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CN101657462B - The preparation method and intermediates of capecitabine - Google Patents

The preparation method and intermediates of capecitabine Download PDF

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CN101657462B
CN101657462B CN200780052717.9A CN200780052717A CN101657462B CN 101657462 B CN101657462 B CN 101657462B CN 200780052717 A CN200780052717 A CN 200780052717A CN 101657462 B CN101657462 B CN 101657462B
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deoxidation
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capecitabine
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CN101657462A (en
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蒋翔锐
欧洋
沈敬山
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Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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    • 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
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Abstract

The present invention relates to the preparation method and intermediates of capecitabine. The present invention provides a new synthesis route for capecitabine, in which doxifluridine is used as the starting material and capecitabine is obtained through three steps of reaction. The present invention also provides the intermediates in the said synthesis route. The synthesis has short route, which can avoid producing stereoisomers. The method has a high yield, the technical process is easy to control and the quality of the products is stable.

Description

The Preparation Method And Their Intermediate of capecitabine
Technical field
The present invention relates to the Preparation Method And Their Intermediate of capecitabine.
Background technology
Capecitabine (Capecitabine) is the prodrug of 5 FU 5 fluorouracil, and tumour cell is had selectively acting, can be used as oral cytotoxicity preparation.
Capecitabine itself is cytotoxicity not, has Cytotoxic 5 FU 5 fluorouracil but be converted into through three steps under the effect of enzyme in vivo.High in concentration compared with normal tissue with capecitabine metabolism involved enzyme in tumor tissues, thus make it have selecting cell toxicity to tumour cell.Its structural formula is as follows:
Figure GPA00000671272000011
The synthetic method of the capecitabine of report mainly comprises following several at present:
1. use the triacetoxyl group ribofuranose of racemization to dock with 5-flurocytosine, then obtain acylate with acyl chloride reaction, then be hydrolyzed and obtain capecitabine (Bioorganic﹠amp; MedicinalChemistry 8,2000,1697-1706)
Figure GPA00000671272000012
2. use 5 '-deoxidation-5-fluoro-cytidine as starting raw material through two acidylate steps, then hydrolysis obtain product (Drug of the Future 21,1996,358-360).
Figure GPA00000671272000021
3. use the pentyloxy formyl chloride as acylating reagent, hydroxyl and amino are carried out acidylate, then selective hydrolysis obtains the finished product (US005476932).
Figure GPA00000671272000022
4. acylated 5-flurocytosine is as raw material in use, and docking reaction then hydrolysis obtains the finished product (CN166089).
Figure GPA00000671272000023
5. use ribose to be raw material, transform through seven steps and obtain final product (Chinese pharmaceutical chemistry magazine, 15,2005,173).
Figure GPA00000671272000024
Summary of the invention
The invention provides a kind of new capecitabine synthetic route, prepare capecitabine take deoxidation fluorouracil glucoside as raw material.
Technical scheme of the present invention is as follows:
The invention provides a kind of compound, the deoxidation fluorouracil glycoside derivates, shown in (I):
(I), wherein, R 1Can be selected from hydrogen atom, contain the phenyl ring of straight or branched alkyl, phenyl ring or the replacement of 1～8 carbon atom; R 2Can be selected from hydrogen atom, contain the phenyl ring of straight or branched alkyl, phenyl ring or the replacement of 1～8 carbon atom.
The present invention also provides the preparation method of deoxidation fluorouracil glycoside derivates shown in formula (I), and the method is carried out condensation reaction with deoxidation fluorouracil glucoside and aldehydes or ketones and obtained deoxidation fluorouracil glycoside derivates shown in formula (I) in the presence of an acidic catalyst.
The invention provides a kind of compound, the deoxidation fluorcytidines, shown in (II):
Figure GPA00000671272000032
(II), wherein, R 1Can be selected from the phenyl ring of hydrogen atom, alkyl, phenyl ring or replacement; R 2Can be selected from the phenyl ring of hydrogen atom, alkyl, phenyl ring or replacement.
