. that intermediate (VI) is changed into the different isomer mixture of 2-position configuration (II ') again.
Two). will have general formula R * OCH
2The hydroxy-acetaldehyde derivative that has chiral auxiliary(reagent) of CHO is at organic bases (for example pyridine); protonic acid (for example tosic acid) or lewis acidic catalysis are down with 1; 4-dithian-2; 5-glycol reaction obtains intermediate (VI), and acylating agent or halogenating agent change into the different isomer mixture of 2-position configuration (II ') with intermediate (VI) then.
Three). with the 2-methylol-1 shown in the structural formula (VII), 3-oxygen thia pentane and the chiral auxiliary(reagent) that can link by covalent linkage with hydroxyl (preferred chiral carboxylic acids, the chirality carboxylic acid halides, chirality acid anhydrides or chirality chloro-formic ester) reaction obtains suc as formula isomer mixture shown in (II '), 2-methylol-1 wherein, 3-oxygen thia pentane (VII) can be synthetic by the disclosed methods of United States Patent (USP) 5466806.
R1 is the group of a chirality, and R2 is an alkyl or aryl.
The general formula of using in aforesaid method is that R*OCH2CHO hydroxy-acetaldehyde derivative can obtain by following method:
The chiral auxiliary(reagent) that can link by covalent linkage with hydroxyl (preferred chiral carboxylic acids, the chirality carboxylic acid halides, chirality acid anhydrides or chirality chloro-formic ester) and vinylcarbinol or 1, obtain having on the hydroxyl vinylcarbinol or 1 of chiral auxiliary(reagent) after the reaction of 4-butylene glycol, the derivative of 4-butylene glycol, then with the vinylcarbinol or 1 that obtains, the derivative of 4-butylene glycol carries out ozonization, and to obtain general formula be R*OCH2CHO hydroxy-acetaldehyde derivative.
Reaction process 1 has shown a route using the synthetic lamivudine of above-mentioned first preferable methods, synthesize specific target product though used specific raw material and reagent in the shown synthetic route, but the person skilled in the art can recognize, uses similar agents and raw material can prepare similar compounds.
The concrete steps of each step reaction are briefly described as follows:
Step 1A: at appropriate organic solvent (methylene dichloride for example, anhydrous acetonitrile) middle with (-)-camphor acyl chlorides and 2-methylol-5-acetoxyl group-1,3-oxygen thia pentane (1-VII, the method preparation that discloses according to United States Patent (USP) 5466806) reaction in the presence of triethylamine and catalyzer dimethyl aminopyridine obtains configuration different non-enantiomer mixture in 2-position shown in the structural formula (1-II ').
Step 1B: the non-enantiomer mixture that the 2-position configuration that obtains among the step 1A is different (1-II ') reacts the mixture that obtains 2-position shown in the structural formula (1-III ') and 5-position configuration all four diastereomers all inequality under the catalysis of Iodotrimethylsilane or Iodotrimethylsilane base triflate with the cytosine(Cyt) with the hexamethyldisilazane protection.
Step 1C: four mixture of isomers that obtain in step 1B in polar solvent (for example methyl alcohol and ethanol) are carried out recrystallization in the above temperature range of subzero 20 degree, separation obtains the mixture of two cis-isomerides.
Step 1D: the mixture of two cis-isomerides that will obtain in step 1C separates the lamivudine camphoric acid ester (1-IV) that obtains having required configuration in the following recrystallization of low temperature (78 ℃-0 ℃) in esters solvent (for example ethyl formate).
Step 1E: will be in step 1D lamivudine camphoric acid ester (1-IV) in alcoholic solvent, obtain lamivudine with alkali (for example ammoniacal liquor, n-Butyl Amine 99 and sodium methylate) hydrolysis.
Reaction process 1
9377 pages of JACS 113 phases of 1991 annual reports reported use anhydrous stannic chloride catalysis arbitrarily the pyrimidine base of protection and 2-position hydroxymethyl protection 1; the condensation of 3-oxygen thia pentane can obtain cis-product by Stereoselective; we find that this method is applied to 2-position methylol and has 1 of chiral auxiliary(reagent); during the condensation reaction of 3-oxygen thia pentane, also has the cis stereoselectivity.
Second preferable methods of the present invention is that the pyrimidine base and the analogue thereof of the isomer mixture of isomorphism type (II ') and protection arbitrarily do not react under the catalysis of tin tetrachloride with the 2-position; Stereoselective obtains the mixture of two cis-isomerides of compound (III); this mixture fractional crystallization under appropriate solvent and temperature condition is obtained single steric isomer (IV); remove chiral auxiliary(reagent) then and obtain 1 of cis-L-configuration, 3-oxygen thia pentane class nucleosides (I).
