CN1982323B - A preparing process of 1-(2'-deoxy-2',2'-difluoro-D-ribofuranosyl)-4-aminopyrimidin-2-on or thereof hydrochloric salt - Google Patents
A preparing process of 1-(2'-deoxy-2',2'-difluoro-D-ribofuranosyl)-4-aminopyrimidin-2-on or thereof hydrochloric salt Download PDFInfo
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- CN1982323B CN1982323B CN200610160960XA CN200610160960A CN1982323B CN 1982323 B CN1982323 B CN 1982323B CN 200610160960X A CN200610160960X A CN 200610160960XA CN 200610160960 A CN200610160960 A CN 200610160960A CN 1982323 B CN1982323 B CN 1982323B
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- 238000000034 method Methods 0.000 title claims abstract description 10
- 150000003839 salts Chemical class 0.000 title 1
- 239000000126 substance Substances 0.000 claims abstract description 73
- 150000001875 compounds Chemical class 0.000 claims description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 43
- 238000002360 preparation method Methods 0.000 claims description 33
- 230000014509 gene expression Effects 0.000 claims description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- -1 methyl sulphonyl Chemical group 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- 230000002829 reductive effect Effects 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 8
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 150000001720 carbohydrates Chemical class 0.000 claims description 5
- 239000011260 aqueous acid Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000468 ketone group Chemical group 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 18
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 abstract 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 abstract 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 235000011167 hydrochloric acid Nutrition 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 229930182470 glycoside Natural products 0.000 description 5
- 150000002338 glycosides Chemical class 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000002777 nucleoside Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- SYVNVEGIRVXRQH-UHFFFAOYSA-N 3-fluorobenzoyl chloride Chemical compound FC1=CC=CC(C(Cl)=O)=C1 SYVNVEGIRVXRQH-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
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 2
- 235000011130 ammonium sulphate Nutrition 0.000 description 2
- 229940104302 cytosine Drugs 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- HTBVGZAVHBZXMS-UHFFFAOYSA-N lithium;tris[(2-methylpropan-2-yl)oxy]alumane Chemical compound [Li].[Al+3].CC(C)(C)[O-].CC(C)(C)[O-].CC(C)(C)[O-] HTBVGZAVHBZXMS-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- AZYTZQYCOBXDGY-UHFFFAOYSA-N 2-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=CC=N1 AZYTZQYCOBXDGY-UHFFFAOYSA-N 0.000 description 1
- OEKJNWICKQULIB-UHFFFAOYSA-N 3-fluorobenzoyl bromide Chemical class FC1=CC=CC(C(Br)=O)=C1 OEKJNWICKQULIB-UHFFFAOYSA-N 0.000 description 1
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 1
- YMVDTXSRLFAIKI-UHFFFAOYSA-N 7h-purine Chemical compound C1=NC=C2NC=NC2=N1.C1=NC=C2NC=NC2=N1 YMVDTXSRLFAIKI-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000002991 Ring chromosome 4 syndrome Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 230000003327 cancerostatic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical class CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- YMXFJTUQQVLJEN-UHFFFAOYSA-N pyrimidine Chemical compound C1=CN=CN=C1.C1=CN=CN=C1 YMXFJTUQQVLJEN-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 229960000344 thiamine hydrochloride Drugs 0.000 description 1
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 1
- 239000011747 thiamine hydrochloride Substances 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
-
- 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
Abstract
This invention related to the chemical formula 1 which represent by 1-(2'- to oxidize-2', 2' - two fluorin - D -furan ribose) - 4 - amido pyridine -2 - ketone or the method to produce its hydrochloride.
Description
Technical field
The present invention relates to the preparation method of 1-(2 '-deoxidation-2 ', 2 '-two fluoro-D-ribofuranosyls)-4-aminopyrimidine-2-ketone or its hydrochloride.
