CN105601688A - Preparation methods for clofarabine intermediate and clofarabine - Google Patents
Preparation methods for clofarabine intermediate and clofarabine Download PDFInfo
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- UUDZSJZEINMJRS-UHFFFAOYSA-N O=C(c1ccccc1)OC(C1)C11OCC2(CC2)C1 Chemical compound O=C(c1ccccc1)OC(C1)C11OCC2(CC2)C1 UUDZSJZEINMJRS-UHFFFAOYSA-N 0.000 description 1
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- 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
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention provides preparation methods for a clofarabine intermediate and clofarabine. The preparation method for the clofarabine intermediate, provided by the invention, comprises the steps of firstly mixing tertiary butanol, acetonitrile and calcium hydride; secondly mixing a to-be-reacted liquid obtained after stirring at the room temperature until no bubbles are generated, and 2-chloroadenine and reacting for 2-4 hours; and finally reacting with a 1-bromo-3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-Arabic ribofuranose solution to obtain clofarabine. Therefore, the time of reaction with the 1-bromo-3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-Arabic ribofuranose solution is greatly shortened; and the method is simple in post-treatment and relatively high in yield.
Description
Technical field
The present invention relates to field of medicaments, relate in particular to the preparation of a kind of clofarabine intermediate and clofarabineMethod.
Background technology
Nucleoside medicine be treatment leukaemia and other neoplastic hematologic disorders obtain a class very important and very effectively carefullyBorn of the same parents' endotoxin medicine. Purine nucleoside analogs Cladribine and NSC-118218 treatment acute leukemia inThrough showing good effect, but two kinds of medicines will produce neurotoxicity in the time of therapeutic dose. Although two kindsMedicine can change in cell has active triphosphoric acid metabolite, and the latter can suppress DNA'sSynthetic, but their Main Function mode is different. Cladribine triphosphate mainly suppresses ribose coreAcid pond, and NSC-118218 triphosphate mainly suppresses archaeal dna polymerase. In order to improve curative effect and reduced toxicity,On the basis of Cladribine and NSC-118218, develop clofarabine. Clofarabine is taken off in cellOxygen cytidine kinases changes into 5-monophosphate metabolite, has then been changed into work by monophosphate and diphosphate kinaseThe form of the 5-triphosphate of property. Triphosphoric acid clofarabine is many by suppressing ribonucleotide reductase and DNAPoly-enzyme suppresses the synthetic of DNA, and external Fast Growth and static cancer cell are all had to CDCC.Clofarabine has shown good result for the treatment of and tolerance in treatment children ALL. Therefore, chlorine methodDrawing shore is a kind of initiative medicine to children acute lymphoblastic leukaemia, its listing early at home,Can bring hope for children acute lymphoblastic leukaemia.
At present, about clofarabine intermediate, ((2-deoxidation-2-is fluoro-3,5-bis--O-benzene first for the chloro-9-of 6-amino-2-Acyl-beta-D-arabinofuranose base)-9H-purine) synthetic method be mainly: by 2-chloroadenine andAcetonitrile mixes, and mechanical agitation, to dissolving completely, then adds the tert-butyl alcohol, fully reaction. And then by uncleButanols potassium adds reactant liquor, more slowly adds above-mentioned reactant liquor to continue to stir calcium hydride, and heating systems extremelyTemperature is 50 DEG C. Be incubated 40 minutes. By bromo-1-3,5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-IUncle's ribofuranose adds, and adds DCE, and insulation reaction more than 12 hours, obtains clofarabine intermediate,Its reaction equation is as follows:
But when this preparation method prepares clofarabine intermediate, productive rate is lower, and post processing is more multipleAssorted, need to repeatedly be recrystallized.
Summary of the invention
In view of this, technical problem to be solved by this invention is to provide a kind of clofarabine intermediatePreparation method, method product yield provided by the invention is high, and post processing is simple.