Reaction process 2 has shown that using above-mentioned second preferable methods implements suitable-2-L-5-(5 '-flucytosine-1 '-)-1, route of the synthetic of 3-oxygen thia pentane (FTC), synthesize specific target product though used specific raw material and reagent in the shown synthetic route, but the person skilled in the art can recognize, uses similar agents and raw material can prepare similar compounds.
Each step reaction is briefly described as follows:
Step 2A: in methylene dichloride, D-menthol chloro-formic ester and vinylcarbinol are obtained carbonic ether (2-V) at low-temp reaction in the presence of triethylamine.
Step 2B: the carbonic ether (78 ℃ to room temperature) in suitable temperature range that the previous step reaction is obtained decomposes the hydroxy-acetaldehyde derivative (2-VI) that obtains having this chiral auxiliary(reagent) of D-menthol with ozone.
Step 2C: with the hydroxy-acetaldehyde derivative (2-VI) and 1 that obtains among the step 2B, 4-dithian-2, the 5-glycol obtains the different 5-acetoxyl group-1 of 2-position configuration after reacting acetylize again, the mixture of the steric isomer of 3-oxygen thia pentane (2-III ').
The 5-acetoxyl group-1 that step 2D: step 2C obtains, the mixture of the steric isomer of 3-oxygen thia pentane obtain a pair of cis diastereomer shown in structural formula (2-IV) and (2-IV ') with 5-flurocytosine condensation with hexamethyldisilazane protection under the catalysis of anhydrous stannic chloride.
Step 2E: the mixture of two cis diastereomers that in alcoholic solvent, step 2D obtained at low temperatures fractional crystallization to obtain 2 be the cis diastereomer (2-IV) of L configuration.
Step 2F: the cis diastereomer (2-IV) of the L configuration that in alcoholic solvent step 2E is obtained obtains suitable-2-L-5-(5 '-flucytosine-1 '-)-1,3-oxygen thia pentane (FTC) with alkali (for example ammoniacal liquor, n-Butyl Amine 99 and sodium methylate) hydrolysis
Reaction process 2
The 3rd preferable methods of the present invention is to utilize the isomer of the single configuration in 2-position of compound (II) as initiator.Pyrimidine base and analogue condensation under the catalysis of Iodotrimethylsilane or Iodotrimethylsilane base triflate thereof of the isomer of the 2-L configuration of the compound (II) shown in the formula (IIA) and protection are arbitrarily obtained 1, and the 2-position of 3-oxygen thia pentane nucleosides (III) has the mixture of the cis-trans-isomer of identical configuration.Because the existence of chiral auxiliary(reagent), trans-isomer(ide) in the mixture can be removed by the method for fractional crystallization easily, thereby obtain suc as formula the single steric isomer shown in (IV), remove the single optical isomer (I) that obtains cis-L configuration behind the chiral auxiliary(reagent).
Isomer IIA and IIB as the single configuration in 2-position of the compound (II) of aforesaid method initiator can obtain with following method:
A kind of method be general formula be the hydroxy-acetaldehyde derivative of R*OCH2CHO and Thiovanic acid under the condition of acid catalysis and heating, react the 2-position racemization that obtains shown in the structure formula V 1,3-oxygen thia pentane-5-ketone (V), utilize method two isomer separation that 2-position configuration is different of fractional crystallization to obtain 1 of L type respectively then, 1 of 3-oxygen thia pentane-5-ketone (V) and D type, 3-oxygen thia pentane-5-ketone (VB).These two kinds of isomer are changed into again the isomer IIA and the IIB of the single configuration in 2-position after with suitable reductive agent (for example three tert.-butoxy lithium aluminum hydrides, Dibal, borine-dimethyl sulphide complex compound etc.) reduction with suitable reagent such as acylating agent or halogenating agent.
Another kind method is to obtain 2-L-methylol-1 by reducing the have carbonyl or carbonyl derivative compounds X A and XB that known 2-position has a single configuration, the isomer (VIIB) of 3-oxygen thia pentane (VIIA) and its 2-D-configuration and the chiral auxiliary(reagent) that can link by covalent linkage with hydroxyl (preferred chiral carboxylic acids, chirality carboxylic acid halides, chirality acid anhydrides or chirality chloro-formic ester) reaction obtains Compound I IA and IIB.
Wherein Rc represents carbonyl or carbonyl derivative.