The present invention also provides the preparation method of deoxidation fluorcytidines shown in formula (II), and the method obtains deoxidation fluorcytidines shown in formula (II) with deoxidation fluorouracil glycoside derivates shown in formula (I) and phosphorus oxychloride, organic bases, ammoniacal liquor effect.
The invention provides a kind of compound, the deoxidation fluorcytidines, shown in (III):
Figure GPA00000671272000041
(III), wherein, R 1Can be selected from the phenyl ring of hydrogen atom, alkyl, phenyl ring or replacement; R 2Can be selected from the phenyl ring of hydrogen atom, alkyl, phenyl ring or replacement.
The present invention also provides the preparation method of deoxidation fluorcytidines shown in formula (III), and the method is reacted deoxidation fluorcytidines shown in the formula of obtaining (III) with compound shown in deoxidation fluorcytidines shown in formula (II) and formula (IV).
Figure GPA00000671272000042
R is leavings group.Compound shown in formula (IV) is preferably following three kinds:
Figure GPA00000671272000043
The present invention also provides the preparation method of capecitabine, and the method is sloughed hydroxy-protective group with deoxidation fluorcytidines shown in formula (III) and obtained capecitabine under acidic conditions.
Deoxidation fluorcytidines shown in described formula (III) reacts deoxidation fluorcytidines shown in the formula of obtaining (III) with compound shown in deoxidation fluorcytidines shown in formula (II) and formula (IV).
Deoxidation fluorcytidines shown in described formula (II) obtains deoxidation fluorcytidines shown in formula (II) with deoxidation fluorouracil glycoside derivates shown in formula (I) and phosphorus oxychloride, organic bases, ammoniacal liquor effect.
Deoxidation fluorouracil glycoside derivates shown in described formula (I) carries out condensation reaction with deoxidation fluorouracil glucoside and aldehydes or ketones and obtains deoxidation fluorouracil glycoside derivates shown in formula (I) in the presence of an acidic catalyst.
Above method concrete steps are as follows:
Figure GPA00000671272000051
Deoxidation fluorouracil glucoside carries out condensation reaction from different aldehydes or ketones and obtains deoxidation fluorouracil glycoside derivates shown in formula (I); then pass through and phosphorus oxychloride; organic bases; the effect of ammoniacal liquor obtains deoxidation fluorcytidines shown in formula (II); obtain deoxidation fluorcytidines shown in formula (III) with acylating reagent generation acylation reaction shown in formula (IV) again, slough hydroxy-protective group at last under acidic conditions and obtain capecitabine.
In above reaction, the condensation reaction that deoxidation fluorouracil glucoside and aldehydes or ketones carry out can be carried out in arbitrarily than mixed solvent at a kind of of the toluene, benzene, acetone, tetrahydrofuran (THF), methylene dichloride or the ethylene dichloride that add an acidic catalyst or its.Described an acidic catalyst can be selected from tosic acid, zinc chloride, tin chloride.Temperature of reaction can change in the larger context, is generally-20 ℃-120 ℃, and preferred 80 ℃-120 ℃, the molar ratio of deoxidation fluorouracil glucoside and aldehydes or ketones is 1: 1-1: 2.
The reaction of deoxidation fluorouracil glycoside derivates and phosphorus oxychloride, organic bases, ammoniacal liquor shown in formula (I) can be carried out in the aprotic solvent mixed solvent that acetonitrile or other and water dissolve each other.Temperature of reaction is-10 ℃-30 ℃, preferably carries out at-5 ℃-20 ℃.
Acylating reagent shown in deoxidation fluorcytidines shown in formula (II) and formula (IV) can carry out in the acetonitrile that adds basic catalyst or other non-protonic solvents.Described basic catalyst can be mineral alkali or organic bases, specifically can be selected from salt of wormwood, triethylamine, pyridine.Temperature of reaction is-10 ℃-50 ℃, preferably carries out at 0 ℃-20 ℃.Shown in deoxidation fluorcytidines shown in formula (II) and formula (IV), the molar ratio of acylating reagent is 1: 1.1-1: 3, be preferably 1: 1.1-1: 2.
