CN101203525B - 制备α-端基异构体富集的2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯的方法及其制备β核苷的应用 - Google Patents
制备α-端基异构体富集的2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯的方法及其制备β核苷的应用 Download PDFInfo
- Publication number
- CN101203525B CN101203525B CN2006800195200A CN200680019520A CN101203525B CN 101203525 B CN101203525 B CN 101203525B CN 2006800195200 A CN2006800195200 A CN 2006800195200A CN 200680019520 A CN200680019520 A CN 200680019520A CN 101203525 B CN101203525 B CN 101203525B
- Authority
- CN
- China
- Prior art keywords
- anomer
- alkyl
- alpha
- beta
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 45
- 239000002777 nucleoside Substances 0.000 title claims abstract description 13
- 150000003833 nucleoside derivatives Chemical class 0.000 title abstract description 6
- 239000000203 mixture Substances 0.000 claims abstract description 40
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims abstract description 3
- 229960005277 gemcitabine Drugs 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 241001597008 Nomeidae Species 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000003835 nucleoside group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 6
- 150000003871 sulfonates Chemical class 0.000 claims 2
- 230000001737 promoting effect Effects 0.000 claims 1
- -1 gemcitabine Chemical class 0.000 abstract description 32
- 238000006243 chemical reaction Methods 0.000 abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 13
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 150000008054 sulfonate salts Chemical class 0.000 abstract 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 14
- 239000003960 organic solvent Substances 0.000 description 10
- 239000002585 base Substances 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- DXNJIEAKJQKLMY-SOOFDHNKSA-N (3r,4s,5r)-2-fluoro-5-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OC[C@H]1OC(O)(F)[C@H](O)[C@@H]1O DXNJIEAKJQKLMY-SOOFDHNKSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 238000003797 solvolysis reaction Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 230000013595 glycosylation Effects 0.000 description 4
- 238000006206 glycosylation reaction Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- KMMHZIBWCXYAAH-UHFFFAOYSA-N 4-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(Br)C=C1 KMMHZIBWCXYAAH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000003880 polar aprotic solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical group ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 238000006345 epimerization reaction Methods 0.000 description 2