Reaction process 3 has shown the third preferable methods has been applied to synthesizing cis-2-L-5-(5 '-flucytosine-1 '-)-1, the concrete route during 3-oxygen thia pentane, and each step reaction is briefly described as follows:
Step 3A: in aromatic hydrocarbon solvent (for example toluene), pivaloyl chloride and L-type amygdalic acid are reacted the special pentyl ester of the 2-hydroxyl that generates L-type amygdalic acid, and then add methyl-sulphoxide or oxalyl chloride converts it into acyl chlorides, the acyl chlorides that obtains is with 1, and the reaction of 4-butylene glycol generates the diester (3-XI) shown in structural formula.
Step 3B: the diester (3-XI) that generates among the step 3A is dissolved in the alcoholic solvent, in this temperature range of room temperature, feed ozone at-78 ℃, after the diester completely consumed is intact, stop to feed ozone, obtain aldehyde shown in structural formula (3-VI) with suitable reductive agent (for example thiocarbamide, dimethyl thioether) reduction ozone affixture.
Ozonization need carry out under extremely low temperature (being lower than-70 ℃) usually, but solvent that we are selected and reactant systems make reaction to carry out in this temperature range of room temperature at 0 ℃, greatly reduce requirement, can be applicable to suitability for industrialized production reaction unit.
Step 3C: the hydroxy-acetaldehyde derivative (3-VI) that obtains among the step 3B is reacted with Thiovanic acid under protonic acid or lewis acidic catalysis, and reaction is chosen in the aromatic hydrocarbon solvent to be carried out, and by heating azeotropic removal of water branch.With this understanding, the reaction high productivity generate 2-position configuration shown in structural formula (3-V) different 1, the mixture of the diastereomer of 3-oxygen thia pentane-5-ketone.
Step 3D: with obtain among the step 3C 1, mixture fractional crystallization in the mixed solvent of being made up of toluene and sherwood oil of the diastereomer of 3-oxygen thia pentane-5-ketone obtains the individual isomer (3-VA) of 2-L configuration.
Step 3E: with the 2-L-1 that obtains among the step 3D, 3-oxygen thia pentane-5-ketone (3-VA) obtains corresponding 5-acetoxyl group-1,3-oxygen thia pentane (3-IIA) with reductive agent (preferred three tert.-butoxy lithium aluminum hydrides) reduction at the adding acetic anhydride acylation.
Step 3F: with the 5-acetoxyl group-1 that obtains among the step 3E, 3-oxygen thia pentane (3-IIA) obtains a pair of cis-trans-isomer that the 2-position is the L configuration with 5-flurocytosine condensation under the catalysis of Iodotrimethylsilane or Iodotrimethylsilane base triflate of protecting with hexamethyldisilazane.
Step 3G: a pair of cis-trans-isomer that obtains among the step 3E is carried out fractional crystallization in methyl alcohol.Trans-isomer(ide) at room temperature crystallization is separated out, and obtains cis-isomeride (3IV) after removing by filter.
Step 3H: remove amygdalic acid residue with the n-Butyl Amine 99 hydrolysis with obtaining among the step 3G after compound (3IV) is dissolved in the methyl alcohol, obtain suitable-2-L-5-(5 '-flucytosine-1 '-)-1,3-oxygen thia pentane.
Reaction process 3
The chiral auxiliary(reagent) of using in above-mentioned each method is the chiral radicals that can link by covalent linkage with hydroxyl arbitrarily, they should not have influence on the generation of intermediate or final product in entire synthesis process, also should not be subjected to respectively to go on foot the influence of building-up reactions, for example in using the synthetic route of ozone, should avoid with the chiral auxiliary(reagent) that contains the double bond functional group.Preferred in the present invention chiral auxiliary(reagent) has the L-amygdalic acid, the menthol chloro-formic ester of D-type and L-type and (-) dextrocamphoric acid.
Following examples can help to illustrate better the present invention, but these embodiment do not limit the scope of the invention.
Embodiment 1
Synthetic 2-(-)-camphor acyl-oxygen methyl-5-acetoxyl group-1,3-oxygen thia pentane
To 17.8 gram 2-methylol-5-acetoxyl groups-1 are housed, 3-oxygen thia pentane in the round-bottomed flask of 10 milliliters of pyridines and 200 milliliters of methylene dichloride, slowly splashes into 13.2 gram (-)-camphor acyl chlorides under 0 ℃ temperature condition and nitrogen protection.Dripping the back continues to stir 8 hours.Use anhydrous sodium sulfate drying with gained solution after 1 milliliter of termination reaction of methyl alcohol with after dilute hydrochloric acid (100ml * 3) washing.Obtain a faint yellow oily thing except that after desolvating, obtain 22 gram 2-(-)-camphor acyl-oxygen methyl-5-acetoxyl groups-1,3-oxygen thia pentane after separating with silica gel column chromatography.