Shown in formula (III), the deoxidation fluorcytidines is sloughed blocking group, obtains the reaction of capecitabine, can carry out in the proton aqueous acid, can carry out in the alcoholic solution of protonic acid or in ethereal solution, also can carry out in the solution of aprotic acid.Preferably carry out in the alcoholic solution of protonic acid.
The technique effect that the present invention realizes is as follows:
The method uses the definite deoxidation fluorouracil glucoside of configuration as raw material, has obtained capecitabine through three-step reaction, and synthetic route is short, has avoided the generation of steric isomer.Through evidence, the yield of the method is high, and technological process is easily controlled, and product quality is stable.
Specific implementation method:
The present invention further illustrates by following examples, and following examples only limit technical scheme of the present invention for the preferred embodiment of the present invention more specifically being described, being not used in.The technical scheme of the invention described above is the technical scheme that can realize the object of the invention.Be temperature that following examples adopt and reagent, all available relevant temperature mentioned above and reagent substitute to realize the present invention's purpose.
Embodiment 1:
Figure GPA00000671272000061
0.26 gram (1.5mmol) tosic acid is dissolved in 20ml acetone, add 3.69 grams (15mmol) deoxidation fluorouracil glucoside, stirring at room 24 hours adds solid carbonic acid potassium in reaction system, regulating the pH value is 7, filter, filtrate concentrating removed acetone and got white solid, and dissolving adds methylene chloride, wash with water, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtain white solid (Ia) 3.83 grams, yield 89.2%.Ia： 1H?NMR(300MHz，CDCl 3)：δ7.36(d，1H，J＝7.6Hz)，5.67(s，1H)，4.67(dd，1H，J＝8.0，3.2Hz)，4.50(dd，1H，J＝4.5，3.6Hz)，4.24(m，1H)，1.56(s，3H)，1.40(d，3H，J＝6.3Hz)，1.34(s，3H)；ESI-MS?m/z(M+1 +)287。
Embodiment 2:
0.2 gram (1.5mmol) zinc chloride is dissolved in 20ml acetone, add 3.69 grams (15mmol) deoxidation fluorouracil glucoside,-20 ℃ were stirred 24 hours, added salt of wormwood in reaction system, and regulating the pH value is 7, filter, filtrate concentrating removed acetone and got white solid, and the dissolving that adds methylene chloride washes with water, anhydrous sodium sulfate drying, removal of solvent under reduced pressure get white solid Ia.
Embodiment 3:
Figure GPA00000671272000071
0.35 gram (2mmol) tosic acid is dissolved in 100ml toluene, add 4.92 grams (20mmol) deoxidation fluorouracil glucoside and 6.87 grams (65.0mmol) phenyl aldehyde to reflux, stirred 4 hours, cooling, filter, filter residue is raw material 2.48 grams, and filtrate is concentrated, resistates obtains solid (Ib) 2.80 grams, yield 91.0% with ethyl acetate and normal hexane recrystallization.Ib： 1H?NMR(300MHz，CDCl 3)：δ9.17(s，1H)，7.32-7.50(m，6H)，6.09(s，1H)，5.74(d，1H，J＝2.7Hz)，4.96(dd，1H，J＝3.0，3.9Hz)，4.69(m，1H)，4.30(m，1H)，1.47(d，3H，J＝6.3Hz)；EI-MS?m/z(M+1 +)334。