- ASCHBOWFKWDVGW-UHFFFAOYSA-N fluorobenzene;sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O.FC1=CC=CC=C1 ASCHBOWFKWDVGW-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 0 *c1c(*)ncnc1 Chemical compound *c1c(*)ncnc1 0.000 description 1
- JPBGQGOQYGYTTA-UHFFFAOYSA-N 1,3,5-trimethylbenzene;hydrochloride Chemical compound Cl.CC1=CC(C)=CC(C)=C1 JPBGQGOQYGYTTA-UHFFFAOYSA-N 0.000 description 1
- CFQPVBJOKYSPKG-UHFFFAOYSA-N 1,3-dimethylimidazol-2-one Chemical compound CN1C=CN(C)C1=O CFQPVBJOKYSPKG-UHFFFAOYSA-N 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- MWWNNNAOGWPTQY-UHFFFAOYSA-N 3-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC(S(Cl)(=O)=O)=C1 MWWNNNAOGWPTQY-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OJIKWFOITYJUSO-UHFFFAOYSA-N CC(C)[SiH2]O[SiH3] Chemical compound CC(C)[SiH2]O[SiH3] OJIKWFOITYJUSO-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- RZKYEQDPDZUERB-UHFFFAOYSA-N Pindone Chemical group C1=CC=C2C(=O)C(C(=O)C(C)(C)C)C(=O)C2=C1 RZKYEQDPDZUERB-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 125000005431 alkyl carboxamide group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- RRIJYVGANIXLNL-UHFFFAOYSA-N anisole;sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O.COC1=CC=CC=C1 RRIJYVGANIXLNL-UHFFFAOYSA-N 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000003327 cancerostatic effect Effects 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000004651 carbonic acid esters Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000002243 furanoses Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- HGALOWHSZJDJIR-UHFFFAOYSA-N iodobenzene;sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O.IC1=CC=CC=C1 HGALOWHSZJDJIR-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- PWXJULSLLONQHY-UHFFFAOYSA-N phenylcarbamic acid Chemical compound OC(=O)NC1=CC=CC=C1 PWXJULSLLONQHY-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/048—Pyridine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/12—Triazine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/22—Pteridine radicals
-
- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种制备α-端基异构体富集的2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯的方法,所述2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯在β核苷如抗癌剂吉西他滨的制备中用作中间体。在没有促进转化的有效量的磺酸盐的情况下,将β-2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯加热并且转化为α-2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯。另外,可以将2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯的α-端基异构体和β-端基异构体的端基异构体混合物溶解于水和溶剂的混合物中,并且加热以制备内半缩醛,所述内半缩醛可以进一步转化为α-端基异构体富集的2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯。
Description
相关申请
本申请要求2005年6月3日提交的美国临时专利申请系列号60/687,593的优先权。
发明背景
1.技术领域
本发明属于一种制备α-端基异构体富集的2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯的方法,所述2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯在作为抗癌剂的β核苷的制备中可用作中间体。具体而言,本发明属于一种将β-2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯转化为α-2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯的方法,所述α-2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯还可以进一步转化为所需的β核苷。
2.相关技术描述
用于制备核苷的立体选择性方法包括呋喃糖在端基异构位置的立体化学反转,因此当β-核苷是需要的产物时,优选使用适合的α端基异构体富集的糖中间体作为在糖基化反应中的底物。例如,已知的物质吉西他滨是处于β-构型的核苷,因此,它可以优选通过由在适合的α-构型糖磺酸酯中间体上封闭胞嘧啶的SN2置换产生的中心反转而制备。
现在已知的技术通过封闭糖内半缩醛与磺化试剂在低温下的反应来制备α-端基异构体富集的磺酸酯。需要的α-端基异构体可以以提高的纯度,但是以低的产率结晶。残留的材料通常是α和β端基异构体的混合物,从中不能容易地分离富集的α-端基异构体。在没有回收这种材料并且将它转化为需要的α增加的端基异构体的有效方法的情况下,α端基异构体的产率 低,并且方法的商业可行性是危险的。
美国专利5,256,798公开了通过在高温下,在惰性有机溶剂中,用磺酸的共轭阴离子源(即,磺酸盐)处理β-端基异构体呋喃核糖基磺酸酯制备α-端基异构体富集的呋喃核糖基磺酸酯的方法。然而,将磺酸的共轭阴离子溶解在溶剂中的困难和必须除去溶剂以及含水处理(aqueous workup)限制了这种方法的实用性。因此,仍然需要更有效的方法。
发明概述
本发明提供一种用于制备α-端基异构体富集的式(I)的呋喃核糖基甲磺酸酯的方法,
所述方法包括在没有促进β-端基异构体向α-端基异构体转化的有效量的磺酸盐的情况下,将式(II)的β-端基异构体
加热以将β-端基异构体转化为α-端基异构体;其中每一个Y独立地选自羟基保护基,并且R是烷基、取代的烷基、芳基或取代的芳基。
另外,本发明提供一种制备式(III)的内半缩醛的方法,
所述方法包括下列步骤:
a)将式(I)的α-端基异构体和式(II)的β-端基异构体的混合物溶解于有机溶剂(优选为极性有机溶剂)和水的混合物中;
b)将混合物在高温下加热以引起溶剂分解反应;和
c)用水稀释混合物,并且用有机溶剂萃取式(III)的内半缩醛。
可以通过与磺化试剂反应,将式III的内半缩醛转化为呋喃核糖基磺酸酯,优选式(I)的α-端基异构体富集的呋喃核糖基磺酸酯。
可以使式I的α-端基异构体与核碱(nucleobase)衍生物反应以制备式(IV)的β-端基异构体富集的核苷。
其中R′是核碱。
参考下列描述和后附权利要求书,本发明的这些和其它特征、方面和优点将变得更好理解。
本发明的优选实施方案详述
如在此所用的,术语″α/β混合物″指式(I)和(II)的2-脱氧-2,2-二氟-D-呋喃核糖的磺酸酯。它表示为重量/重量比或百分比。
术语″差向异构表异构化″指式(I)和(II)的磺酸酯的异构化。
术语“内半缩醛”指式(III)的2-脱氧-2,2-二氟-D-呋喃核糖。
术语″α-富集的″或″α-增加的″混合物指α和β端基异构体的比率大于1∶1的混合物,并且包含基本上纯的α端基异构体。
术语″水解″或″溶剂分解″指磺酸酯被羟基取代以形成内半缩醛。
术语″热异构化″指在不加入磺酸盐促进β-端基异构体转化为α-端基异构体的情况下,加热α/β混合物以将β端基异构体转化为α端基异构体。
术语″烷基″指直链、环状或支链脂族烃基。
术语″低级烷基″指含有至多7个碳原子的烷基,如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、正己基或3-甲基戊基。
术语″芳基″指碳环或杂环基团,如苯基、萘基或噻吩基。
术语″低级芳基″指含有6至12个碳原子的芳基,如苯基、取代的苯基、萘基等。
在α-端基异构体式(I)和β-端基异构体(II)中的R优选为低级烷基或芳基。