Embodiment 2
2-(-)-camphor acyl-oxygen methyl-5-(cytosine(Cyt)-1 '-)-1,3-oxygen thia pentane
Under nitrogen protection, cytosine(Cyt) 9.8 is restrained; 20 milliliters of hexamethyldisilazanes and small amount of ammonium sulfate join in one 500 milliliters the round-bottomed flask; add again 250 milliliters 1, in the 2-ethylene dichloride, white solid disappeared and forms settled solution after this mixture heating up refluxed about four hours.Add 22 gram 2-(-)-camphor acyl-oxygen methyl-5-acetoxyl groups-1 after this solution is cooled to 0 ℃, 3-oxygen thia pentane, and then add 10.8 milliliters of Iodotrimethylsilanes.Reaction solution stirred spend the night and allow the temperature of reaction solution be raised to room temperature gradually.Obtain 30 gram syrupy shape resistatess with under vacuum, removing behind the aqueous solution of sodium bisulfite washing reaction liquid to desolvate.This resistates is directly used in next step recrystallization without purifying.
Embodiment three
Suitable-2-L-(-)-camphor acyl-oxygen methyl-5-(cytosine(Cyt)-1 '-)-1,3-oxygen thia pentane
With thick 2-(-)-camphor acyl-oxygen methyl-5-(cytosine(Cyt)-1 '-)-1 that obtains among the embodiment 2, the heating of the stereoisomer mixture of 3-oxygen thia pentane is dissolved in 50 ml methanol, has solid to separate out behind the cool to room temperature.Mother liquor reheat after the solids removed by filtration is concentrated to 30 milliliters of postcooling to room temperature, has more solid to separate out.After the solids removed by filtration filtrate vaporising under vacuum is removed methyl alcohol, obtain yellow solid 17 grams.The heating of this yellow solid is dissolved in 200 milliliters of ethyl formates, to be cooledly is being positioned over crystallisation by cooling in-80 ℃ the refrigerator-freezer to the room temperature.After-filtration was collected 8.5 gram white solids, fusing point: 176-178 ℃, specific rotation [α] in 2 hours
D 20-96 ° (c 0.25, CH
2Cl
2).
Embodiment four
Suitable-L-2-methylol-5-(cytosine(Cyt)-1 '-)-1,3-oxygen thia pentane (lamivudine)
With suitable-2-L-(-)-camphor acyl-oxygen methyl-5-(cytosine(Cyt)-1 '-)-1,3-oxygen thia pentane 8.5 gram is dissolved in 150 methyl alcohol, slowly adds 20 milliliters of the methanol solutions of the sodium methylate of 1N then, stirring at room reaction 2 hours.After the solvent removed in vacuo, obtain suitable-L-2-methylol-5-(cytosine(Cyt)-1 '-)-1,3-oxygen thia pentane (lamivudine) 3.8 grams, fusing point: 156-158 ℃, specific rotation [α] after the gained resistates separated with silica gel column chromatography
D 20-116 ° (c 0.35, methyl alcohol).Its enantiomeric purity of chirality HPLC assay determination is 94.5%.
Embodiment five
D-menthol propenyloxy group manthanoate (2-V)
In with 5 liters of reaction flasks of ice bath refrigerative, add 2500 milliliters of methylene dichloride, DMAP 0.5 gram, 50 milliliters of triethylamines and vinylcarbinol 26 grams.Start and stir, under nitrogen protection, drip 118 milliliters of D-menthol chloro-formic esters.Dropwising the relief reacting liquid temperature is raised to room temperature automatically and stirs and spend the night.Reaction solution except that desolvating, obtains weak yellow liquid 130 grams, yield 89% with the anhydrous sodium sulfate drying final vacuum with 1N hydrochloric acid (2000 milliliters * 3) washing.
Embodiment six
2-(D-peppermint oxygen methanoyl) acetaldehyde (2-VI)
In having three mouthfuls of round-bottomed flasks of device for absorbing tail gas, add D-menthol propenyloxy group manthanoate (2-V) 130 gram and 2000 ml methanol.Feed ozone and keep temperature of reaction with behind the ice-water bath cooling reaction solution to 5 ℃ below 20 ℃.Feed ozone after 5 hours thin-layer chromatography (silica-gel plate use ethyl acetate: normal hexane=launch at 1: 4,1% sulfuric acid methanol solution colour developing) detect the discovery reaction raw materials and disappear.After feeding nitrogen removing in 10 minutes ozone, start to stir, with ice-water bath with reaction solution to be cooled to after 5 ℃ with per minute 1 gram speed adding thiocarbamide (32g, 0.4mol), after adding thiocarbamide, reaction is stirred and is spent the night, and after the solids removed by filtration, filtrate obtains sticky solid after concentrating under vacuum, with obtaining white solid 96 grams behind the sherwood oil recrystallization, yield is 85%, fusing point: 46-48 ℃, [α]
D 20+ 90.8 ° (c 0.35, methylene dichloride).