Embodiment 4:
Figure GPA00000671272000081
0.2 gram (1.2mmol) tosic acid is dissolved in 40ml toluene, add 3.0 grams (12.2mmol) deoxidation fluorouracil glucoside and 2.01 grams (14.3mmol) m chlorobenzaldehyde, reflux, stirred 4 hours, cooling, filter, filter residue is raw material 0.7 gram, filtrate is concentrated, and resistates obtains solid (Ic) 3.15 grams, yield 91.0% with ethyl acetate and normal hexane recrystallization.Ic： 1H?NMR(300MHz，CDCl 3)：δ9.17(s，1H)，7.32-7.50(m，6H)，6.09(s，1H)，5.74(d，1H，J＝2.7Hz)，4.96(dd，1H，J＝3.0，3.9Hz)，4.69(m，1H)，4.30(m，1H)，1.47(d，3H，J＝6.3Hz)；EI-MS?m/z(M+1 +)368。
Embodiment 5:
Figure GPA00000671272000082
0.2 gram (1.2mmol) tosic acid is dissolved in 40 acetonitriles, add 3.0 grams (12.2mmol) deoxidation fluorouracil glucoside and 3.26 grams (14.3mmol) methoxyl group ditan, reflux, stirred 4 hours, cooling, to filter, filtrate is concentrated, resistates obtains solid (Id) 2.3 grams, yield 46.0% with ethyl acetate and normal hexane recrystallization.Id： 1H?NMR(300MHz，CDCl 3)：δ9.22(brs，1H)，7.31-7.52(m，6H)，5.82(d，1H，J＝2.1Hz)，4.88(dd，1H，J＝6.9，2.4Hz)，4.55(dd，1H，J＝6.6，4.2Hz)，4.42(dd，1H，J＝6.6，4.5Hz)，1.42(d，3H，J＝6.6Hz)；EI-MS?m/z(M +)410。
Embodiment 6:
Figure GPA00000671272000091
3.83 grams (13.4mmol) Ia is dissolved in the 35ml anhydrous acetonitrile, adds 3.17 grams (40.0mmol) pyridine and 4.88 grams (40.0mmol) N, the N-Dimethylamino pyridine, be cooled to 0 ℃, drip 6.14 grams (40.0mmol) phosphorus oxychloride, stirred 6 hours, reaction solution is poured in 0 ℃ of ammoniacal liquor, stirred 0.5 hour, separatory, the organic phase washed with dichloromethane merges organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtain crude product (IIa) 6.0 grams.IIa： 1H?NMR(300MHz，CDCl 3)：δ7.42(d，1H，J＝5.7Hz)，5.57(d，1H，J＝1.2Hz)，4.93(dd，1H，J＝6.6，1.8Hz)，4.49(dd，1H，J＝6.6，1.5Hz)，4.27(dd，1H，J＝6.3，4.2Hz)，1.55(s，3H)，1.38(d，1H，J＝6.6Hz)，1.32(s，3H)；EI-MS?m/z(M +)285。
Embodiment 7:
3.83 grams (13.4mmol) Ia is dissolved in the 35ml anhydrous acetonitrile, adds 3.17 grams (40.0mmol) pyridine and 4.88 grams (40.0mmol) N, the N-Dimethylamino pyridine, 30 ℃, drip 6.14 grams (40.0mmol) phosphorus oxychloride, stirred 6 hours, reaction solution is poured in 0 ℃ of ammoniacal liquor, stirred 0.5 hour, separatory, the organic phase washed with dichloromethane merges organic phase, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtain crude product (IIa) 6.0 grams.
Embodiment 8-10:
Take Ib, Ic or Id as raw material, the method according to identical with embodiment 7 has obtained Compound I Ib, IIc and IId respectively.
