WO2008144980A1 - Procédé de préparation et intermédiaires de la capécitabine - Google Patents
Procédé de préparation et intermédiaires de la capécitabine Download PDFInfo
- Publication number
- WO2008144980A1 WO2008144980A1 PCT/CN2007/070051 CN2007070051W WO2008144980A1 WO 2008144980 A1 WO2008144980 A1 WO 2008144980A1 CN 2007070051 W CN2007070051 W CN 2007070051W WO 2008144980 A1 WO2008144980 A1 WO 2008144980A1
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- WIPO (PCT)
- Prior art keywords
- formula
- deoxyfluorocytidine
- derivative
- preparation
- reaction
- Prior art date
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- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 title claims abstract description 26
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 229960004117 capecitabine Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000000543 intermediate Substances 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical class C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 150000001555 benzenes Chemical group 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 230000002378 acidificating effect Effects 0.000 claims description 10
- 150000001299 aldehydes Chemical class 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 150000002576 ketones Chemical class 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 7
- 238000006482 condensation reaction Methods 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims 1
- 239000003377 acid catalyst Substances 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 239000007858 starting material Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 abstract 1
- 229950005454 doxifluridine Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000000203 mixture Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000003032 molecular docking Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- VVFUURQYZOTWKS-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) pentyl carbonate Chemical compound CCCCCOC(=O)ON1C(=O)CCC1=O VVFUURQYZOTWKS-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 description 1
- YSNABXSEHNLERR-ZIYNGMLESA-N 5'-Deoxy-5-fluorocytidine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)N=C(N)C(F)=C1 YSNABXSEHNLERR-ZIYNGMLESA-N 0.000 description 1
- ICBBLGSFZYLZQK-UHFFFAOYSA-N C(OC1=C(C=CC=C1)[N+](=O)[O-])(OCCCCC)=O Chemical compound C(OC1=C(C=CC=C1)[N+](=O)[O-])(OCCCCC)=O ICBBLGSFZYLZQK-UHFFFAOYSA-N 0.000 description 1
- AYYYEWLZYOERAD-UHFFFAOYSA-N CN(C)C1=NC=CC=C1.NN Chemical compound CN(C)C1=NC=CC=C1.NN AYYYEWLZYOERAD-UHFFFAOYSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- NYRVXYOKUZSUDA-UHFFFAOYSA-N [dimethoxy(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(OC)(OC)C1=CC=CC=C1 NYRVXYOKUZSUDA-UHFFFAOYSA-N 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical class 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
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960004413 flucytosine Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 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
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- XHRRYUDVWPPWIP-UHFFFAOYSA-N pentyl carbonochloridate Chemical compound CCCCCOC(Cl)=O XHRRYUDVWPPWIP-UHFFFAOYSA-N 0.000 description 1
- -1 phosphorus fluorouridine derivative Chemical class 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000002023 wood Substances 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
- 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
Definitions
- the invention relates to a process for preparing capecitabine and an intermediate thereof. Background technique
- Capec i tabine is a prodrug of 5-fluorouracil that has a selective effect on tumor cells and can be used as an oral cytotoxic agent.
- Capecitabine itself is not cytotoxic, but can be converted to cytotoxic 5-fluorouracil in three steps by the action of enzymes in the body. Enzymes associated with the metabolism of capecitabine are higher in tumor tissues than in normal tissues, giving them selective cytotoxicity against tumor cells. Its
- the structure is as follows: .
- the currently reported synthesis methods of capecitabine mainly include the following:
- the present invention provides a novel capecitabine synthesis route for preparing capecitabine from deoxy fluorouridine.
- the present invention provides a compound, a deoxyfluorouridine derivative, as shown in formula (I):
- ⁇ is selected from a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, a benzene ring or a substituted benzene ring; and R 2 may be selected from a hydrogen atom and containing 1 to 8 a linear or branched alkyl group of a carbon atom, a benzene ring or a substituted benzene ring.
- the present invention also provides a process for preparing a deoxyfluorouridine derivative of the formula (I), which comprises a condensation reaction of deoxyfluorouridine with an aldehyde or a ketone in the presence of an acidic catalyst to obtain a formula (I).
- Oxyfluorouridine derivatives are also provided.
- the present invention provides a compound, a deoxyfluorocytidine derivative, as shown in formula (II):
- ⁇ may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring; and R 2 may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring.
- the present invention also provides a method for preparing a deoxyfluorocytidine derivative represented by the formula (II), which is obtained by reacting a deoxyfluorouridine derivative represented by the formula (I) with phosphorus oxychloride, an organic alkali or ammonia water.
- (II) Deoxyfluorocytidine derivative shown.