1H-NMR(CDCl
3)：0.77(d，3H，J＝7Hz)，0.91(t，6H，J＝7Hz)，0.86-2.06(m，9H)，4.68(s，2H)，9.86(s，1H)。
Embodiment seven
2-(D-peppermint oxygen methanoyl methyl)-5-acetoxyl group-1,3-oxygen thia pentane (2-III ')
2-(D-peppermint oxygen methanoyl) acetaldehyde (2-VI) 98 grams are dissolved in 500 milliliters of pyridines, add 1 then, 4-dithian-2,5-glycol 23 grams, reaction mixture is removed suspended substance at 2 hours after-filtration of 60 ℃ of following stirring reactions.Filtrate adds 1000 milliliters of methylene dichloride after concentrating and removing 80% pyridine under vacuum, then with ice-water bath with reaction solution to being cooled to 5 ℃.Diacetyl oxide slowly drips under the condition of nitrogen protection, and reaction continues at room temperature to carry out 2 hours.Reaction solution is used anhydrous sodium sulfate drying with 1N hydrochloric acid (1000 milliliters * 3) washing back, and solvent removed in vacuo obtains yellow sticky solid 139 grams, and with obtaining white solid 116 grams behind the sherwood oil recrystallization, yield is 83%.
Embodiment eight
Suitable-2-(D-peppermint oxygen methanoyl methyl)-5-(5 '-flucytosine-1 '-)-1,3-oxygen thia pentane
Under nitrogen protection, 5-flurocytosine 27.8 is restrained; 150 milliliters of hexamethyldisilazanes; 1,1000 milliliters of 2-ethylene dichloride and small amount of solid ammonium sulfate join in one 2000 milliliters the round-bottomed flask, and white solid disappeared and forms settled solution after this mixture heating up was refluxed about four hours.Add 2-(D-peppermint oxygen methanoyl methyl)-5-acetoxyl group-1 after this solution is cooled to 0 ℃, and 3-oxygen thia pentane (2-III ') 69 grams.450 milliliters of the solution of anhydrous stannic chloride in methylene dichloride that under nitrogen protection, add 1M.React after 5 hours, in reaction solution, slowly add 500 milliliters of the ammoniacal liquor of 2N.Stir and divide the phase of anhydrating after ten minutes, organic phase is filtered the concentrated resistates that obtains that desolvates that removes of final vacuum and is obtained sticky solid 83 grams, yield 89% with purification by silica gel column chromatography.
Embodiment nine
Suitable-2-L-(D-peppermint oxygen methanoyl methyl)-5-(5 '-flucytosine-1 '-)-1,3-oxygen thia pentane (2-IV)
The mixture 83 gram heating of the 2-IV that obtains among the embodiment eight and 2-IV ' are dissolved in 1500 ml methanol are placed on-20 ℃ of freezing and crystallizings and spend the night, filter and obtain white solid 32 grams.The 32 gram solids that obtain are heated once more to be dissolved in 700 ml methanol and are placed on-20 ℃ of freezing and crystallizings, filter and obtain white solid 26 grams, yield is 63%, fusing point: 153-155 ℃, [α]
D 20-10.8 ° (c 0.35, methylene dichloride).
1H-NMR(CDCl
3)0.78(d，3H，J＝7Hz)，0.91(t，6H，J＝7Hz)，0.96-2.06(m，9H)，3.12(dd，J＝12，4Hz.1H)，3.46(dd，J＝11，5Hz，1H)，3.78(m，2H)，5.13(t，J＝4Hz，1H)，6.38(m，1H)，7.47(br?s，1H，NH)，7.89(brs，1H，NH)，8.35(d，Ar-H).
Embodiment nine
Suitable-2-L-5-(5 '-flucytosine-1 '-)-1,3-oxygen thia pentane (FTC)
With suitable-2-L-(D-peppermint oxygen methanoyl methyl)-5-(5 '-flucytosine-1 '-)-1,3-oxygen thia pentane (2-IV) 26 gram is dissolved in 250 methyl alcohol, slowly adds 80 milliliters of the methanol solutions of the sodium methylate of 1N then, stirring at room reaction 2 hours.Remove in a vacuum after the neutrality with acetic acid neutralization reaction liquid and to desolvate.With resistates with petroleum ether after the solid recrystallizing methanol of gained, obtain suitable-2-L-5-(5 '-flucytosine-1 '-)-1,3-oxygen thia pentane (FTC) 12.8 grams, yield is 93%.Fusing point: 184-186 ℃, specific rotation [α]
D 20-116.8 ° (c 1.03, methyl alcohol).Its enantiomeric purity of chirality HPLC assay determination is 97.5%.