Background technology
1-(2 '-deoxidation-2 ', 2 '-two fluoro-D-ribofuranosyls)-4-aminopyrimidine-2-ketone (1-(2 '-deoxy-2 ', 2 '-difluoro-D-ribofuranosyl)-4-aminopyrimidin-2-on) [perhaps knownly has 2 '-deoxidation-2 ', 2 '-difluoro cytidine (Cytidine) or Ji Xita pyridine (Gemcitabine)] be 2 '-deoxidation-2 ' as known in the art, in 2 '-Difluoronucleosides series one.This compound has been disclosed among US 4526988 and the US 4808614, as antiviral agent and carcinostatic agent.
2 '-deoxidation-2 ', 2 '-Difluoronucleosides be by after preparing carbohydrate and alkali respectively, and these two compositions are carried out condensation prepared.Particularly, 2 '-deoxidation-2 ', the beta-nucleosides compound is very effective in 2 '-Difluoronucleosides, and the typical compound of such beta-nucleosides is known the Ji Xita pyridine.
US 4526988 discloses the 2 '-deoxidation-2 ' that will be dissolved in the protection hydroxyl in the methylene dichloride; 2 '-two fluoro-D-ribofuranosyls; in suitable de-acidying agent such as triethylamine; reacted 3 hours at 25 ℃ with Methanesulfonyl chloride; 1-methyl sulphonyl-the 2 '-deoxidation-2 ' of preparation protection hydroxyl, 2 '-two fluoro-D-ribofuranose radical derivatives.The gained compound combines with purine (purine) or pyrimidine (pyrimidine) alkali, forms the one-tenth glycosides isomer (anomer) (anomer) of nucleosides.
In addition, Korean Patent Registration discloses have erythro (erythro) and the stereochemical 2 '-deoxidation-2 ' of β, the preparation method of 2 '-Difluoronucleosides for No. 117181.
Though nucleosides synthesizes creative development, still needs to develop β-2 '-deoxidation-2 ', the preparation method of the industrial production of 2 '-Difluoronucleosides.
Summary of the invention
The object of the invention provides the 2 '-deoxidation-2 ' that realizes industrial production, the preparation method of 2 '-Difluoronucleosides.
In addition, the other purpose of the present invention provides and is used for 2 '-deoxidation-2 ', intermediate of 2 '-Difluoronucleosides preparation and preparation method thereof.
The present invention relates to 1-(2 '-deoxidation-2 ', 2 '-two fluoro-D-the ribofuranosyls)-4-aminopyrimidine-2-ketone represented by following Chemical formula 1 or the preparation method of its hydrochloride.
[Chemical formula 1]
Specifically, the present invention relates to the Ji Xita pyridine represented by above-mentioned Chemical formula 1 or the preparation method of its hydrochloride, it is characterized in that this method comprises:
(1) will be by following Chemical formula 2 carbohydrate of representing of having protected and the alkali reaction of representing by following chemical formula 3, preparation is by the step of the compound of following chemical formula 4 expressions;
(2) will carry out the step of deprotection by the hydroxyl protecting group of the compound of following chemical formula 4 expressions.
[Chemical formula 2]
[chemical formula 3]
[chemical formula 4]
In the present invention, the compound of being represented by above-mentioned chemical formula 4 is new midbody compound, can be used as useful as intermediates.
In above-mentioned (1) step, behind Chemical formula 2 carbohydrate of representing of having protected and the alkali reaction of being represented by chemical formula 3, suitable organic solvent and the aqueous acid of the reaction mixture utilization that obtains handled, and is separated into β-one-tenth glycosides isomer compound.Specifically, this method also comprise be dissolved in reaction mixture in the Virahol after, add Hydrogen bromide (HBr) aqueous solution and carry out crystallization, separate step by the β-one-tenth glycosides isomer compound of chemical formula 4 expressions.
The present invention also comprises the pure state β-one-tenth glycosides isomer Ji Xita pyridine represented by Chemical formula 1 or the preparation method of its hydrochloride.
The invention provides 1-(the 2 '-deoxidation-2 ' represented by above-mentioned Chemical formula 1 that realizes industrial production, 2 '-two fluoro-D-ribofuranosyls)-preparation method of 4-aminopyrimidine-2-ketone or its hydrochloride, and provide the Stereoselective of realizing industrial production to prepare the method for the β-one-tenth glycosides isomer of 1-(2 '-deoxidation-2 ', 2 '-two fluoro-D-ribofuranosyls)-4-aminopyrimidine-2-ketone.