Figure GPA00000671272000101
IIb： 1H?NMR(300MHz，CDCl 3)：δ8.00(d，1H，J＝8.6Hz)，7.40-7.54(m，5H)，6.11(s，1H)，5.88(d，1H，J＝4.4Hz)，4.94(dd，1H，J＝8.8，4.0Hz)，4.69(m，1H)，4.20(m，1H)，1.36(d，3H，J＝7.6Hz)；EI-MSm/z?(M +)333。
IIc：EI-MS?m/z(M +)367。
IId： 1H?NMR(300MHz，CDCl 3)：δ8.00(d，1H，J＝8.6Hz)，7.26-7.52(m，10H)，6.11(s，1H)，5.73(d，1H，J＝2.4Hz)，4.96(dd，1H，J＝6.8，2.4Hz)，4.59(dd，1H，J＝6.6，4.2Hz)，4.46(m，1H)，1.42(d，3H，J＝6.6Hz).ESI-MS?m/z(M+Na +)432。
Embodiment 11:
6.0 gram IIa are dissolved in the 40ml acetonitrile, add 7.6 grams (26.8mmol) N-, penta oxygen ketonic oxygen base succimide and 3.7 grams (26.8mmol) salt of wormwood, stirring at room 24 hours is filtered, removal of solvent under reduced pressure, resistates is dissolved in methylene dichloride, and with 1N hydrochloric acid washed twice, the saturated common salt water washing once, anhydrous sodium sulfate drying, removal of solvent under reduced pressure gets resistates, gets product (IIIa) 3.43 grams through column chromatography, and two step yields are 64%.IIIa： 1H?NMR(300MHz，CDCl 3)：δ12.05(brs，1H)，7.41(d，1H，J＝4.8Hz)，5.65(s，1H)，4.87(d，1H，J＝5.4Hz)，4.49(dd，1H，J＝4.2，6.3Hz)，4.14-4.28(m，1H)，1.70(m，2H)，1.56(s，3H)，1.28-1.42(m，11H，J＝6.3Hz)，0.89(t，3H，J＝7.2Hz)；ESI-MS?m/z(M+Na +)422。
Embodiment 12:
6.0 gram IIa are dissolved in the 40ml acetonitrile, add 6.78 grams (26.8mmol) m-nitro base n-pentyl carbonic ether and 3.7 grams (26.8mmol) salt of wormwood, stirring at room 24 hours is filtered, removal of solvent under reduced pressure, resistates is dissolved in methylene dichloride, and with 1N hydrochloric acid washed twice, the saturated common salt water washing once, anhydrous sodium sulfate drying, removal of solvent under reduced pressure gets resistates, must produce (IIIa) 3.33 grams through column chromatography, and two step yields are 62%.
Embodiment 13:
6.0 gram IIa are dissolved in the 40ml acetonitrile, add 4.02 grams (26.8mmol) n-amyl chlorocarbonate and 2.1 grams (26.8mmol) salt of wormwood, 0 ℃ was stirred 2 hours, and removal of solvent under reduced pressure is dissolved in methylene dichloride with resistates, with 1N hydrochloric acid washed twice, the saturated common salt water washing once, anhydrous sodium sulfate drying, removal of solvent under reduced pressure gets resistates, must produce (IIIa) 3.63 grams through column chromatography, two step yields are 66%.
Figure GPA00000671272000111
Embodiment 14～16:
Take IIb and IIc as raw material, the method according to identical with embodiment 11 has obtained compound III b, IIIc and IIId respectively.