The preparation method who the invention provides a kind of clofarabine intermediate, comprising:
1) tert-butyl alcohol, acetonitrile and calcium hydride are mixed, stirring at room temperature, to without Bubble formation, obtains question responseLiquid;
2) by step 1) question response liquid and 2-chloroadenine hybrid reaction 2～4 hours, obtain reactant liquor;
3) by step 2) reactant liquor and 1-bromo-3,5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-IUncle's ribofuranose solution hybrid reaction, obtains clofarabine intermediate.
Preferably, the volume ratio of the described tert-butyl alcohol and described acetonitrile is (1～3): 1.
Preferably, the mol ratio of described 2-chloroadenine and described calcium hydride is 1:(1～1.3).
Preferably, described step 2) reaction temperature be 52～58 DEG C.
Preferably, described 2-chloroadenine and described 1-are bromo-3,5-bis--O-benzoyl-2-deoxidation-2-fluoro-alphaThe mol ratio of the Arabic ribofuranose of-D-is 1:(0.8～1.1).
Preferably, described step 3) reaction temperature be 45～55 DEG C.
Preferably, described 1-is bromo-3, the Arabic ribofuranose of 5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-Solvent in solution is carrene.
Preferably, described step 3) be specially:
3-1) by step 2) reactant liquor and 1-bromo-3,5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-AhDraw uncle's ribofuranose solution reaction, after completion of the reaction, add carrene to mix 0.5～1.5 hour, filter,Concentrated, obtain clofarabine intermediate crude product;
3-2), by the clofarabine intermediate crude product recrystallization obtaining, obtain clofarabine.
Preferably, the solvent of described recrystallization is methyl alcohol and DMF.
The present invention also provides a kind of preparation method of clofarabine, in clofarabine provided by the inventionMesosome prepares.
Compared with prior art, the invention provides a kind of preparation method of clofarabine intermediate, comprising:First the tert-butyl alcohol, acetonitrile and calcium hydride are mixed, stirring at room temperature, to without Bubble formation, obtains question response liquid;Then with 2-chloroadenine hybrid reaction 2～4 hours, obtain reactant liquor; Finally by this reactant liquor and 1-bromineThe Arabic ribofuranose solution reaction of-3,5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-, obtains chlorine faradMiddle Binhai mesosome; Wherein, by first the tert-butyl alcohol, acetonitrile and calcium hydride being mixed, stirring at room temperature is extremely without gasAfter bubble produces the question response liquid that obtains again with 2-chloroadenine hybrid reaction 2～4 hours, last and 1-is bromo-3,5-The Arabic ribofuranose solution reaction of two-O-benzoyl-2-deoxidation-2-fluoro-alpha-D-, the chlorine farad obtainingShore, makes with 1-bromo-ly 3, and the Arabic ribofuranose solution of 5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-is anti-The time of answering shortens greatly, and post processing is simple, and yield is higher, and experimental result shows, the invention providesMethod yield can be up to more than 50%, and crude product is recrystallized once, can make purity reach more than 99%.
Brief description of the drawings
Fig. 1 is the clofarabine intermediate HPLC testing result that the embodiment of the present invention 2 prepares.
Detailed description of the invention
The preparation method who the invention provides a kind of clofarabine intermediate, comprising:
1) tert-butyl alcohol, acetonitrile and calcium hydride are mixed, stirring at room temperature, to without Bubble formation, obtains question responseLiquid;
2) by step 1) question response liquid and 2-chloroadenine hybrid reaction 2～4 hours, obtain reactant liquor;
3) by step 2) reactant liquor and 1-bromo-3,5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-IUncle's ribofuranose solution reaction, obtains clofarabine intermediate.
According to the present invention, the present invention mixes the tert-butyl alcohol, acetonitrile and calcium hydride, and stirring at room temperature is extremely without bubbleProduce, obtain question response liquid; Wherein, the volume ratio of the described tert-butyl alcohol and described acetonitrile is (1～3): 1,Be preferably (1.8～2.5): 1. The present invention does not have particular/special requirement, well known in the art stirring to the mode stirringThe mode of mixing all can.