- the present invention provides a deoxyfluorocytidine derivative, as shown by the formula (in):
- ⁇ may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring; and R 2 may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring.
- the present invention also provides a process for preparing a deoxyfluorocytidine derivative represented by the formula (in), which comprises reacting a deoxyfluorocytidine derivative represented by the formula (II) with a compound represented by the formula (IV) to obtain a formula ( III) Deoxyfluorocytidine derivative as shown.
- the present invention also provides a process for the preparation of capecitabine which is obtained by deamination of a hydroxy protecting group under acidic conditions with a deoxyfluorocytidine derivative of the formula (in) to give capecitabine.
- the deoxyfluorocytidine derivative represented by the formula (III) is reacted with a compound represented by the formula (IV) by a deoxyfluorocytidine derivative represented by the formula (II) to obtain a deoxyfluoride cell represented by the formula (III). Glycoside derivatives.
- the deoxyfluorocytidine derivative represented by the formula (II) is reacted with a phosphorus fluorouridine derivative represented by the formula (I), phosphorus oxychloride, an organic alkali or ammonia water to obtain a deoxyfluoride represented by the formula (II). Cytidine derivatives.
- deoxyfluorouridine derivative of the formula (I) is subjected to a condensation reaction of deoxy fluorouridine with an aldehyde or a ketone in the presence of an acidic catalyst to obtain a deoxyfluorouridine derivative of the formula (I).
- the specific steps of the above method are as follows:
- the condensation reaction of deoxy fluorouridine with different aldehydes or ketones gives the deoxyfluorouridine derivative of formula (I), and then reacts with phosphorus oxychloride, organic alkali, and ammonia to obtain formula (II).
- the deoxyfluorocytidine derivative is acylated with an acylating reagent of the formula (IV) to obtain a deoxyfluorocytidine derivative of the formula (III), and finally the hydroxy protecting group is removed under acidic conditions. Capecitabine.
- the condensation reaction of deoxy fluorouridine with an aldehyde or a ketone may be carried out in a mixed solvent of toluene, benzene, acetone, tetrahydrofuran, dichloromethane or dichloroethane of an acidic catalyst or any ratio thereof. get on.
- the acidic catalyst may be selected from the group consisting of p-toluenesulfonic acid, zinc chloride, and tin chloride.
- the reaction temperature can be varied within a wide range, generally -2 ⁇ rC - 120 ° C, preferably 80 ° C - 120 ° C, and the molar ratio of deoxy fluorouridine to aldehyde or ketone is 1: 1-1: 2.
- the reaction of the deoxyfluorouridine derivative of the formula (I) with phosphorus oxychloride, an organic base, and aqueous ammonia can be carried out in a mixed solvent of acetonitrile or another water-miscible aprotic solvent.
- the reaction temperature is -io°c -
- the deoxyfluorocytidine derivative represented by the formula (II) and the acylating reagent represented by the formula (IV) can be carried out in an acetonitrile or other aprotic solvent to which a basic catalyst is added.
- the basic catalyst can be
- the inorganic base or organic base may be specifically selected from the group consisting of potassium carbonate, triethylamine, and pyridine.
- the reaction temperature is -io°c-
- the molar ratio of the deoxyfluorocytidine derivative represented by the formula (II) to the acylating reagent represented by the formula (IV) is 1:1.1-1:3, preferably 1:1.1-1:2.
- the deprotected group of the deoxyfluorocytidine derivative represented by the formula (III) is obtained by reacting capecitabine, and can be carried out in an aqueous solution of a protic acid, or in an alcohol solution of a protic acid or an ether solution. It can also be carried out in a solution of an aprotic acid. It is preferably carried out in an alcohol solution of a protic acid.
- the method uses the deoxy fluorouridine determined by the configuration as a raw material, and after three steps of reaction, capecitabine is obtained, and the synthetic route is short, and the formation of stereoisomers is avoided. It has been proved by experiments that the yield of the method is high, the process is easy to control, and the product quality is stable. Specific implementation method:
- the invention is further illustrated by the following examples, which are merely used to illustrate the preferred embodiments of the invention, and are not intended to limit the invention.
- the technical solutions of the present invention described above are all technical solutions for achieving the object of the present invention. That is, the temperatures and reagents used in the following examples can be replaced with the corresponding temperatures and reagents described above to achieve the objects of the present invention.
- Example 12 6.0 g of Ila was dissolved in 40 ml of acetonitrile, 6.78 g (26.8 mmol) of nitrophenyl n-pentyl carbonate and 3.7 g (26.8 ol) of potassium carbonate were added, and the mixture was stirred at room temperature for 24 hours, filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed twice with 1N EtOAc EtOAc (EtOAc)EtOAc. The step yield was 62%.
