CN102250178A - Synthesis of nelarabine - Google Patents
Synthesis of nelarabine Download PDFInfo
- Publication number
- CN102250178A CN102250178A CN2011101543707A CN201110154370A CN102250178A CN 102250178 A CN102250178 A CN 102250178A CN 2011101543707 A CN2011101543707 A CN 2011101543707A CN 201110154370 A CN201110154370 A CN 201110154370A CN 102250178 A CN102250178 A CN 102250178A
- Authority
- CN
- China
- Prior art keywords
- nelzarabine
- ethanoyl
- methylguanosine
- compound
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- GMCGIJAGGXYJEW-QJLPTJENSA-N COc(nc(N)nc1C2)c1N=CC2C([C@H]1O)OC(C2)([C@@H]2O)[C@H]1O Chemical compound COc(nc(N)nc1C2)c1N=CC2C([C@H]1O)OC(C2)([C@@H]2O)[C@H]1O GMCGIJAGGXYJEW-QJLPTJENSA-N 0.000 description 1
Images
Landscapes
- Saccharide Compounds (AREA)
Abstract
The invention discloses a preparation and refining method of nucleoside compounds, and particularly discloses a preparation method of nelarabine and refining treatment of nelarabine. The preparation method has the advantages of lower equipment requirement, fewer synthesis steps and simpler operation process; and the entire synthesis route is high in yield and low in preparation cost. Thus, the preparation method is economically feasible and suitable for industrial production. Besides, the invention also discloses an intermediate for nelarabine synthesis.
Description
The application be that January 28, application number in 2008 are 200810009146.7 an applying date, denomination of invention divides an application for " Nelzarabine synthetic and refining ".
Technical field
The present invention relates to the preparation method and the refinement treatment of nucleoside compound, relate to the preparation method of Nelzarabine specifically, also comprise refinement treatment Nelzarabine.
Background technology
Nelzarabine is the precursor medicine of pancreatic desoxyribonuclease analogue 9-β-D-arabinofuranosyl adenin sugar guanine (ara-G), and the listing that gone through in 2005 can be used for treating T cell acute lymphoblastic leukemia (T-ALL) and T cell LBL (T-LBL).
Nelzarabine has following structural formula, and its chemistry is called 2-amino-9-β-D-arbinofuranose base-6-methoxyl group-9H-purine.ZL88103820 discloses the preparation technology of Nelzarabine, and this processing method is with 2-ammonia
Base-6-methoxyl group purine and uridylic arabinose glycosides are raw material, obtain the product Nelzarabine under the effect of purine nucleoside phosphorylase and Uridine phosphorylase, and bacterial classification is more difficult to get in this method, long reaction time, strict to equipment requirements, cause cost to increase, there is the difficulty of suitability for industrialized production aspect.Another synthetic method is also disclosed in the prior art, with 2-amino-6-chloropurine is raw material, through methyl alcohol nucleophilic substitution, 2,3,5-three-oxygen-benzyl-1-oxygen-p-nitrophenyl formyl-D-arbinofuranose is through chlorination, and both obtain Nelzarabine at condensation, but raw material 2 in this scheme, 3,5-three-oxygen-benzyl-1-oxygen-p-nitrophenyl formyl-D-arbinofuranose costs an arm and a leg, and yield is not high yet, and its manufacturing cost is higher.In view of above-mentioned condition, be necessary to develop a kind of not high to equipment requirements, low cost of manufacture, yield is higher, economically feasible and be suitable for the method for suitability for industrialized production.
Summary of the invention
The invention provides a kind of preparation method of Nelzarabine, comprising: formula III compound and nucleophilic substitution reagent react obtain the formula IV compound of 2 ' configuration reversal, and formula IV compound and deacylated tRNA base reagent react obtain Nelzarabine.
The present invention also comprises the preparation method of described formula III compound; it comprises: the whole hydroxyl of 6-O-methylguanosine and acylating reagent reaction protection obtains formula I compound; then obtain formula II compound with regioselective deacylation base reagent react, the reaction of formula II compound and sulfonylation agent obtains formula III compound then.
R in above-mentioned formula I, II, III, the IV compound
1Identical, can be selected from C
1-3The alkyl of atom is as methyl, ethyl, propyl group, sec.-propyl; Phenyl; By 1-3 phenyl that is selected from the group replacement of methyl, halogen, nitro or methoxyl group, R
1Be preferably C
1-3The alkyl of atom, most preferable.