According to the present invention, the present invention is by step 1) question response liquid and 2-chloroadenine hybrid reaction 2～4Hour, obtain reactant liquor; Wherein, the mol ratio of described 2-chloroadenine and described calcium hydride is preferably 1:(1～1.3), more preferably 1:(1.1～1.2), the present invention does not have particular/special requirement to the source of calcium hydride,The calcium hydride that market can be bought all can; The time of described reaction is preferably 2.5～3 hours; The temperature of described reactionDegree is preferably 52～58 DEG C, more preferably 53～55 DEG C.
By step 2) reactant liquor and 1-bromo-3,5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-ArabRibofuranose solution hybrid reaction, obtains clofarabine intermediate; Wherein, described 1-is bromo-3,5-bis--O-benzeneSolvent in the Arabic ribofuranose solution of formoxyl-2-deoxidation-2-fluoro-alpha-D-is preferably carrene; 2-Chloroadenine and described 1-are bromo-3, the Arabic ribofuranose of 5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-Mol ratio is preferably 1:(0.8～1.1), more preferably 1:(0.9～1); The temperature of described reaction is preferredBe 45～55 DEG C, more preferably 50～53 DEG C; The time of described reaction is preferably 2～5 hours, more preferably3～4 hours.
In the present invention, for the purity of the clofarabine intermediate that makes to obtain is higher, preferred steps 3 of the present invention)Be specially:
3-1) by step 2) reactant liquor and 1-bromo-3,5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-AhDraw uncle's ribofuranose solution reaction, after completion of the reaction, add carrene to mix 0.5～1.5 hour, filter,Concentrated, obtain clofarabine intermediate crude product;
3-2), by the clofarabine intermediate crude product recrystallization obtaining, obtain clofarabine intermediate.
In the present invention, by step 2) reactant liquor and 1-bromo-3,5-bis--O-benzoyl-2-deoxidation-2-is fluoro-The Arabic ribofuranose solution reaction of α-D-, after completion of the reaction, adds carrene mixing 0.5～1.5 littleTime, filter, concentrated, obtain clofarabine intermediate crude product; Wherein, when the present invention adds carrene,The temperature of reaction system is preferably 20～25 DEG C; The present invention does not have particular/special requirement, this area to the mode of filteringThe known mode of crossing all can.
The present invention, by the clofarabine intermediate crude product recrystallization obtaining, obtains clofarabine intermediate; InstituteThe solvent of stating recrystallization is preferably methyl alcohol and DMF, wherein, and described methyl alcohol and described N, N-The volume ratio of dimethyl formamide is (2～3): 1, and more preferably (2.5～2.8): 1.
Concrete, the reaction equation of preparing clofarabine intermediate of the present invention is as follows:
The present invention also provides a kind of preparation method of clofarabine, in clofarabine provided by the inventionMesosome prepares. It is special that the preparation method that the present invention prepares clofarabine to clofarabine intermediate does not haveRestriction, the method that clofarabine intermediate well known in the art is prepared clofarabine all can.
The preparation method of a kind of clofarabine intermediate provided by the invention, by first by the tert-butyl alcohol, secondNitrile and calcium hydride mix, and stirring at room temperature is to mixed with 2-chloroadenine again without the question response liquid obtaining after Bubble formationClose reaction 2～4 hours, last and 1-are bromo-3,5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-Arab furansRibose solution reaction, the clofarabine obtaining, make with 1-bromo-3,5-bis--O-benzoyl-2-deoxidation-2-fluorineThe time of the Arabic ribofuranose solution reaction of-α-D-shortens greatly, and yield is higher, and post processing is simple,Only need once be recrystallized and can obtain the product that purity is higher, and in product, content of isomer is low.
Technical scheme below in conjunction with the embodiment of the present invention is clearly and completely described, obviously, and instituteThe embodiment describing is only the present invention's part embodiment, instead of whole embodiment. Based on thisEmbodiment in bright, those of ordinary skill in the art obtain under creative work prerequisite not makingEvery other embodiment, belongs to the scope of protection of the invention.