Embodiment
The preparation method of the compound of being represented by above-mentioned Chemical formula 1 is described in detail as follows more by each step.
At first, will stir 1～2 hour 120～140 ℃ of temperature ranges by the compound of above-mentioned chemical formula 3 expressions and the mixture of ammonium sulfate and hexamethyl silazane.1-methyl sulphonyl-the 2 '-deoxidation-2 ' of protecting hydroxyl that to represent by Chemical formula 2; 2 '-two fluoro-D-ribofuranose radical derivatives slowly divide and join several times in the above-mentioned reaction mixture; afterwards after 120～140 ℃ of temperature ranges stir 1～4 hour, concentrating under reduced pressure.Reaction can be carried out in organic solvent, also can carry out in the presence of the organic solvent not having, and organic solvent can use methylene dichloride, acetonitrile, methyl-phenoxide etc.
In the reaction mixture that obtains, add Virahol, and after slowly adding aqueous acid, stirred 30 minutes to 2 hours 70～80 ℃ of temperature ranges.Preferred hydrochloric acid or the Hydrogen bromide (HBr) of using of acid, working concentration is 1～6 mol (N), preferably uses 4～5 mol concentration.
Then, temperature is reduced to 10 ℃, filters, and with distilled water and washed with isopropyl alcohol.In the solids that filtration obtains, add aqueous acid once more, after the stirring, reduce temperature, filter, with distilled water and washed with isopropyl alcohol after drying.
Exsiccant is filtered the solids obtain is dissolved in the methyl alcohol, add 30% ammonium hydroxide after, stir drying under reduced pressure after 10 minutes.After being dissolved in reactant in the ethyl acetate fully, the dried over sodium sulfate after-filtration is used in water and salt solution washing.With filtrate decompression distill a certain amount of after, reduce temperature, filter.The solids that filtration obtains washs with ethyl acetate, and drying obtains the compound by chemical formula 4 expressions.
After will using US 5223608 disclosed technology to carry out deprotection by the hydroxyl protecting group of the compound of chemical formula 4 expression, can prepare the compound or its salt phosphate compounds of representing by Chemical formula 1.
After the compound dissolution of chemical formula 4 expression is in methanol solvate, add solution of ammonium hydroxide, at room temperature stirred 3 hours.After removing solvent under reduced pressure, add distilled water, after ethyl acetate solution washing 2～3 times, with the water layer underpressure distillation.
Then, add ethanol and carry out heat filtering (hot filtration).After adding concentrated hydrochloric acid and stirring in the filtrate, filter, obtain the hydrochloride compound of representing by Chemical formula 1.
The compound of being represented by Chemical formula 2 that uses among the present invention prepares by following reaction formula 1.
[reaction formula 1]
Above-mentioned graphic in, P represents 3-fluorobenzoyl protecting group, L represents methyl sulphonyl.
In addition, the invention still further relates to the preparation method of the compound of being represented by above-mentioned Chemical formula 2, it is characterized in that, this method comprises:
(1) will be hydrolyzed by the compound of above-mentioned chemical formula 5 expressions after, with the water component distillation, the step that lactonizes;
(2) hydroxyl with lactone compound utilizes the protection of 3-fluoro benzoyl, and preparation is by the step of the compound of above-mentioned chemical formula 6 expressions;
(3) will be reduced by Sauerstoffatom on the ketone group of the compound of chemical formula 6 expression, preparation is by the step of the compound of above-mentioned chemical formula 7 expressions;
(4) will introduce the step of leavings group by the compound and the Methanesulfonyl chloride reaction of chemical formula 7 expressions.
Among the present invention, provide as new midbody compound by erythro enantiomorph (erythro enantiomer) compound of chemical formula 6 expressions with by the compound that Chemical formula 2 is represented.
The preparation method of the compound of being represented by above-mentioned Chemical formula 2 specifies as follows by each step more.