术语″取代的″指氢或共同部分被一个或多个基团取代,所述一个或多个基团为例如氰基、卤素、烷氧羰基(carboalkoxy)、芳基、硝基、烷氧基、烷基和二烷基氨基。
在此所用的核碱(R′)对于有机化学家通常是公知的,并且无需讨论它们的合成。然而,为了用于本发明的糖基化方法,根据选择的核碱衍生物的性质,含有氨基或羟基的核苷衍生物或它们的互变异构等价物优选含有保护基,如伯氨基保护基(W)和/或羟基保护基(Z)。保护基封闭可能提供β-或α-端基异构体碳水化合物的竞争反应位点的羟基或氨基。将保护基连接到与式(I)的α-端基异构体富集的碳水化合物反应的核碱(R′)上,随后从其上除去。在美国专利4,526,988中描述了用于保护核碱衍生物的方法,该美国专利的全部内容结合在此作为参考。同样,有机化学家可以容易地选择用于将需要的核碱(R′)连接到式(I)或(II)的α或β碳水化合物上的适合的核碱衍生物。例如,美国专利5,426,183和4,526,988公开了大量核碱和核碱衍生物。美国专利5,426,183和4,526,988的全部内容结合在此作为参考。
例如,没有保护基的核碱包括下列:
其中R1选自氢、烷基、卤素及其衍生物;并且R2选自氢、烷基、卤素及其衍生物。
被保护的核碱包括例如下列:
其中Z是羟基保护基;W是氨基保护基;R1选自氢、烷基、卤素及其衍生物;并且R2选自氢、烷基、卤素及其衍生物。
适合的核碱衍生物包括例如下列:
其中Z是羟基保护基;W是氨基保护基;R1选自氢、烷基、卤素及其衍生物;并且R2选自氢、烷基、卤素及其衍生物。
如在美国专利5,256,798中说明,术语″磺酸盐″指磺酸的共轭阴离子源,该美国专利的全部内容结合在此作为参考。
术语″磺化试剂″指可以与式(III)的内半缩醛反应以制备式(I)或(II)的2-脱氧-2,2-二氟-D-呋喃核糖的磺酸酯的试剂。适合的磺化试剂可以选自芳基磺酰卤、取代的芳基磺酰卤、芳基磺酰酐和取代的芳基磺酰酐。取代的芳基磺酰卤选自2-硝基苯磺酰氯、对氰基苯磺酰基3-硝基苯磺酰氯、2,4-二硝基苯磺酰氯、对溴苯磺酰氯、对氟苯磺酰氯、2,4,6-三异丙基苯磺酰氯、2,4,6-三甲基苯磺酰氯、对碘苯磺酰氯、对氯苯磺酰氯、对甲氧基苯磺酰氯和对甲苯磺酰氯;优选的是2-硝基苯磺酰氯、3-硝基苯磺酰氯、对溴苯磺酰氯、对氟苯磺酰氯和对氯苯磺酰氯;最优选的是对溴苯磺酰氯。优选的芳基磺酰酐选自苯磺酸酐和对溴苯磺酸酐。优选的芳基磺酰卤选自苯磺酰氯和2-萘磺酰氯;更优选的是苯磺酰氯。
如在此所用的,术语″羟基保护基″(Y和Z)指在合成程序中使羟基免于不需要的反应的不稳定化学部分。在所述合成程序之后,可以选择性除去如在此所述的羟基保护基。羟基保护基在本领域中是已知的,并且在下列文献中有描述:Protective Groups in Organic Chemistry的第3章,McOmieEd.,Plenum Press,New York(1973);和Protective Groups in OrganicSynthesis的第2章,Green,John,J.Wiley and Sons,New York(1981);这些参考文献的全部内容结合在此作为参考。优选的羟基保护基是酯形成基团,如甲酰基、乙酰基、取代的乙酰基、丙酰基、丁酰基、新戊酰基、2-氯乙酰基、苯甲酰基、取代的苯甲酰基、苯氧基-羰基、甲氧基乙酰基;碳酸酯衍生物,如苯氧基羰基、叔丁氧基羰基、乙氧基羰基、乙烯氧基羰基、2,2,2-三氯乙氧基羰基和苄氧基羰基;烷基醚形成基团,如苄基、二苯基甲基、三苯基甲基、叔丁基、甲氧基-甲基、四氢吡喃基、烯丙基、四氢噻吩基、2-甲氧基乙氧基甲基;以及甲硅烷基醚形成基团,如三烷基甲硅烷基、三甲基甲硅烷基、异丙基二烷基甲硅烷基、烷基二异丙基甲硅烷基、三异丙基甲硅烷基、叔丁基二烷基-甲硅烷基和1,1,3,3,-四异丙基二硅氧烷基(disloxanyl);氨基甲酸酯如N-苯基氨基甲酸酯和N-咪唑基氨基甲酸酯。然而,更优选的是苯甲酰基、单取代的苯甲酰基和双取代的苯甲酰基、乙酰基、新戊酰基、三苯基甲基醚以及甲硅烷基醚形成基团,特别是叔丁基二甲基甲硅烷基;而最优选的是苯甲酰基。
如在此所用的,术语″氨基保护基″(W)指在合成程序中使氨基免于不需要的反应的不稳定化学部分。在所述合成程序之后,可以选择性除去如在此所述的氨基保护基。氨基保护基在本领域中是已知的,在下列文献中有概括性描述:T.H.Greene和P.G.M.Wuts,Protective Groups in OrganicSynthesis,第3版,John Wiley & Sons,New York(1999);其全部内容结合在此作为参考。氨基保护基的实例包括但不限于甲硅烷基醚形成基团,如三烷基甲硅烷基、叔丁基二烷基甲硅烷基和叔丁基二芳基甲硅烷基;氨基甲酸酯如叔丁氧基羰基、苄氧基羰基、4-甲氧基苄氧基羰基、9-芴基甲氧基羰基和4-硝基苄氧基羰基;甲酰基、乙酰基、苯甲酰基和新戊酰氨基;醚形成基团,如甲氧基甲基、叔丁基、苄基、烯丙基和四氢吡喃基;烷基氨甲酰、卤代烷基氨甲酰和芳基氨甲酰基,如2-三烷基甲硅烷基乙氧基甲 基、4-甲氧基苄基、3,4-二甲氧基苄基、叔丁基、邻苯二酰氨基、四氢吡喃基、四氢呋喃基、甲氧基甲基醚、甲氧基硫代甲基、三苯甲基、新戊酰氨基、叔丁基二甲基甲硅烷基、叔己基二甲基甲硅烷基、三异丙基甲硅烷基、三氯乙氧基羰基、三氟乙酰基、萘甲酰基、甲酰基、乙酰基;磺酰胺如烷基磺基酰氨基和芳基磺基酰氨基。
术语″卤素″指氟、氯、溴和碘。