Embodiment ten
1,4-two (2 '-pivaloyl oxygen base-L-almond acyloxy)-2-butylene (3-XI)
L-amygdalic acid 100 grams reacted 8 hours at 50 ℃ under the situation that feeds nitrogen in 200 milliliters of toluene for 100 milliliters with pivaloyl chloride.To add 10 milliliters of DMF behind the reaction solution cool to room temperature that obtain, slow then dripping thionyl chloride.Be reflected at 35 ℃ and continue three hours concentrated oily liquids that obtain of final vacuum.This oily liquids slowly joined after with 500 milliliters of dilutions of methylene dichloride be equipped with 1,4-butylene glycol 28ml, triethylamine 110ml is in the there-necked flask of DMAP0.4g and methylene dichloride 1600ml, continue in the process that drips to stir, and keep temperature of reaction below 10 ℃.Dropwise and in reaction solution, add saturated potassium hydrogen carbonate aqueous solution 40ml after half an hour is stirred in the back, after continuing to stir half an hour, hydrochloric acid with 5% (1000ml) is washed 3 times, 0.1M yellow soda ash (1000ml) is washed 1 time, after water (1000ml) was washed 1 time, rotary evaporation was drained solvent and is got yellow oily liquid 180ml.
1H-NMR(CDCl
3)1.28(S，9H)，4.62(t，J＝1.6Hz，2H)，5.61(t，J＝4Hz，1H)，5.86(s，1H)，7.27-7.47(m，5H)。
Embodiment 11
2-(2 '-pivaloyl oxygen base-L-almond acyloxy) acetaldehyde (3-VI)
In having three mouthfuls of round-bottomed flasks of device for absorbing tail gas, add 1,2000 milliliters of 4-two (2 '-pivaloyl oxygen base-L-almond acyloxy)-180 milliliters of 2-butylene (3-XI) and methyl alcohol.Bathing the cooling reaction solution with cryosel feeds ozone and keeps temperature of reaction below 10 ℃ after-5 ℃.Feed ozone after 8 hours thin-layer chromatography (silica-gel plate use ethyl acetate: normal hexane=launch at 1: 2,1% sulfuric acid methanol solution colour developing) demonstration reaction raw materials disappear.After feeding nitrogen removing in 10 minutes ozone, start and stir, the speed with per minute 1 gram adds thiocarbamide 12.6g after 5 ℃ to being cooled to reaction solution with ice-water bath, after adding thiocarbamide, reaction is stirred and is spent the night, and after the solids removed by filtration, filtrate adds methylene dichloride 500ml after concentrating and removing methyl alcohol again under vacuum, after water 500ml washing is removed residual thiocarbamide 2 times, drain to such an extent that yellow oily liquid 150 restrains.
1H-NMR(CDCl
3)：1.29(s，9H)，4.62(s，2H)，6.01(s，1H)，7.27-7.55(m，5H)，9.52(s，1H)。
Embodiment 12
2-(2 '-pivaloyl oxygen base-L-almond acyl-oxygen methyl)-1,3-oxygen thia pentane-5-ketone (3-V)
With 2-(2 '-pivaloyl oxygen base-L-almond acyloxy) acetaldehyde (3-VI) 150 gram, Thiovanic acid 35.8ml, tosic acid 1 gram and toluene 800ml join in one 2000 milliliters the round-bottomed flask.Load onto the water trap afterreaction that has prolong and be heated to 120 ℃ of backflows two hours, have 18 ml waters therebetween and told with oil bath.Thin-layer chromatography (silica-gel plate is used ethyl acetate: normal hexane=launch at 1: 2,1% sulfuric acid methanol solution colour developing) shows that reaction is complete.To wash 3 times with 1M yellow soda ash 1000ml behind the reaction solution cool to room temperature, rotary evaporation obtains 200 milliliters of yellow oily liquid after removing and desolvating, be heated and be dissolved in 1000 milliliters of Virahols: in 6: 1 the mixed solvent of water, be positioned over 5 ℃ of 12 hours white crystals then and separate out, filter and obtain solid 180 grams.