At first, after will being hydrolyzed by the compound of chemical formula 5 expressions, with the water component distillation, with 3-fluorobenzoyl protecting group protection hydroxyl, preparation is by the compound of chemical formula 6 expressions.Use gentle hydrolysing agent during hydrolysis, for example water-soluble acetate, propionic acid, Hydrogen bromide (HBr), Mono Chloro Acetic Acid or oxalic acid are used for hydrolysis.Appropriate solvent has methyl alcohol, ethanol, Virahol isopolarity solvent, acetonitrile, aromatic solvent (toluene).
Before Sauerstoffatom on the reduction ketone group, preferably protect the hydroxyl of lactone with 3-fluorobenzoyl protecting group.Protective reaction is to carry out in basic solvents such as pyridine or lutidine, can use 4-dimethylamino pyridine or 4-pyrrolidyl pyridine acylation catalysts such as (pyrrolidinopyridine) in the reaction.Acylation reaction is to carry out-25～100 ℃ of temperature ranges, with acylation reactions such as 3-fluorobenzoyl chloride, 3-fluorobenzoyl bromines.
In addition, the invention provides the method for optionally separating the erythro enantiomorph of representing by chemical formula 6 reaction mixture that after protecting, obtains with the 3-fluoro benzoyl.After will being dissolved in the ethyl acetate with the reaction mixture that obtains after the protection of 3-fluoro benzoyl, slowly add hexane, cooling separates the erythro enantiomorph by chemical formula 6 expressions.
To become alcohol by hydrogen reduction on the ketone group of the compound of chemical formula 6 expression, generate compound by chemical formula 7 expressions.Reductive agent can use lithium tri-t-butoxyaluminium hydride, reduces 0 ℃ to-10 ℃ temperature range under tetrahydrofuran solvent.
In order will effectively to react, introduce leavings group by the compound and the alkali of chemical formula 7 expressions.Can use alkyl sulphonyl as leavings group, preferably use methyl sulphonyl.In the presence of suitable sour remover such as Trimethylamine 99, triethylamine, tripropyl amine, Tributylamine, will be by the compound and the alkyl sulphonyl halide reaction of chemical formula 7 expressions, the compound that preparation is represented by Chemical formula 2.Reaction solvent can use methylene dichloride, acetone, toluene, tetrahydrofuran (THF), chloroform, reacts 0～30 ℃ of temperature range.
Aforesaid the present invention describes in detail more according to the following examples, but the present invention is not limited to these.
Embodiment 1
2-deoxidation-2,2-two fluoro-D-are red-penta furanose-1-glycosides base-3, the preparation of 5-two (3 '-fluorobenzoic acid ester)
In 70 milliliters of acetonitriles, add 2 of 13 grams, after the dissolving of 2-two fluoro-3-hydroxyl-3-(2,2-dimethyl-1,3-two oxa-s penta ring-4-yl) ethyl propionate, add 5 milliliters of Purified Waters and 0.46 gram acetate, stirred 4～5 hours at reflux temperature (about 78 ℃).100 milliliters of toluene are bit by bit added, and are that solvent is eliminated in air distillation under certain condition keeping solvent volume.After reaction finished, concentrating under reduced pressure added new 20 milliliters of toluene, concentrating under reduced pressure once more.After in concentrated solution, adding 70 milliliters of acetic acid ethyl dissolutions, add the gac of 1.3 grams and the sodium sulfate of 25 grams, stirred 10 minutes.Behind the filtering reacting liquid, with 30 milliliters of ethyl acetate washings.Filtrate is cooled to 0～5 ℃, behind the 3-fluorobenzoyl chlorides of adding 16.2 grams and the dimethylamino pyridines of 1.25 grams, adds the pyridines of 12.2 grams.Reaction mixture is heated to about 60 ℃, stirred 12 hours.Reaction solution is cooled to normal temperature, washs with the hydrochloric acid soln of 100 milliliters 2 mol, 100 milliliters water, 10 milliliters sodium bicarbonate aqueous solution, 100 milliliters saturated nacl aqueous solution successively.After organic layer dried over sodium sulfate, the filtration,, filtrate decompression is concentrated with 30 milliliters of ethyl acetate washings.After being dissolved in concentrated solution in 20 milliliters of ethyl acetate, slowly add 30～40 milliliters of hexanes at about 25 ℃, cooling was stirred 1 hour at 0～3 ℃.The crystal that filter to generate with 30 milliliters ethyl acetate/hexane mixing solutions thorough washing, drying being cooled to 0 ℃, obtains the 2-deoxidations-2 of 7.3 grams, and 2-two fluoro-D-are red-penta furanose-1-glycosides base-3,5-two (3 '-fluorobenzoic acid ester).