如在此所用的,术语″极性惰性溶剂″指对反应条件是惰性的极性溶剂。极性惰性溶剂的实例包括酰胺、亚砜、腈和醚,更具体而言,二甲亚砜、乙腈、甘醇二甲醚、二甘醇二甲醚、四氢呋喃、二噁烷、吡啶、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、1,3-二甲基-2-咪唑酮、N,N-二甲基乙酰胺和它们的混合物;最优选的是N,N-二甲基甲酰胺。
溶剂的选择应该允许一些水溶解度以进行制备式(III)的内半缩醛的水解反应。
可以通过任何适合的方法,例如在美国专利5,606,048中所述的方法,该美国专利的全部内容结合在此作为参考,进行在式(I)的α-端基异构体和核碱衍生物之间的糖基化反应。例如,可以在约50℃至约100℃的范围内的温度下、在惰性溶剂如芳族、卤代烷基、烷氧基以及卤素取代的芳族溶剂中进行糖基化反应。优选惰性溶剂是极性惰性溶剂。
可以通过在现有技术中公布的方法,如美国专利4,526,988;4,965,374;和5,252,756,容易地合成2-脱氧-2,2-二氟-D-呋喃核糖磺酸酯的端基异构体混合物。这些专利的每一个的全部内容都结合在此作为参考。已经表明反应温度极大地影响α-磺酸酯相对于β-磺酸酯的形成(参见美国专利5,401,861)。使用更高的温度导致α-磺酸酯的形成的增加更少,因此在结晶后的富集的α-磺酸酯的产率更低。
本发明提供再增加在结晶后留下的α/β混合物,以将再增加的混合物反向循环到α-磺酸酯增加的产物中的几种方法。
第一种方法利用在极性有机溶剂和水的混合物中将磺酸酯溶剂分解回到内半缩醛的能力。这在下面得到说明。
然后将得到的内半缩醛容易地经过磺化方法以制备α-磺酸酯,特别是富集α-磺酸酯的端基异构体混合物。这种循环极大增加可以由最初的内半缩醛获得的富集的α-甲磺酸酯的产率。由内半缩醛制备α-磺酸酯,特别是富集α-磺酸酯的端基异构体混合物的磺化方法可以是任何适合的方法,如在美国专利5,401,861中公开的低温方法,该美国专利的全部内容结合在此作为参考。
溶剂分解通过在热条件下的SN1机制发生。优选水可溶于其中的高沸点非亲核有机溶剂。适合的溶剂可以是但不限于水溶性醚、酰胺、腈和亚砜。对于更好的反应速率,优选至少100℃的温度,并且更优选约100℃至约140℃的温度范围。磺酸酯的完全转化可以在几分钟至几小时内发生,并且可以通过加入水并且萃取到有机溶剂中容易地回收内半缩醛产物。
根据本发明的一个实施方案,由式V的磺酸酯制备式III的内半缩醛的方法可以如下进行:a)将式V的α/β磺酸酯混合物溶解于水混溶的溶剂、水和任选的pH在4-9之间的弱碱性材料如羧酸盐如乙酸钠、叔胺缓冲溶液的混合物中;b)在高温下加热a)的混合物直至溶剂分解完成;c)用水稀释混合物并且用有机溶剂萃取以生成式(III)的内半缩醛。
用于萃取内半缩醛的有机溶剂可以是不混溶于水的任何溶剂,如甲苯、二氯甲烷、乙酸乙酯等。
回收α-增加的呋喃核糖基磺酸酯的第二种方法在不加入被美国专利5,256,798的方法使用的任何磺酸盐的情况下,通过α/β混合物的直接热异构化进行。
美国专利5,256,798公开了“在延长的时间内将2-脱氧-2,2-二氟呋喃核糖基甲磺酸酯在惰性有机溶剂中的溶液加热至130℃不影响端基异构体的端基异构体构型”。因此,美国专利5,256,798提出了通过在高温下在惰性溶剂中用磺酸盐处理β-端基异构体呋喃核糖基磺酸酯得到α-端基异构体 富集的呋喃核糖基磺酸酯的端基异构化方法。
我们已经惊奇地发现在没有任何磺酸盐的情况下,在至多约130℃的高温下只加热基本上没有任何溶剂的式(II)的β-端基异构体磺酸酯,容易产生端基异构体异构化。优选的温度范围是约90℃至约130℃。实际上,可以使用这种方法通过下列步骤直接由甲磺酰化反应制备增加的α混合物:只照常规逐步建立反应,除去溶剂,加热残留物,加入适合的有机溶剂并且使富集的α磺酸酯结晶。在富集的α-磺酸酯的每次分离之后,可以通过除去溶剂,加热残留物,加入适合的有机溶剂并且使富集的α-磺酸酯结晶,而将残留物再循环。在进行这种方法以制备增加的α混合物的上下文中,基本上没有任何溶剂的条件指在没有基本上防止增加的α混合物的生成的量的溶剂的存在下。
实施例
下列实施例说明本发明的具体方面,并且不意图在任何方面限制其范围,并且应该是这样解释的。
实施例1:2-脱氧-2,2-二氟-D-呋喃核糖甲磺酸酯的端基异构体混合物的异构化
将10gα/β比为1.43的2-脱氧-2,2-二氟-D-呋喃核糖甲磺酸酯放入适合的烧瓶中。在没有溶剂的情况下,将混合物在120℃加热3小时以实现异构化。将混合物冷却至75℃,并且HPLC显示了约2∶1的α/β比。将28ml乙酸乙酯和42ml庚烷以及1g活性炭装填到这种混合物中。将混合物在70℃下搅拌1小时,过滤并且冷却至20℃。在搅拌的情况下,将2-脱氧-2,2-二氟-D-呋喃核糖α-甲磺酸酯的晶种和混合物进一步冷却至0℃。在搅拌2小时后,通过过滤收集产物并且收集α-甲磺酸酯。具有20∶1的α/β比的材料的产量为2.3g。可以将溶剂从滤液中除去,并且重复异构化和结晶过程,得到类似的结果。
实施例2:将2-脱氧-2,2-二氟-D-呋喃核糖β-甲磺酸酯异构化为富集2-脱氧-2,2-二氟-D-呋喃核糖α-甲磺酸酯的混合物
在没有任何溶剂的情况下,将含有大量2-脱氧-2,2-二氟-D-呋喃核糖β-甲磺酸酯(α/β 1∶8)的混合物在130℃加热3小时。HPLC分析表明α/β比为1.7∶1。
实施例3:2-脱氧-2,2-二氟-D-呋喃核糖甲磺酸酯的端基异构体混合物的水解
将250ml DMF和12ml水加入容纳有50g 2-脱氧-2,2-二氟-D-呋喃核糖甲磺酸酯端基异构体混合物(α/β 1∶1)的烧瓶中。将混合物在回流下加热4小时,此时分析表明已经将所有甲磺酸酯转化回到2-脱氧-2,2-二氟-D-呋喃核糖。将混合物用水稀释并且用乙酸乙酯萃取。将溶液用水洗涤,并且除去溶剂。将甲苯加入并且蒸馏以制备可以用于低温反应(例如,在美国专利5,401,861中公开的低温方法)的油(48g),以制备2-脱氧-2,2-二氟-D-呋喃核糖α-甲磺酸酯富集的产物。