R in the formula III compound
3The optional electron-withdrawing group of improving oneself, as perfluoroalkyl, preferred C
1-4Perfluoroalkyl, most preferably be CF
3
R in the formula IV compound
2Can be selected from C
1-4The alkyl of atom is as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl; Phenyl; By 1-3 phenyl that is selected from the group replacement of methyl, halogen, nitro or methoxyl group, R
2Be preferably C
1-4The alkyl of atom, most preferable.
The present invention also provides the synthesis step of following Nelzarabine:
Above-mentioned reactions steps is described below:
(1) the 6-O-methylguanosine with the acylating reagent reaction, is protected 2 ', 3 ', 5 ' hydroxyl in the solvent that is fit to, and obtains formula I compound;
(2) the formula I compound blocking group of optionally sloughing 2 ' hydroxyl under the condition that suitable selectivity deprotection agent exists obtains formula II compound;
(3) formula II compound and sulfonylation agent reaction obtains the formula III compound that 2 ' alkylsulfonyl replaces;
(4) nucleophilic substitution reaction takes place in formula III compound in the presence of nucleophilic substitution reagent, and configuration reversal obtains formula IV compound simultaneously;
(5) formula IV compound removes whole protecting groups under the existence condition of deacylated tRNA base reagent, promptly obtains Nelzarabine.
The preparation of Nelzarabine of the present invention specifically can be undertaken by following step:
A. the preparation of formula I compound: with 6-O-methylguanosine dissolving or be suspended in the appropriate solvent; as acetonitrile; pyridine; can further contain DMAP in the reaction system; the organic bases that triethylamine etc. are suitable; in reaction system, add the normal acylating reagent of 3-20; acylating reagent can be acid halide such as Acetyl Chloride 98Min. or Benzoyl chloride or acid anhydrides; preferred anhydrides; as diacetyl oxide; propionic anhydride; butyryl oxide; isobutyric anhydride or benzoyl oxide; preferably reaction under agitation; temperature remains on 0 ℃-90 ℃; be preferably under the anhydrous condition and carry out, can select the protection of rare gas element in case of necessity, as nitrogen protection.After reaction finishes; acylate can obtain by the proper method separation; as with behind the reaction mixture concentrating under reduced pressure; adding appropriate amount of organic such as ethyl acetate dilutes; ethyl acetate layer washs with dilute sodium bicarbonate solution then; ethyl acetate layer after drying, concentrating under reduced pressure promptly obtains formula I compound.
B. the preparation of formula II compound: with formula I compound and the dissolving of suitable selectivity deprotecting regent or be suspended in appropriate organic solvent such as the pyridine and react; temperature remains on 10-70 ℃ of reaction 1-20 hour; products therefrom separates and obtains crude product, crude product is carried out purifying can obtain formula II compound.Described selectivity deprotecting regent can be directly to add reaction system; as azanol, hydrazine or its solubility carboxylate salt; participate in reaction directly after also can in reaction system, generating by chemical reaction; as being solvent with the pyridine; add sodium-acetate and oxammonium hydrochloride, thereby produce the pyridine solution that obtains the acetic acid azanol.Participate in reaction directly after preferably in reaction system, generating by chemical reaction.The purification process of crude product comprises silica gel column chromatography, preparation liquid phase purifying, crystallization purifying etc., and preferred earlier by the silica gel column chromatography purification, eluting solvent is preferably ethyl acetate, further uses the crystallization process purifying, and recrystallisation solvent is preferably methylene dichloride-heptane.
C. the preparation of formula III compound: with formula II compound, triethylamine, DMAP dissolve or are suspended in the appropriate solvent, as halogenated solvent, pyridine; add sulfonylation agent then; as sulphonic acid anhydride, SULPHURYL CHLORIDE, preferred trifluoromethanesulfchloride chloride, trifluoromethanesulfanhydride anhydride, most preferably trifluoromethanesulfanhydride anhydride.Temperature remains on-20 ℃～30 ℃ reactions 1-24 hour.After reaction finished, thin up was used organic solvent such as the chloroform extraction not miscible with water, and washing is concentrated into the dried formula III compound that promptly obtains after the drying.