1H NMR (CDCl
3); δ=4.49,4.56 (multiplet, 2H), 5.48 (quartet, 1H), 5.10 (multiplet, 1H), 7.17 to 7.76 (wide multiplet, 8H)
Embodiment 2
2-deoxidation-2,2-two fluoro-D-ribofuranosyls-3, the preparation of 5-two (3 '-fluorobenzoic acid ester)
With the 2-deoxidation-2 that obtains among the embodiment 1 of 7.3 grams, 2-two fluoro-D-are red-penta furanose-1-glycosides base-3, after 5-two-3 '-fluorobenzoic acid ester is dissolved in 60 milliliters of tetrahydrofuran (THF)s, be cooled to 0 ℃ to-5 ℃.After adding the lithium tri-t-butoxyaluminium hydride of 5.4 grams, and under temperature, stirred 1 hour.After reaction finishes, add hydrochloric acid soln and 80 milliliters of ethyl acetate of 100 milliliter of 2 mol, carry out layering.Organic layer is used 150 ml waters and 100 milliliters of saturated common salt water washings respectively.After 30 dried over sodium sulfate that restrain, filtration, filtrate decompression is concentrated, obtain the 2-deoxidations-2 of 7.3 required grams, 2-two fluoro-D-ribofuranosyls-3,5-two (3 '-fluorobenzoic acid ester).
1H NMR (CDCl
3); δ=2.0 (wide multiplet, 1H), 4.49,4.56 (multiplet, 2H), 5.48 (quartet, 1H), 5.10 (multiplet, 1H), 6.20 (doublet, 1H), 7.17 to 7.76 (wide multiplet, 8H)
Embodiment 3
2-deoxidation-2,2-two fluoro-D-ribofuranosyls-3, the preparation of two (3 '-fluoro benzoyl)-1-methanesulfonate esters of 5-
The 2-deoxidation-2 that obtains among the embodiment 2 with 7.3 grams, 2-two fluoro-D-ribofuranosyls-3 after 5-two (3 '-fluorobenzoic acid ester) is dissolved in 80 milliliters of methylene dichloride, add 3.95 milliliters of triethylamines.Slowly cool off one side in the reaction solution on one side and slowly add 1.75 milliliters of Methanesulfonyl chlorides, stirred 3 hours.After reaction finishes, slowly add the hydrochloric acid soln of 80 milliliter of 1 mol, carry out layering.Organic layer is used 80 ml waters, 15 milliliters of saturated sodium bicarbonates, 70 milliliters of saturated common salt water washings respectively.After organic layer dried over sodium sulfate, filtration, filtrate decompression is concentrated, obtain the 2-deoxidations-2 of 9.3 required grams, 2-two fluoro-D-ribofuranosyls-3, two (3 '-fluoro benzoyl)-1-methanesulfonate esters of 5-.