Embodiment 1
In 100mL reaction bulb, add the 22.8mL tert-butyl alcohol, add 11.4mL acetonitrile, 336.70mgCalcium hydride (1.0eq), stirs under room temperature, emerges without obvious bubble. Take 1.35g2-chloroadenine (1.0eq)Add reaction system, be warming up to 53 DEG C after stir-activating 2.5 hours, by bromo-3.37g1-3,5-bis--O-benzene firstAfter being dissolved in 16.4mL carrene, the Arabic ribofuranose of acyl group-2-deoxidation-2-fluoro-alpha-D-adds reaction bodySystem, at 50 DEG C of interior temperature, insulated and stirred reaction is spent the night, and TLC detects raw material point, react end in 3 hours, insteadShould be complete.
Above-mentioned reactant liquor is cooled to room temperature, decompress filter, 4mL acetonitrile, 4mL × 2 acetic acid for filter cakeEthyl ester washing, filtrate drips acetic acid until filtrate is placed in decompression rotary evaporator by solution PH=6 with dropperUpper distillation, steams to obtain dope. Add 1.5mL ethyl acetate, 5mL benzinum recrystallization, obtains faint yellowSolid 3.80g, re-crystallizing in ethyl acetate, obtains 1.50g faint yellow solid, and filtrate is continued concentrated rear crystallization and is obtained0.68g faint yellow solid, is total to obtain 2.18g clofarabine intermediate product, and yield is 53.43%.
By high efficiency liquid phase, the clofarabine intermediate obtaining is carried out to purity detecting, result shows, it is pureDegree is 96.23%.
Embodiment 2
In 100mL reaction bulb, add the 22.8mL tert-butyl alcohol, add 11.4mL acetonitrile, 336.70mgCalcium hydride (1.0eq), stirs under room temperature, emerges without obvious bubble. Take 1.35g2-chloroadenine (1.0eq)Add reaction system, be warming up to 53 DEG C after stir-activating 2.5 hours, by bromo-3.37g1-3,5-bis--O-benzene firstAfter being dissolved in 16.4mL carrene, the Arabic ribofuranose of acyl group-2-deoxidation-2-fluoro-alpha-D-adds reaction bodySystem, insulated and stirred 3 hours at 50 DEG C of interior temperature, TLC detects raw material point disappearance, reacts complete.
After completion of the reaction, be cooled to 20～25 DEG C, in system, add 16.4mL carrene, stir 1Hour. Funnel pad diatomite, filters. Filtrate rotary evaporation, reclaims after solvent, obtains yellow dope.Added in 100mL reaction bulb, added 26.0mL absolute methanol and 9.5mLDMF, temperature rising refluxAll dissolve to solid, slow cooling, to room temperature (20～25 DEG C), filters, and filter cake is with after a small amount of methanol washObtain clofarabine intermediate 2 highly finished product. Product forced air drying 8 hours at 45 DEG C, obtains 3.06g chlorineFarad shore intermediate product, yield is 75.00%.
By high efficiency liquid phase, the clofarabine intermediate obtaining is carried out to purity detecting, the results are shown in Figure 1, Fig. 1For the clofarabine intermediate HPLC testing result that the embodiment of the present invention 2 prepares, result shows,Its purity is 99.44%, and content of isomer is 0.008%.
Clofarabine intermediate obtained in the previous step is added in 10mL absolute methanol, after stirring, addNaOCH3/CH3OH solution (193.41mg is dissolved in 2mL absolute methanol), stirs 2h at 15～20 DEG C,TLC detects raw material point and disappears, and reacts complete. React the complete insoluble matter that removes by filter, filtrate is separated out in a large numberSolid, adds acetic acid to regulate pH=6.5～7.5 under stirring. Regulate complete stirring at room temperature 30 minutes, filter,Filter cake washs with a small amount of cold methanol, obtains clofarabine, and 50 DEG C of vacuum drying, obtain clofarabine product1.73g, yield is 95.41%. Liquid phase result: 99.85%.