D. the preparation of formula IV compound: with formula III compound dissolution in appropriate organic solvent such as ethyl acetate, DMSO or DMF.Add nucleophilic substitution reagent in the reaction system, suitable nucleophilic substitution reagent is selected from the benzoate such as the 4-nitrobenzoate of carboxylate salt such as acetate, propionic salt, butyrates, benzoate, replacement, carboxylate salt also can obtain with suitable alkali generation by add carboxylic acid in reaction system, described carboxylic acid can be acetic acid, propionic acid or phenylformic acid, suitable amine can be selected from tertiary amine, as triethylamine, diisopropyl ethyl amine, diisopropyl aniline.Preferably, in reaction system, add excessive tertiary amine and excessive acid, the preferred normal N of 1.2-8, the normal acetate of N-diisopropyl ethyl amine or triethylamine and 1.2-10, propionic acid acid or phenylformic acid, the reaction mixture reflux stirs, reaction finishes and adds appropriate solvent again such as ethyl acetate is diluted, solution with water after the dilution, sodium bicarbonate aqueous solution and saturated common salt water washing, dry back concentrating under reduced pressure, obtain the crude product of formula IV compound, also can be further with suitable solvent recrystallization, as dehydrated alcohol.
E. the preparation of Nelzarabine: the acyl group that removes in the compound IV 2 ', 3 ', 5 ' makes it all change hydroxyl into, can adopt this area method that removes acyl group commonly used.Can feed anhydrous ammonia gas then to reacting completely with formula IV compound dissolution in suitable organic solvent such as dehydrated alcohol, products therefrom is placed in refrigerator, and concentrating under reduced pressure concentrates the back and uses ethyl alcohol recrystallization then, is drying to obtain Nelzarabine.
The preparation method of Nelzarabine provided by the invention is preferably as follows:
(1) 6-chlorine guanosine and methoxylation reagent react replace generation 6-O-methylguanosine;
(2) reaction of 6-O-methylguanosine and acetylation reagent obtain 2 ', 3 ', 5 '-three-O-ethanoyl-6-O-methylguanosine;
(3) 2 ', 3 ', 5 '-three-O-ethanoyl-6-O-methylguanosine under the protectant effect of selectively removing, slough 2 ' ethanoyl of position obtains 3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine;
(4) 3 ', the reaction of 5 '-two-O-ethanoyl-6-O-methylguanosine and sulfonylation agent obtains 2 '-O-trifyl-3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine;
(5) 2 '-O-trifyl-3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine and nucleophilic substitution reagent react, obtain 2 ' configuration reversal 2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-three-O-ethanoyl arbinofuranose base) purine;
(6) remove compound 2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-three-O-ethanoyl arbinofuranose base) whole acyl groups of purine, obtain Nelzarabine.
Preferred synthetic route is:
The specific descriptions of above-mentioned synthetic method are as follows:
(1) is raw material with 6-chlorine guanosine,, obtains the 6-O-methylguanosine with the sodium methylate reaction;
(2) 6-O-methylguanosine and acetic anhydride carry out acetylization reaction obtain 2 ', 3 ', 5 '-three-O-ethanoyl-6-O-methylguanosine;
(3) add in the reaction system oxammonium hydrochloride and sodium-acetate make 2 ', 3 ', the ethanoyl that 5 '-three-O-ethanoyl-6-O-methylguanosine selectivity is sloughed 2 ' position obtains 3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine;
(4) 3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine sulfonylation under the effect of trifluoromethanesulfanhydride anhydride obtains 2 '-O-trifyl-3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine;
(5) use acetate and N, N-diisopropyl ethyl amine and 2 '-O-trifyl-3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine carries out nucleophilic substitution, configuration reversal obtain 2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-three-O-ethanoyl arbinofuranose base) purine;
(6) and EtOH/NH
3The reaction remove 2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-three-O-ethanoyl arbinofuranose base) the whole acyl group of purine, obtain Nelzarabine.
The present invention also provides the new compound shown in the formula II, and this compound can be used for the synthetic of Nelzarabine.
R wherein
1Can be selected from C
1-3The alkyl of atom is as methyl, ethyl, propyl group, sec.-propyl; Phenyl; By 1-3 phenyl that is selected from the group replacement of methyl, halogen, nitro or methoxyl group.R
1Be preferably C
1-3The alkyl of atom.
The preferred R of formula II compound
1Be the compound 2 of methyl, structural formula is as follows:
The present invention also provides the new compound shown in the formula III, and this compound can be used for the synthetic of Nelzarabine.
R wherein
1Can be selected from C
1-3The alkyl of atom is as methyl, ethyl, propyl group, sec.-propyl; Phenyl; By 1-3 phenyl that is selected from the group replacement of methyl, halogen, nitro or methoxyl group, R
1Be preferably C
1-3The alkyl of atom, most preferable;
R wherein
3Can be selected from C
1-4Perfluoroalkyl, most preferably be CF
3
The preferred R of formula III compound
1Be methyl, R
3Be CF
3Compound 3, structural formula is as follows:
More than two new compounds 3 '; 5 '-two-O-ethanoyl-6-O-methylguanosine (formula 2 compounds) and 2 '-O-trifyl-3 '; the intermediate that 5 '-two-O-ethanoyl-6-O-methylguanosine (formula 3 compounds) all can be used as in the Nelzarabine preparation process uses; can be convenient by the synthetic Nelzarabine of these two compounds, obtain Nelzarabine cheaply.