Embodiment 13
2-L-(2 '-pivaloyl oxygen base-L-almond acyl-oxygen methyl)-1,3-oxygen thia pentane-5-ketone (3-VA)
With 2-(2 '-pivaloyl oxygen base-L-almond acyl-oxygen methyl)-1,3-oxygen thia pentane-5-ketone (3-V) 180 grams are dissolved in 600 milliliters of toluene at 60 ℃: in the mixed solvent of sherwood oil=2: 1, solution is positioned over 8 hours after-filtration of room temperature and collects the crystal of separating out.Under similarity condition, obtain white crystal 58 grams behind twice of the repeated recrystallization.
1H-NMR(CDCl
3)：1.29(s，9H)，3.54(s，2H)，4.28-4.43(m，2H)，5.52-5.55(m，1H)，5.90(s，1H)，7.38-7.49(m，5H)。
Embodiment 14
2-L-(2 '-pivaloyl oxygen base-L-almond acyl-oxygen methyl)-5-acetoxyl group-1,3-oxygen thia pentane (3-IIA)
Add lithium aluminium hydride 12.8g in the there-necked flask of a 2L, 328 milliliters of anhydrous tetrahydro furans drip the mixture of trimethyl carbinol 82ml and tetrahydrofuran (THF) 82ml under 0 ℃ and nitrogen protection.Rate of addition is per minute 2ml.Remove ice bath after dropwising, the temperature of question response system rises to the water-bath that again reaction unit is placed 30 degree after the room temperature, continues stirring reaction, stops to discharge bubble in reaction system.Change ice-water bath, in addition funnel, add 2-L-(2 '-pivaloyl oxygen base-L-almond acyl-oxygen methyl)-1, the mixture of 3-oxygen thia pentane-5-ketone (3-VA) 58 grams and THF160ml, with p.s. 1 speed add this mixture, add the back and continued stirring reaction 2 hours, thin-layer chromatography (silica-gel plate, ethyl acetate: normal hexane=launch at 1: 4,1% vitriolic methanol solution colour developing) shows that raw material has consumed fully.Add diacetyl oxide 270ml in addition funnel, join in the reactant with the speed that p.s., 2-3 dripped in ice-water bath, continue stirring reaction and spend the night, thin-layer chromatography shows that reaction finishes.Add diatomite 100 grams, stirring reaction half an hour, mixture filters, and filtrate is with saturated potassium hydrogen carbonate (500ml) washing 3 times, behind the anhydrous sodium sulfate drying, after the solvent removed in vacuo 65 milliliters of light green oily liquids.
Embodiment 15
Suitable-2-L-(2 '-pivaloyl oxygen base-L-almond acyl-oxygen methyl)-5-(5 '-flucytosine-1 '-) 1,3-oxygen thia pentane (3IV)
With 5-flurocytosine 20g, hexamethyldisilane 100ml, ammonium sulfate solids a little and anhydrous 1,2-ethylene dichloride 460ml reflux under nitrogen protection after about four hours white solid disappear and form settled solution.Add 2-L-(2 '-pivaloyl oxygen base-L-almond acyl-oxygen methyl)-5-acetoxyl group-1,65 milliliters of 3-oxygen thia pentanes (3-IIA) after this solution is cooled to 0 ℃.Under nitrogen protection, add 21.8 milliliters of Iodotrimethylsilanes.Reaction solution stirred spend the night and allow the temperature of reaction solution be raised to room temperature gradually.Obtain the brown resistates of 100 gram syrupy shapes with under vacuum, removing behind 300 milliliters of washing reaction liquid of aqueous solution of sodium bisulfite to desolvate.This resistates heating is dissolved in 200 ml methanol postcooling to room temperature, and placing had solid to separate out after 12 hours.After the solids removed by filtration mother liquor is concentrated 1/3rd, being positioned over room temperature 12 hours has solid to separate out after again.Solids removed by filtration, mother liquor is removed methyl alcohol under vacuum, and resistates is positioned over-20 ℃ of freezing and crystallizings after being dissolved in 300 milliliters of ethyl acetate, filters to obtain white solid 32 grams, and yield is 43%, fusing point: 56-58 ℃, [α]
D 20+ 97.8 ° (c 0.45, methylene dichloride).
1H-NMR(CDCl
3)：1.29(s，9H)，3.19(d，J＝12Hz，1H)，3.43(dd，J＝5.2，12.8Hz，1H)，4.25(ddd，J＝4，12.4，16.4Hz，2H)，5.46(br?s，NH，1H)，5.90(S，1H)，6.27(d，J＝4.8Hz，1H)，7.18(br?s，NH，1H)，7.27-7.51(m，5H)。
Embodiment 16
Suitable-2-L-5-(5 '-flucytosine-1 '-)-1,3-oxygen thia pentane.