本发明不限于只作为实施例描述的上述实施方案,而可以在由后附专利权利要求书所限定的保护范围内以各种方式进行修改。
Claims (11)
2.权利要求1所述的方法,其中所述β-端基异构体在从90℃至130℃的温度下加热。
3.权利要求1所述的方法,其中R是芳基或含有至多七个碳原子的烷基。
4.权利要求1所述的方法,其中R是甲基。
5.权利要求1所述的方法,其中R是苯甲酰基或被氰基、卤素、烷氧羰基、芳基、硝基、烷氧基、烷基或二烷基氨基取代的苯甲酰基。
6.权利要求1所述的方法,其中所述制备的α-端基异构体存在于α-端基异构体富集的混合物中,并且所述被加热的β-端基异构体存在于端基异构体混合物中。
11.权利要求7所述的方法,其中式(IV)的核苷还被去保护以生成吉西他滨。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US68759305P | 2005-06-03 | 2005-06-03 | |
US60/687,593 | 2005-06-03 | ||
PCT/US2006/020131 WO2006132808A1 (en) | 2005-06-03 | 2006-05-24 | Process of making an alpha-anomer enriched 2-deoxy-2,2-diflouro-d-ribofuranosyl sulfonate and use thereof for making a beta nucleoside |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101203525A CN101203525A (zh) | 2008-06-18 |
CN101203525B true CN101203525B (zh) | 2012-06-13 |
Family
ID=37498755
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006800195200A Expired - Fee Related CN101203525B (zh) | 2005-06-03 | 2006-05-24 | 制备α-端基异构体富集的2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯的方法及其制备β核苷的应用 |
Country Status (13)
Country | Link |
---|---|
US (1) | US7572898B2 (zh) |
EP (1) | EP1891087A4 (zh) |
JP (2) | JP5091126B2 (zh) |
KR (1) | KR101171087B1 (zh) |
CN (1) | CN101203525B (zh) |
AR (1) | AR053620A1 (zh) |
AU (1) | AU2006255706B2 (zh) |
BR (1) | BRPI0610950A2 (zh) |
CA (2) | CA2689979C (zh) |
MX (1) | MX2007015174A (zh) |
NZ (1) | NZ563995A (zh) |
TW (1) | TWI322812B (zh) |
WO (1) | WO2006132808A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102140124B (zh) * | 2011-02-26 | 2013-05-15 | 湖南欧亚生物有限公司 | 一种新型的卡培他滨的合成工艺 |
CN109796506A (zh) * | 2019-01-28 | 2019-05-24 | 江苏八巨药业有限公司 | 一种吉西他滨关键中间体的制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5256798A (en) * | 1992-06-22 | 1993-10-26 | Eli Lilly And Company | Process for preparing alpha-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl sulfonates |
US5606048A (en) * | 1992-06-22 | 1997-02-25 | Eli Lilly And Company | Stereoselective glycosylation process for preparing 2'-Deoxy-2', 2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides |
US5608043A (en) * | 1995-02-03 | 1997-03-04 | Eli Lilly And Company | Process for the preparation of 2-deoxy-2,2-difluoro-β-D-ribo-pentopyranose compounds |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4526988A (en) * | 1983-03-10 | 1985-07-02 | Eli Lilly And Company | Difluoro antivirals and intermediate therefor |