1H NMR (CDCl
3); δ=2.94 (unimodal, 3H), 4.45 to 4.38 (multiplet, 2H), 4.85 (multiplet, 2H), 6.20 (doublet, 1H), 7.20 to 7.75 (multiplet, 8H)
Embodiment 4
1-(2-oxo-4-amino-1H-pyrimidine-1-yl)-3 ', 5 '-two (3-fluoro benzoyl)-2 '-deoxidation-2 ', the preparation of 2 '-difluoro ribofuranose
In 100 milliliters of hexamethyl silazane, add the cytosine (cytosine) of 19.7 grams and the ammonium sulfate of 2.34 grams, reflux at about 125 ℃ and stir.After confirming reactants dissolved, further reflux and stir after 1 hour, slowly add the 2-deoxidation-2 that obtains among the embodiment 3 several times with 2 little time-divisions, 2-two fluoro-D-ribofuranosyls-3, two (3 '-fluoro benzoyl)-1-methanesulfonate esters of 5-continue stirring 2 hours.After reaction finishes, with the reactant concentrating under reduced pressure, be cooled to 40 ℃ after, the HBr solution of 22 milliliters of Virahols and 200 milliliter of 4.4 mol is slowly added.The temperature of reactant is risen to 70 ℃, stir after 1 hour, be cooled to 10 ℃, filter the crystal that generates.After crystal used 200 milliliters of Purified Waters and 22 milliliters of washed with isopropyl alcohol respectively, join and obtain outstanding turbidly in the HBr solution of 70 milliliter of 4.4 mol, stirred 1 hour at 70 ℃ afterwards.After reaction solution is cooled to 60 ℃, filter, with 90 milliliters of Purified Waters, 22 milliliters of washed with isopropyl alcohol, with the crystal drying that obtains.The exsiccant crystal is joined in 80 ml methanol, be heated to more than 40 ℃, fully dissolving.At 25～30 ℃ of 30% ammoniacal liquor that add 0.85 milliliter, stir after 10 minutes concentrating under reduced pressure.In the enriched material residue, add 150 milliliters of ethyl acetate, after the heating for dissolving, use the washing of 150 milliliters of warm water (about 32 ℃) and 80 milliliters of saturated aqueous common salts (about 32 ℃) respectively, carry out layering.In organic layer, add sodium sulfate, after the filtration, filtrate decompression is concentrated into till about 20 milliliters, be cooled to 5 ℃.Filter the gained crystal,, obtain 1-(2-oxo-4-amino-1H-pyrimidine-1-yl)-3 ', 5 '-two (3-fluoro benzoyl)-the 2 '-deoxidation-2 ' of 1.79 required grams, 2 '-difluoro ribofuranose with 20 milliliters of ethyl acetate washings, drying.
1H NMR (CDCl
3); δ=4.80 (multiplet, 2H), 5.20 (multiplet, 1H), 5.93 to 6.01 (multiplet, 2H), 6.65 (triplet, 1H), 7.62 to 7.78 (wide multiplet, 3H)
Embodiment 5
The preparation of Ji Xita thiamine hydrochloride
1-(2-oxo-4-amino-1H-pyrimidine-1-yl)-3 ', 5 '-two (3-fluoro benzoyl)-the 2 '-deoxidation-2 ' that obtains among the embodiment 4 with 1.79 grams, 2 '-difluoro ribofuranose joins in 20 ml methanol, and adds 0.75 milliliter 30% ammoniacal liquor.20～25 ℃ of stirring underpressure distillation after 3 hours.Add 20 ml waters and 10 milliliters of ethyl acetate, carry out layer and separate, water layer is washed the back underpressure distillation with 10 milliliters of ethyl acetate.After adding 30 milliliters of ethanol, reflux and stirred 1 hour, keep carrying out heat filtering (hot filter) under 70 ℃ of temperature, remove solid.Add 2 milliliters of concentrated hydrochloric acids, stir after 30 minutes, cooling is filtered.The solid that generates obtains 0.9 target compound that restrains with 10 milliliters of washing with alcohol and dry.
1H NMR (CDCl
3); δ=3.81 (triplet, 2H), 3.93 (doublet, 1H), 4.23 (triplet, 1H), 4.80 (doublet, 2H), 6.08 (doublet, 1H), 6.32 (doublet, 1H), 8.21 (doublet, 1H), 9.3 (unimodal, 1H), 10.17 (unimodal, 1H).