- the capecitabine was obtained in the same manner as in Example 17 using IIIb, IIIc or Illd as the starting materials, respectively.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne le procédé de préparation ainsi que des intermédiaires de la capécitabine. La présente invention concerne une nouvelle voie de synthèse de la capécitabine, dans laquelle de la doxifluridine est utilisée en tant que produit de départ et la capécitabine est obtenue à travers trois étapes de réaction. La présente invention concerne également les intermédiaires utilisés dans ladite voie de synthèse. La voie de synthèse est courte, ce qui permet d'éviter la production de stéréoisomères. Le procédé est caractérisé par un rendement élevé, le processus technique est facile à contoler et la qualité des produits est stable.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2007/070051 WO2008144980A1 (fr) | 2007-05-25 | 2007-05-25 | Procédé de préparation et intermédiaires de la capécitabine |
CN200780052717.9A CN101657462B (zh) | 2007-05-25 | 2007-05-25 | 卡培他滨的制备方法及其中间体 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2007/070051 WO2008144980A1 (fr) | 2007-05-25 | 2007-05-25 | Procédé de préparation et intermédiaires de la capécitabine |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2008144980A1 true WO2008144980A1 (fr) | 2008-12-04 |
Family
ID=40316812
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2007/070051 WO2008144980A1 (fr) | 2007-05-25 | 2007-05-25 | Procédé de préparation et intermédiaires de la capécitabine |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN101657462B (fr) |
WO (1) | WO2008144980A1 (fr) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009094847A1 (fr) * | 2007-12-28 | 2009-08-06 | Topharman Shanghai Co., Ltd. | Dérivé hydroxyle de capécitabine, procédés de préparation et d' utilisation de la capécitabine |
CN101845070A (zh) * | 2010-05-25 | 2010-09-29 | 郑州大学 | 抗肿瘤药物卡培他滨的合成方法 |
WO2011067588A1 (fr) | 2009-12-04 | 2011-06-09 | Generics [Uk] Limited | Esters sulfinyle cycliques de cytidine |
WO2011104540A1 (fr) | 2010-02-24 | 2011-09-01 | Generics [Uk] Limited | Procédé en une étape pour la préparation de la capécitabine |
CN103113441A (zh) * | 2013-03-13 | 2013-05-22 | 上海龙翔生物医药开发有限公司 | 一种制备卡培他滨的方法 |
CN101469008B (zh) * | 2007-12-29 | 2013-08-07 | 上海特化医药科技有限公司 | 卡培他滨羟基衍生物、其制备方法和用于制备卡培他滨 |
CN104478975A (zh) * | 2014-11-24 | 2015-04-01 | 苏州乔纳森新材料科技有限公司 | 一种卡培他滨的合成方法 |
CN106699825A (zh) * | 2016-12-01 | 2017-05-24 | 齐鲁天和惠世制药有限公司 | 一种以卡培他滨废水提取物制备卡培他滨的方法 |
CN103897005B (zh) * | 2012-12-27 | 2017-07-28 | 鲁南制药集团股份有限公司 | 一种连续操作合成卡培他滨的方法 |
WO2019143860A1 (fr) * | 2018-01-19 | 2019-07-25 | Nucorion Pharmaceuticals, Inc. | Composés de 5-fluorouracile |
US10435429B2 (en) | 2017-10-03 | 2019-10-08 | Nucorion Pharmaceuticals, Inc. | 5-fluorouridine monophosphate cyclic triester compounds |
EP3950673A1 (fr) | 2014-04-30 | 2022-02-09 | Inspirna, Inc. | Inhibiteurs de transport de créatine et leurs utilisations |
US11427550B2 (en) | 2018-01-19 | 2022-08-30 | Nucorion Pharmaceuticals, Inc. | 5-fluorouracil compounds |
US11566041B2 (en) | 2020-04-21 | 2023-01-31 | Ligand Pharmaceuticals, Inc. | Nucleotide prodrug compounds |
US12110311B2 (en) | 2019-07-17 | 2024-10-08 | Nucorion Pharmaceuticals, Inc. | Cyclic deoxyribonucleotide compounds |