The present invention also provides a kind of fine purification treatment process of Nelzarabine, can obtain a kind of crystallization of Nelzarabine by this method, this crystallization has advantages of excellent stability and physicochemical property, compare with other solid form of Nelzarabine, this crystallization is particularly suitable for the preparation (described medicament preparation is meant the whole process that is become the pharmaceutical dosage forms that can directly use for the people by the bulk drug preparation) and the storage (storage of bulk drug and solid preparation) of medicine.
The fine purification treatment process of described Nelzarabine is: Nelzarabine adds methanol mixed and is heated to backflow, dissolving back filtered while hot, and filtrate concentrates, and stirs down to add ethanol or ether, places cooling crystallization, filters, and uses absolute ethanol washing, and drying obtains the Nelzarabine crystallization.
Preferred fine purification treatment process is: 50.0g Nelzarabine adding 1500ml methyl alcohol mixes and is heated to backflow, stir after 1 hour, material dissolves substantially, filters while hot, and filtrate is concentrated into about 750ml, stir and add 1500ml dehydrated alcohol and 500ml ether down, place cooling, 0 ℃ of crystallization 12h filters, use absolute ethanol washing, drying.
The crystallization of the Nelzarabine that refinement treatment of the present invention obtains, it is in X-ray powder diffraction (XRD) collection of illustrative plates, crystal face is about 8.9996,8.4665,5.4137,4.3838,4.1992,3.7667,3.4556,3.3682,3.2384,3.0702 places apart from the d value the peak, preferably at 13.3409,8.9996,8.4665,7.8517,6.5924,5.7564,5.4137,4.4713,4.3838,4.1992,4.1183,3.7667,3.5957,3.5201,3.4556,3.3682,3.2384,3.0702,3.0016 places the peak is arranged.Its differential scanning calorimetric (DSC) collection of illustrative plates is under the condition of 10 ℃/min of temperature rise rate, and initial fusing point is 199 ℃, and peak temperature is 202 ℃.
Need to prove, in XRD, distinctive often by the diffraction spectrogram that crystalline compounds obtains for specific crystal formation, the relative intensity of bands of a spectrum (especially at low angle) the advantage orientation effect that may produce and changing wherein because of the difference of crystallization condition, particle diameter and other condition determination.Therefore, the relative intensity of diffraction peak at crystal formation be not to be distinctive, judge whether when identical with known crystal formation, more it should be noted the relative position at peak rather than their relative intensity.In the XRD figure spectrum, represent the peak position with 2 θ angles or crystal face apart from d usually,, therefore represent to have more representativeness apart from d with crystal face because 2 θ angles are relevant with the wavelength of incident X-rays.Have simple conversion relation between the two: d=λ/2sin θ, wherein d represents the crystal face distance, λ represent incident X-rays wavelength (for Cu-Ka,
), θ is a diffraction angle.For the crystal formation of the same race of compound of the same race, its XRD spectra has similarity on the whole, and the d value error that characterizes the peak position is generally within ± 2%, and most of error is no more than ± 1%; The relative intensity error can be bigger, but the variation tendency unanimity.In addition, judge when crystal formation is whether the same and should note keeping organic conception that because be not that a diffracted ray represent thing phase, but one overlap specific " d-I/I
1" data just represent a certain thing phase.Should be noted also that in the evaluation of mixture,, at this moment, need not to rely on observed whole bands of a spectrum in high-purity sample, even bands of a spectrum may be distinctive to given crystallization also because the degradation factor can cause the disappearance of part diffracted ray under the content.
DSC measures when crystallization and changes owing to its crystalline structure or the crystal fusion absorbs or transition temperature during rejected heat.Crystal formation of the same race for compound of the same race, in successive was analyzed, thermal transition temperature and fusing point error were typically within about 5 ℃, usually within about 3 ℃, when we said that a compound has a given DSC peak or fusing point, this was meant this DSC peak or fusing point ± 5 ℃.DSC provides a kind of householder method of distinguishing different crystal forms.Different crystal habits can be discerned according to its different transition temperature feature.It is to be noted that for mixture its DSC peak or fusing point may change in the larger context.In addition since in the process of material fusing with decomposition, so temperature of fusion and temperature rise rate are closely related.