By the clofarabine obtaining is carried out to nuclear-magnetism detection, result shows, its1The resolution data of HNMRIn table 1, the hydrogen spectrum data of the clofarabine that table 1 prepares for embodiment 2;
The hydrogen spectrum data of the clofarabine that table 1 prepares for embodiment 2
Its13The resolution data of CNMR is in table 2, the carbon of the clofarabine that table 2 prepares for embodiment 2Spectrum data;
The carbon spectrum data of the clofarabine that table 2 prepares for embodiment 2
By high efficiency liquid phase, the clofarabine obtaining is carried out to purity detecting, result shows, its purity is99.85％。
By the clofarabine obtaining is carried out to mass spectral analysis, its mass spectrometric data is: 304.059273 with reasonOpinion value 304.061270 matches.
Comparative example 1
Accurately take 2-chloroadenine 1.35g, be placed in 100mL there-necked flask, measure 7mL acetonitrile and addEnter there-necked flask, mix. Mechanical agitation is to dissolving completely. In reactant liquor, add the 13.4mL tert-butyl alcohol,Fully reaction. Continue to stir, take 1.00g potassium tert-butoxide and add reactant liquor, accurately take 0.35g hydrogenationCalcium slowly adds reactant liquor to continue to stir, and heating systems to temperature is 50 DEG C. Be incubated 40 minutes. By 3.37g1-is bromo-3, and the Arabic ribofuranose of 5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-adds, and adds13.4mLDCE, insulation reaction 12 hours, TLC detects raw material point and disappears, and impure point is more.
System is cooled to room temperature, decompress filter, 4mL acetonitrile, the washing of 4mL × 2 ethyl acetate for filter cake,Filtrate drips acetic acid with dropper until solution PH=6 are placed in filtrate on decompression rotary evaporator and distill, and steamsObtain dope. Add 1.5mL ethyl acetate, 5mL benzinum recrystallization, obtains faint yellow solid 2.80g,Re-crystallizing in ethyl acetate, obtains 0.94g faint yellow solid, and it is faint yellow that the concentrated rear crystallization of filtrate continuation obtains 0.38gSolid, is total to obtain 1.32g clofarabine intermediate, and yield is 32.35%.
The purity of clofarabine intermediate comparative example 1 being obtained by high efficiency liquid phase detects liquid phase inspectionSurvey, result shows, its purity is 92.14%.
Comparative example 2
Accurately take 2-chloroadenine 1.35g, be placed in 100mL there-necked flask, measure 7mL acetonitrile and addEnter there-necked flask, mix. Mechanical agitation is to dissolving completely. In reactant liquor, add the 13.4mL tert-butyl alcohol,Fully reaction. Continue to stir, take 1.00g potassium tert-butoxide and add reactant liquor, accurately take 0.35g hydrogenationCalcium slowly adds reactant liquor to continue to stir, and heating systems to temperature is 50 DEG C. Be incubated 40 minutes. By 3.37g1-is bromo-3, and the Arabic ribofuranose of 5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-adds, and adds13.4mLDCE, insulation reaction 12 hours, TLC detects raw material point and disappears, and impure point is more.
React complete and be cooled to 20～25 DEG C, in system, add 16.4mL carrene, stir 1 hour.Funnel pad diatomite, filters. Filtrate rotary evaporation, reclaims after solvent, obtains yellow dope. By itAdd in 100mL reaction bulb, add 26.0mL absolute methanol and 9.5mLDMF, temperature rising reflux is to solidBody all dissolves, and slow cooling, to room temperature (20～25 DEG C), filters, and filter cake is with obtaining after a small amount of methanol washClofarabine intermediate 2 highly finished product. Product forced air drying 8 hours at 45 DEG C, to obtain 1.40g chlorine farad altogetherShore intermediate product, yield is 34.31%.
By high efficiency liquid phase, the clofarabine intermediate obtaining is carried out to purity detecting, result shows, it is pureDegree is 99.33%.
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof. ShouldPoint out, for those skilled in the art, under the premise without departing from the principles of the invention,Can also carry out some improvement and modification to the present invention, these improvement and modification also fall into right of the present invention and wantIn the protection domain of asking.