IIIb： 1H?NMR(300MHz，CDCl 3)：δ12.09(brs，1H)，7.42-7.58(m，6H)，6.13(s，1H)，5.75(d，1H，J＝2.7Hz)，5.03(m，1H)，4.74(m，1H)，4.19-4.40(m，3H)，1.74(m，2H)，1.48(d，3H，J＝8.4Hz)，1.29-1.43(m，5H，J＝6.3Hz)，0.90(t，3H，J＝7.2Hz)；ESI-MS?m/z(M+Na +)470。
IIIc： 1H?NMR(300MHz，CDCl 3)：δ12.05(brs，1H)，7.30-7.50(m，5H)，6.07(s，1H)，5.68(m，1H)，4.97-5.11(m，1H)，4.66(m，1H)，4.17-4.44(m，3H)，1.70(m，2H)，1.48(d，3H，J＝8.4Hz)，1.20-1.37(m，5H)，0.85(t，3H，J＝7.2Hz)；ESI-MS?m/z(M+Na +)504。
IIId： 1H?NMR(300MHz，CDCl 3)：δ12.03(brs，1H)，7.31-7.51(m，11H)，5.80(d，1H，J＝2.1Hz)，4.90(m，1H)，4.55(dd，1H，J＝6.9，4.2Hz)，4.45(dd，1H，J＝5.4，4.8Hz)，4.01-4.18(m，2H)，1.72(m，2H)，1.40(d，3H，J＝8.4Hz)，1.25-1.37(m，5H，J＝6.3Hz)，0.90(t，3H，J＝7.2Hz)。
Figure GPA00000671272000121
Embodiment 17:
1.3 gram IIIa are dissolved in 10ml ethanol, are cooled to 0 ℃, stir, slowly drip the 10mlHCl/ ethanolic soln, keeping temperature of reaction is 0 ℃, and removal of solvent under reduced pressure after 4 hours is dissolved in methylene dichloride with resistates, uses saturated NaHCO 3Solution washing, anhydrous sodium sulfate drying filters, and removal of solvent under reduced pressure gets 1.0 gram products (capecitabine). 1H?NMR(300MHz，d-DMSO)：δ8.03(brs，1H)，5.67(d，1H，J＝4.8Hz)，4.08(m，3H)，3.90(m，1H)，3.68(q，1H，J＝6.0Hz)，1.60(m，2H)，1.22-1.31(m，7H)，0.88(t，3H，J＝6.4Hz)；ESI-MS?m/z(M +)358。
Figure GPA00000671272000131
Embodiment 18～20:
Take IIIb, IIIc or IIId as raw material, the method according to identical with embodiment 17 has obtained capecitabine respectively.

Claims (4)

1.一种化合物，去氧氟脲苷衍生物，如式（I）所示：1. A kind of compound, deoxyfluridine derivative, as shown in formula (I):
Figure FDA00002806344100011
Figure FDA00002806344100011
 其中，R1为氢原子、含有1～8个碳原子的直链或支链烷基或者苯基；R2为氢原子、含有1～8个碳原子的直链或支链烷基或者苯基；Wherein, R 1 is a hydrogen atom, a straight chain or branched chain alkyl or phenyl group containing 1 to 8 carbon atoms; R 2 is a hydrogen atom, a straight chain or branched chain alkyl group or benzene containing 1 to 8 carbon atoms base; 或者，所述化合物为
Figure FDA00002806344100012
Alternatively, the compound is
Figure FDA00002806344100012
 其中，所述化合物不为 Wherein, the compound is not 2.权利要求1所述式（I）所示去氧氟脲苷衍生物的制备方法，该方法以去氧氟脲苷与醛或酮在酸性催化剂的存在下进行缩合反应得到式（I）所示去氧氟脲苷衍生物。2. The preparation method of doxfluridine derivatives represented by formula (I) according to claim 1, in which method, the condensation reaction of doxfluridine and aldehyde or ketone in the presence of an acidic catalyst is carried out to obtain formula (I) The deoxyfluridine derivatives shown. 3.根据权利要求2所述的制备方法，其特征在于，所述酸性催化剂选自对甲苯磺酸，氯化锌，氯化锡。3. preparation method according to claim 2 is characterized in that, described acidic catalyst is selected from p-toluenesulfonic acid, zinc chloride, tin chloride. 4.权利要求1所述式（I）所示去氧氟脲苷衍生物在制备如下式（II）所示去氧氟胞苷衍生物中的用途，其中，式（I）所示去氧氟胞苷衍生物与三氯氧磷、有机碱和氨水作用得到如下式（II）所示去氧氟胞苷衍生物，4. The use of doxafluridine derivatives represented by formula (I) in claim 1 in the preparation of doxafluridine derivatives represented by formula (II), wherein, deoxyfluridine derivatives represented by formula (I) Flucytidine derivatives are reacted with phosphorus oxychloride, organic base and ammonia water to obtain deoxyflucytidine derivatives shown in the following formula (II),
Figure FDA00002806344100021