Claims (6)
1. the preparation method of a Ji Xita pyridine of being represented by Chemical formula 1 is characterized in that this method comprises:
(1) will be by following Chemical formula 2 carbohydrate of representing of having protected and the alkali reaction of representing by following chemical formula 3, preparation is by the step of the compound of following chemical formula 4 expressions;
(2) will carry out the step of deprotection by the hydroxyl protecting group of the compound of following chemical formula 4 expressions,
[Chemical formula 1]
[Chemical formula 2]
Ms represents methyl sulphonyl in the above-mentioned formula 2,
[chemical formula 3]
[chemical formula 4]
2. the preparation method of the Ji Xita pyridine of representing by Chemical formula 1 according to claim 1; it is characterized in that; this method also comprises: in described step (1); behind Chemical formula 2 carbohydrate of representing of having protected and the alkali reaction of representing by chemical formula 3; with the compound dissolution that obtains in Virahol; add aqueous acid then and carry out crystallization, separate step by the compound of chemical formula 4 expressions.
3. the preparation method of the Ji Xita pyridine of being represented by Chemical formula 1 according to claim 1 is characterized in that the compound of being represented by Chemical formula 2 makes by following steps:
(1) will be hydrolyzed by the compound of following chemical formula 5 expressions after, with the water component distillation, the step that lactonizes;
(2) hydroxyl with lactone compound utilizes the 3-fluoro benzoyl to protect, and preparation is by the step of the compound of following chemical formula 6 expressions;
(3) will be reduced by the Sauerstoffatom on the ketone group of the compound of following chemical formula 6 expressions, preparation is by the step of the compound of following chemical formula 7 expressions;
(4) will introduce the step of leavings group by the compound and the Methanesulfonyl chloride reaction of following chemical formula 7 expressions,
[chemical formula 5]
[chemical formula 6]
[chemical formula 7]
[Chemical formula 2]
Ms represents methyl sulphonyl in the above-mentioned formula 2.
4. the preparation method of the Ji Xita pyridine of being represented by Chemical formula 1 according to claim 3 is characterized in that the hydrolytic reagent in the step (1) is acetate, propionic acid, Hydrogen bromide, Mono Chloro Acetic Acid or oxalic acid.
5. the preparation method of the Ji Xita pyridine of representing by Chemical formula 1 according to claim 3; it is characterized in that; this method also comprises; after the reaction mixture that will obtain after will protecting with the 3-fluoro benzoyl the hydroxyl of the lactone compound in the step (2) is dissolved in the ethyl acetate solvent; slowly add hexane, separate step by the erythro enantiomeric compounds of chemical formula 6 expressions.
6. compound by 4 expressions of following chemical formula:
[chemical formula 4]
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| KR1020050123493A KR101259637B1 (en) | 2005-12-14 | 2005-12-14 | A process of 1-(2´-Deoxy-2´,2´-difluoro-D-ribofuranosyl)-4-aminopyrimidin-2-on or thereof HCl salt |
| KR1020050123493 | 2005-12-14 | ||
| KR10-2005-0123493 | 2005-12-14 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4562988A (en) * | 1984-06-27 | 1986-01-07 | Northern Telecom Limited | Video display mounting mechanism providing pivoting and tilting of the display |
| EP0727433B1 (en) * | 1995-02-03 | 2001-03-14 | Eli Lilly And Company | Process for the preparation of 1-(2'-deoxy-2',2'-difluoro-d-ribo-pentofuranosyl)-cytosine from 2-deoxy-2,2-difluoro-beta-d-ribo-pentopyranose |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5223608A (en) * | 1987-08-28 | 1993-06-29 | Eli Lilly And Company | Process for and intermediates of 2',2'-difluoronucleosides |
| US5637688A (en) * | 1994-12-13 | 1997-06-10 | Eli Lilly And Company | Process for preparing 1-(2'-deoxy-2'-difluoro-d-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride |
-
2005
- 2005-12-14 KR KR1020050123493A patent/KR101259637B1/en not_active IP Right Cessation
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4562988A (en) * | 1984-06-27 | 1986-01-07 | Northern Telecom Limited | Video display mounting mechanism providing pivoting and tilting of the display |
| EP0727433B1 (en) * | 1995-02-03 | 2001-03-14 | Eli Lilly And Company | Process for the preparation of 1-(2'-deoxy-2',2'-difluoro-d-ribo-pentofuranosyl)-cytosine from 2-deoxy-2,2-difluoro-beta-d-ribo-pentopyranose |
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