With suitable-2-L-(2 '-pivaloyl oxygen base-L-almond acyl-oxygen methyl)-5-(5 '-flucytosine-1 '-) 1,3-oxygen thia pentane (3IV) 32 grams are dissolved in 200 methyl alcohol, add 20 milliliters of n-Butyl Amine 99s then, stirring at room reaction 2 hours.Solvent removed in vacuo, with the gained resistates with petroleum ether after, the gained gray solid.Use recrystallizing methanol, obtain suitable-2-L-5-(5 '-flucytosine-1 '-)-1,3-oxygen thia pentane (FTC) 12.8 grams, yield is 89%.Fusing point: 184-186 ℃, specific rotation [α]
D 20-119.8 ° (c 0.98, methyl alcohol).Its enantiomeric purity of chirality HPLC assay determination is 99.5%.
Claims (7)
1. 1 shown in the preparation formula (I), the method for the single stereoisomers of 3-oxygen thia pentane class nucleosides,
This method comprises the mixture that obtains the steric isomer of the intermediate shown in the formula (III) with the intermediate shown in the formula (II) and pyrimidine base of protecting arbitrarily and analogue thereof at suitable catalyst action in following condensation; method by fractional crystallization is separated and is removed chiral auxiliary(reagent) again behind the single stereoisomers that obtains the intermediate shown in the formula (III) and obtain 1 shown in the formula (I), the single stereoisomers of 3-oxygen thia pentane class nucleosides.
Wherein, R* represents chiral auxiliary(reagent), and L represents leavings group, and B represents pyrimidine bases and analogue thereof.
2. be cytosine(Cyt) or 5-flurocytosine according to the B that the process of claim 1 wherein.
3. can be suc as formula (IIA) or the steric isomer (IIB) according to the intermediate that the process of claim 1 wherein (II), or steric isomer (IIA) and mixture (IIB).
Wherein, R* represents chiral auxiliary(reagent), and L represents leavings group.
4. according to the process of claim 1 wherein that the used catalyzer of condensation reaction is an Iodotrimethylsilane, Iodotrimethylsilane base triflate or anhydrous stannic chloride.
5. suitable-L-2-methylol-the 5-(5 '-flucytosine-1 '-)-1 that has chiral auxiliary(reagent) shown in the formula (IV-F), the derivative of 3-oxygen thia pentane.
Wherein, R* is a chiral auxiliary(reagent), and R is H or amino protecting group.
6. has general formula R * OCH
2The hydroxy-acetaldehyde derivative that has chiral auxiliary(reagent) of CHO.
Wherein, R* is a chiral auxiliary(reagent).
7. according to each described method among the claim 1-6, wherein chiral auxiliary(reagent) is selected from the L-amygdalic acid, the menthol chloro-formic ester of D-type and L-type and (-) dextrocamphoric acid.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008141485A1 (en) * | 2007-05-18 | 2008-11-27 | Shanghai Desano Pharmaceutical Holding Co., Ltd. | A process for stereoselective synthesis of lamivudine |
| CN104926806A (en) * | 2014-03-22 | 2015-09-23 | 上海创诺制药有限公司 | Synthetic method of lamivudine intermediate |
-
2003
- 2003-11-18 CN CNA2003101086783A patent/CN1618795A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008141485A1 (en) * | 2007-05-18 | 2008-11-27 | Shanghai Desano Pharmaceutical Holding Co., Ltd. | A process for stereoselective synthesis of lamivudine |
| JP2010527336A (en) * | 2007-05-18 | 2010-08-12 | シャンハイ ドゥサノ ファーマシューティカル ホールディング カンパニー リミテッド | Stereoselective production method of lamivudine |
| CN101307048B (en) * | 2007-05-18 | 2011-03-23 | 上海迪赛诺医药发展有限公司 | Method for preparing lamivadin by stereoselectivity |
| AU2007353748B2 (en) * | 2007-05-18 | 2012-02-02 | Shanghai Desano Pharmaceutical Holding Co., Ltd. | A process for stereoselective synthesis of lamivudine |
| US8304540B2 (en) | 2007-05-18 | 2012-11-06 | Shanghai Desano Pharmaceutical Holding Co., Ltd. | Process for stereoselective synthesis of lamivudine |
| CN104926806A (en) * | 2014-03-22 | 2015-09-23 | 上海创诺制药有限公司 | Synthetic method of lamivudine intermediate |
| CN104926806B (en) * | 2014-03-22 | 2020-03-24 | 上海创诺制药有限公司 | Method for synthesizing lamivudine intermediate |
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