Figure FDA00002806344100021
 其中，R1为氢原子、含有1～8个碳原子的直链或支链烷基或者苯基；R2为氢原子、含有1～8个碳原子的直链或支链烷基或者苯基，Wherein, R 1 is a hydrogen atom, a straight chain or branched chain alkyl or phenyl group containing 1 to 8 carbon atoms; R 2 is a hydrogen atom, a straight chain or branched chain alkyl group or benzene containing 1 to 8 carbon atoms base, 或者，所述化合物为 Alternatively, the compound is 其中，所述化合物不为
Figure FDA00002806344100023
Wherein, the compound is not
Figure FDA00002806344100023
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Publication number Priority date Publication date Assignee Title
WO2009094847A1 (en) * 2007-12-28 2009-08-06 Topharman Shanghai Co., Ltd. A capecitabine hydroxyl-derivative, its preparation processes and uses for preparing capecitabine
CN101469008B (en) * 2007-12-29 2013-08-07 上海特化医药科技有限公司 Capecitabine hydroxy derivatives, preparation thereof and use in capecitabine preparation
WO2011067588A1 (en) 2009-12-04 2011-06-09 Generics [Uk] Limited Cyclic sulphinyl esters of cytidine
WO2011104540A1 (en) 2010-02-24 2011-09-01 Generics [Uk] Limited One step process for the preparation of capecitabine
CN101845070B (en) * 2010-05-25 2012-05-16 郑州大学 Synthesis method of antineoplastic medicine capecitabine
CN103897005B (en) * 2012-12-27 2017-07-28 鲁南制药集团股份有限公司 Method for continuously synthesizing capecitabine
CN103113441A (en) * 2013-03-13 2013-05-22 上海龙翔生物医药开发有限公司 Method for preparing capecitabine
US10308597B2 (en) 2014-04-30 2019-06-04 Rgenix, Inc. Inhibitors of creatine transport and uses thereof
CN104478975A (en) * 2014-11-24 2015-04-01 苏州乔纳森新材料科技有限公司 Synthesis method of capecitabine
CN106699825A (en) * 2016-12-01 2017-05-24 齐鲁天和惠世制药有限公司 Method for preparing capecitabine from capecitabine waste water extract
US10435429B2 (en) 2017-10-03 2019-10-08 Nucorion Pharmaceuticals, Inc. 5-fluorouridine monophosphate cyclic triester compounds
CN117402189A (en) 2018-01-10 2024-01-16 广东集宝医药技术有限公司 Aminophosphorus (phosphine) acid acetal and phosphorus (phosphine) acid acetal compounds
CN111801339B (en) * 2018-01-19 2025-06-24 纽科利制药公司 5-Fluorouracil compounds
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
WO2021216427A1 (en) 2020-04-21 2021-10-28 Ligand Pharmaceuticals, Inc. Nucleotide prodrug compounds
CN114644666A (en) * 2020-12-18 2022-06-21 上海特化医药科技有限公司 Process for the preparation of 5' -nucleoside prodrugs and intermediates

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6310039B1 (en) * 1996-09-11 2001-10-30 Felix Kratz Antineoplastic conjugates of transferrin, albumin and polyethylene glycol

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU664948B2 (en) * 1993-02-23 1995-12-07 City Of Hope 4-ethoxy 5-fluoro 2'deoxyuridine
CN100425617C (en) * 2006-10-31 2008-10-15 浙江海正药业股份有限公司 Fluoropyrimidine compound carbalkoxylation method

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6310039B1 (en) * 1996-09-11 2001-10-30 Felix Kratz Antineoplastic conjugates of transferrin, albumin and polyethylene glycol

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
余建鑫等.抗肿瘤药物卡培他滨的合成工艺改进.《中国药物化学杂志》.2005,第15卷(第3期),173-175，187. *
董辉等.去氧氟尿苷合成工艺改进.《中国医药工业杂志》.2002,第33卷(第3期),1-4,13. *

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