Claims (10)
1. a preparation method for clofarabine intermediate, comprising:
1) tert-butyl alcohol, acetonitrile and calcium hydride are mixed, stirring at room temperature, to without Bubble formation, obtains question responseLiquid;
2) by step 1) question response liquid and 2-chloroadenine hybrid reaction 2～4 hours, obtain reactant liquor;
3) by step 2) reactant liquor and 1-bromo-3,5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-IUncle's ribofuranose solution hybrid reaction, obtains clofarabine intermediate.
2. preparation method according to claim 1, is characterized in that, the described tert-butyl alcohol and described secondThe volume ratio of nitrile is (1～3): 1.
3. preparation method according to claim 1, is characterized in that, described 2-chloroadenine and instituteThe mol ratio of stating calcium hydride is 1:(1～1.3).
4. preparation method according to claim 1, is characterized in that, described step 2) reactionTemperature is 52～58 DEG C.
5. preparation method according to claim 1, is characterized in that, described 2-chloroadenine and instituteState 1-bromo-3, the mol ratio of the Arabic ribofuranose of 5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-is 1:(0.8～1.1)。
6. preparation method according to claim 1, is characterized in that, described step 3) reactionTemperature is 45～55 DEG C.
7. preparation method according to claim 1, is characterized in that, described 1-is bromo-3,5-bis--O-Solvent in the Arabic ribofuranose solution of benzoyl-2-deoxidation-2-fluoro-alpha-D-is carrene.
8. preparation method according to claim 1, is characterized in that, described step 3) be specially:
3-1) by step 2) reactant liquor and 1-bromo-3,5-bis--O-benzoyl-2-deoxidation-2-fluoro-alpha-D-AhDraw uncle's ribofuranose solution reaction, after completion of the reaction, add carrene to mix 0.5～1.5 hour, filter,Concentrated, obtain clofarabine intermediate crude product;
3-2), by the clofarabine intermediate crude product recrystallization obtaining, obtain clofarabine.
9. preparation method according to claim 8, is characterized in that, the solvent of described recrystallization isMethyl alcohol and DMF.
10. a preparation method for clofarabine, by the chlorine farad described in claim 1～9 any oneMiddle Binhai mesosome prepares.
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|---|---|---|---|---|
| WO2003011877A2 (en) * | 2001-08-02 | 2003-02-13 | Ilex Oncology Inc. | Process for preparing purine nucleosides |
| CN101153049A (en) * | 2006-09-29 | 2008-04-02 | 北京德众万全药物技术开发有限公司 | Method of producing high purity clofarabine |
| CN101265284A (en) * | 2008-05-07 | 2008-09-17 | 深圳万乐药业有限公司 | Method for synthesizing clofarabine |
| WO2015118558A2 (en) * | 2014-02-04 | 2015-08-13 | Msn Laboratories Private Limited | Process for the preparation of clofarabine |
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2015
- 2015-12-23 CN CN201510979969.2A patent/CN105601688A/en active Pending
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|---|---|---|---|---|
| WO2003011877A2 (en) * | 2001-08-02 | 2003-02-13 | Ilex Oncology Inc. | Process for preparing purine nucleosides |
| CN101153049A (en) * | 2006-09-29 | 2008-04-02 | 北京德众万全药物技术开发有限公司 | Method of producing high purity clofarabine |
| CN101265284A (en) * | 2008-05-07 | 2008-09-17 | 深圳万乐药业有限公司 | Method for synthesizing clofarabine |
| WO2015118558A2 (en) * | 2014-02-04 | 2015-08-13 | Msn Laboratories Private Limited | Process for the preparation of clofarabine |
Non-Patent Citations (4)
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| BRUCE G. ANDERSON，ET AL.: ""Isolation, Synthesis, and Characterization of Impurities and Degradants from the Clofarabine Process"", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| WILLIAM E. BAUTA，ET AL.: ""A New Process for Antineoplastic Agent Clofarabine"", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| 柴雨柱，等: ""抗白血病药氯法拉滨的合成"", 《化工时刊》 * |
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