US12110308B2 (en) | 2018-01-10 | 2024-10-08 | Nucorion Pharmaceuticals, Inc. | Phosphor(n)amidatacetal and phosph(on)atalcetal compounds |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114644666A (zh) * | 2020-12-18 | 2022-06-21 | 上海特化医药科技有限公司 | 5’-核苷前药的制备方法及中间体 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5530110A (en) * | 1993-02-23 | 1996-06-25 | City Of Hope | 4-ethoxy-5-fluoro-2'-deoxyuridine |
US6310039B1 (en) * | 1996-09-11 | 2001-10-30 | Felix Kratz | Antineoplastic conjugates of transferrin, albumin and polyethylene glycol |
CN1935828A (zh) * | 2006-10-31 | 2007-03-28 | 浙江海正药业股份有限公司 | 一种含氟嘧啶类化合物烷氧羰酰化的方法 |
-
2007
- 2007-05-25 WO PCT/CN2007/070051 patent/WO2008144980A1/fr active Application Filing
- 2007-05-25 CN CN200780052717.9A patent/CN101657462B/zh not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5530110A (en) * | 1993-02-23 | 1996-06-25 | City Of Hope | 4-ethoxy-5-fluoro-2'-deoxyuridine |
US6310039B1 (en) * | 1996-09-11 | 2001-10-30 | Felix Kratz | Antineoplastic conjugates of transferrin, albumin and polyethylene glycol |
CN1935828A (zh) * | 2006-10-31 | 2007-03-28 | 浙江海正药业股份有限公司 | 一种含氟嘧啶类化合物烷氧羰酰化的方法 |
Non-Patent Citations (3)
Title |
---|
DATABASE CHEMICAL ABSTRACTS [online] Database accession no. (128:213389) * |
DONG H. ET AL.: "Improved process for the synthesis of Doxifluridine", ZHONGGUO YIYAO GONGYE ZAZHI, vol. 33, no. 3, pages 108 - 109 * |
YU J. ET AL.: "Improved synthesis of anticancer drug capecitabine", ZHONGGUO YAOWU HUAXUE ZAZHI, vol. 15, no. 3, June 2005 (2005-06-01), pages 173 - 175, 187 * |
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WO2009094847A1 (fr) * | 2007-12-28 | 2009-08-06 | Topharman Shanghai Co., Ltd. | Dérivé hydroxyle de capécitabine, procédés de préparation et d' utilisation de la capécitabine |
CN101469008B (zh) * | 2007-12-29 | 2013-08-07 | 上海特化医药科技有限公司 | 卡培他滨羟基衍生物、其制备方法和用于制备卡培他滨 |
WO2011067588A1 (fr) | 2009-12-04 | 2011-06-09 | Generics [Uk] Limited | Esters sulfinyle cycliques de cytidine |
WO2011104540A1 (fr) | 2010-02-24 | 2011-09-01 | Generics [Uk] Limited | Procédé en une étape pour la préparation de la capécitabine |
CN101845070A (zh) * | 2010-05-25 | 2010-09-29 | 郑州大学 | 抗肿瘤药物卡培他滨的合成方法 |
CN101845070B (zh) * | 2010-05-25 | 2012-05-16 | 郑州大学 | 抗肿瘤药物卡培他滨的合成方法 |
CN103897005B (zh) * | 2012-12-27 | 2017-07-28 | 鲁南制药集团股份有限公司 | 一种连续操作合成卡培他滨的方法 |
CN103113441A (zh) * | 2013-03-13 | 2013-05-22 | 上海龙翔生物医药开发有限公司 | 一种制备卡培他滨的方法 |
EP3950673A1 (fr) | 2014-04-30 | 2022-02-09 | Inspirna, Inc. | Inhibiteurs de transport de créatine et leurs utilisations |
CN104478975A (zh) * | 2014-11-24 | 2015-04-01 | 苏州乔纳森新材料科技有限公司 | 一种卡培他滨的合成方法 |
CN106699825A (zh) * | 2016-12-01 | 2017-05-24 | 齐鲁天和惠世制药有限公司 | 一种以卡培他滨废水提取物制备卡培他滨的方法 |
US10435429B2 (en) | 2017-10-03 | 2019-10-08 | Nucorion Pharmaceuticals, Inc. | 5-fluorouridine monophosphate cyclic triester compounds |
US12110308B2 (en) | 2018-01-10 | 2024-10-08 | Nucorion Pharmaceuticals, Inc. | Phosphor(n)amidatacetal and phosph(on)atalcetal compounds |
WO2019143860A1 (fr) * | 2018-01-19 | 2019-07-25 | Nucorion Pharmaceuticals, Inc. | Composés de 5-fluorouracile |
US11427550B2 (en) | 2018-01-19 | 2022-08-30 | Nucorion Pharmaceuticals, Inc. | 5-fluorouracil compounds |
US12110311B2 (en) | 2019-07-17 | 2024-10-08 | Nucorion Pharmaceuticals, Inc. | Cyclic deoxyribonucleotide compounds |
US11566041B2 (en) | 2020-04-21 | 2023-01-31 | Ligand Pharmaceuticals, Inc. | Nucleotide prodrug compounds |
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