US5401861A (en) * | 1992-06-22 | 1995-03-28 | Eli Lilly And Company | Low temperature process for preparing alpha-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl sulfonates |
UA41261C2 (uk) * | 1992-06-22 | 2001-09-17 | Елі Ліллі Енд Компані | Спосіб одержання збагачених бета-аномером нуклеозидів |
-
2006
- 2006-05-24 KR KR1020077028260A patent/KR101171087B1/ko not_active IP Right Cessation
- 2006-05-24 MX MX2007015174A patent/MX2007015174A/es active IP Right Grant
- 2006-05-24 WO PCT/US2006/020131 patent/WO2006132808A1/en active Application Filing
- 2006-05-24 EP EP06771094A patent/EP1891087A4/en not_active Withdrawn
- 2006-05-24 NZ NZ563995A patent/NZ563995A/en not_active IP Right Cessation
- 2006-05-24 JP JP2008514697A patent/JP5091126B2/ja not_active Expired - Fee Related
- 2006-05-24 AU AU2006255706A patent/AU2006255706B2/en not_active Ceased
- 2006-05-24 CA CA2689979A patent/CA2689979C/en not_active Expired - Fee Related
- 2006-05-24 US US11/439,664 patent/US7572898B2/en not_active Expired - Fee Related
- 2006-05-24 CN CN2006800195200A patent/CN101203525B/zh not_active Expired - Fee Related
- 2006-05-24 BR BRPI0610950-0A patent/BRPI0610950A2/pt not_active IP Right Cessation
- 2006-05-24 CA CA2610283A patent/CA2610283C/en not_active Expired - Fee Related
- 2006-06-01 TW TW095119351A patent/TWI322812B/zh not_active IP Right Cessation
- 2006-06-05 AR ARP060102350A patent/AR053620A1/es not_active Application Discontinuation
-
2012
- 2012-08-08 JP JP2012176061A patent/JP2012236851A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5256798A (en) * | 1992-06-22 | 1993-10-26 | Eli Lilly And Company | Process for preparing alpha-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl sulfonates |
US5606048A (en) * | 1992-06-22 | 1997-02-25 | Eli Lilly And Company | Stereoselective glycosylation process for preparing 2'-Deoxy-2', 2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides |
US5608043A (en) * | 1995-02-03 | 1997-03-04 | Eli Lilly And Company | Process for the preparation of 2-deoxy-2,2-difluoro-β-D-ribo-pentopyranose compounds |
Also Published As
Publication number | Publication date |
---|---|
US7572898B2 (en) | 2009-08-11 |
EP1891087A1 (en) | 2008-02-27 |
AR053620A1 (es) | 2007-05-09 |
MX2007015174A (es) | 2008-04-22 |
US20060276638A1 (en) | 2006-12-07 |
CA2610283A1 (en) | 2006-12-14 |
CN101203525A (zh) | 2008-06-18 |
JP5091126B2 (ja) | 2012-12-05 |
CA2689979A1 (en) | 2006-12-14 |
KR20080031172A (ko) | 2008-04-08 |
EP1891087A4 (en) | 2008-07-30 |
CA2610283C (en) | 2011-08-30 |
AU2006255706A1 (en) | 2006-12-14 |
TWI322812B (en) | 2010-04-01 |
KR101171087B1 (ko) | 2012-08-06 |
CA2689979C (en) | 2013-04-23 |
JP2008542374A (ja) | 2008-11-27 |
NZ563995A (en) | 2010-01-29 |
AU2006255706B2 (en) | 2011-06-23 |
WO2006132808A1 (en) | 2006-12-14 |
TW200745150A (en) | 2007-12-16 |
JP2012236851A (ja) | 2012-12-06 |
BRPI0610950A2 (pt) | 2010-08-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1044119C (zh) | 提纯和分离2'-脱氧-2,2'二氟核苷的方法 | |
EP4011896A1 (en) | Diastereoselective synthesis of (sp)-gemcitabine-[phenyl(benzoxy-l-alaninyl)]phosphate nuc-1031 | |
US20080167463A1 (en) | Process for Preparation of Gemcitabine Hydrochloride | |
CN1086519A (zh) | 立体有择阴离子糖基化方法 | |
WO2005080351A1 (fr) | Preparation et application de derives n4-oxycarbonylcytosine | |
CN101589055A (zh) | (Rp)-8-取代的cAMPS的制备方法 | |
CN102219817A (zh) | 活性偶联剂用于氟化嘧啶化合物烷氧羰酰化的方法 | |
EP0521923A1 (en) | METHOD FOR PRODUCING NUCLEOSIDES AND THEIR ANALOGS. | |
CN101203525B (zh) | 制备α-端基异构体富集的2-脱氧-2,2-二氟-D-呋喃核糖基磺酸酯的方法及其制备β核苷的应用 | |
JP5114556B2 (ja) | ゲムシタビンの高立体選択的な新規合成プロセス及び中間体 | |
WO2006070985A1 (en) | METHOD FOR THE PREPARATION OF 2#-DEOXY-2#,2#-DIFLUOROCYTIDINE | |
CN102199180A (zh) | 一种卡培他滨的制备方法 | |
CN102603838A (zh) | 一种制备吉西他滨盐酸盐的方法 | |
CN103483409A (zh) | 一种制备奈拉滨的合成方法 | |
EP1710249A1 (en) | Ribonucleic acid compound and method of liquid-phase synthesis of oligonucleic acid compound | |
WO2008016079A1 (en) | Method for introducing nucleic-acid-protecting group | |
Cheriyan et al. | Preparation of 9-β-D-arabinofuranosylguanine (araG) | |
AU2011202539B2 (en) | Process of making an alpha-anomer enriched 2-deoxy-2,2-difluoro-d-ribofuranosyl sulfonate and use thereof for making a beta nucleoside | |
CN111100172B (zh) | 一种胞嘧啶核苷衍生物及该衍生物制备卡培他滨药物的方法 | |
CN1324800A (zh) | 制备2',3'-二脱氢-3'-脱氧胸苷的新方法 | |
KR20070063421A (ko) | 2′,2′-디플루오로뉴클레오시드 및 중간체의 새로운 제조방법 | |
CN116676358A (zh) | 一种2-氟-2-脱氧尿苷的制备方法 | |
SU1397455A1 (ru) | Способ получени (2 @ -5 @ )- и (3 @ -5 @ )-диаденозинмонофосфатов | |
KR0130942B1 (ko) | 3'-아지도-3'-데옥시티미딘의 제조방법 | |
CN102977170A (zh) | 一种工业化生产卡培他滨中间体的合成工艺 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120613 Termination date: 20180524 |