The Nelzarabine crystal composition that refinement treatment of the present invention obtains, its crystallization that contains Nelzarabine are more than 50%, preferably more than 70%, more preferably more than 90%, most preferably more than 95%.
Preparation method provided by the invention compares with currently known methods, has the following advantages: do not need to use enzyme catalysis, not high to equipment requirements, synthesis step is shorter, operates easier; The raw material that uses is cheap and easy to get, and whole synthetic route yield is higher, and preparation cost is lower, is a kind of economically feasible, the preparation method who is fit to industrialization production.
Description of drawings
Fig. 1 Nelzarabine crystalline XRD (X-ray powder diffraction) collection of illustrative plates-1
Fig. 2 Nelzarabine crystalline XRD (X-ray powder diffraction) collection of illustrative plates-2
Fig. 3 Nelzarabine crystalline DSC collection of illustrative plates
Embodiment
Following examples are used to illustrate the present invention, but should not be counted as limitation of the present invention.
The preparation of embodiment 1:6-O-methylguanosine
Get 248.0 gram sodium methylates and join in the 4.6L methyl alcohol, stir 15min, get white opacity liquid, add 310 gram 6-chlorine guanosine materials and dissolve rapidly, get yellowish solution, separate out white solid subsequently again, be heated to backflow, continue reaction 2.5 hours, be cooled to room temperature, stirring down, careful dripping hydrochloric acid solution is neutralized to PH=8-9, after removing solvent under reduced pressure, add 12L distilled water, 70 ℃ of stirring dissolvings down to the faint yellow dope of residue, add the 12g activated carbon again, heat filtering behind the 10min, filtrate, naturally cooling crystallization, filter, get the colourless crystallization solid, vacuum-drying gets 6-O-methylguanosine white solid 196.7 grams, yield 64.3%, mp:133-135 ℃; TLC (ethyl acetate: methyl alcohol=6: 1), product Rf=0.4, raw material Rf=0.45.
The preparation of embodiment 2:6-O-methylguanosine
Get 128 gram sodium methylates and join in the methyl alcohol, stir, get white opacity liquid, adding 160 gram 6-chlorine guanosine materials dissolves rapidly, get yellowish solution, separate out white solid subsequently again, be heated to backflow, continue reaction, be cooled to room temperature, careful dripping hydrochloric acid solution is neutralized to PH=8-9 under stirring, and steaming desolventizes the back and adds distilled water to the faint yellow dope of residue, 70 ℃ of stirring dissolvings down, add activated carbon again, heat filtering, filtrate, the naturally cooling crystallization, filter, get the colourless crystallization solid, vacuum-drying, get white solid 102.6 gram, i.e. 6-O-methylguanosines.Yield 65.0%, mp:133-135 ℃; TLC (ethyl acetate: methyl alcohol=6: 1), product Rf=0.4, raw material Rf=0.45.
The preparation of embodiment 3:6-O-methylguanosine
Get 800 gram sodium methylates and join in the methyl alcohol, stir, get white opacity liquid, adding 1000 gram 6-chlorine guanosine materials dissolves rapidly, get yellowish solution, separate out white solid subsequently again, be heated to backflow, continue reaction, be cooled to room temperature, careful dripping hydrochloric acid solution is neutralized to PH=8-9 under stirring, and desolventizes the back and adds distilled water to the faint yellow dope of residue, 70 ℃ of stirring dissolvings down, add activated carbon again, heat filtering, filtrate, the naturally cooling crystallization, filter, get the colourless crystallization solid, vacuum-drying, get white solid 598.8 gram, i.e. 6-O-methylguanosines.Yield 60.7%, mp:133-135 ℃; TLC (ethyl acetate: methyl alcohol=6: 1), product Rf=0.4, raw material Rf=0.45.
Embodiment 4:2 ', 3 ', the preparation of 5 '-three-O-ethanoyl-6-O-methylguanosine
Getting 195.0 gram 6-O-methylguanosines is dissolved in the 1950mL anhydrous pyridine, evaporated under reduced pressure, 60 ℃ of vacuum-drying 2 hours, repetitive operation is once, add the 3.9L acetonitrile then and mix stirring, get white opacity liquid, with 8.0gDMAP, the 66mL triethylamine adds in the white opacity liquid, adds the slow earlier back of 202.8mL diacetyl oxide in the reaction flask soon under the nitrogen protection, material dissolves gradually, stirring at room reaction 2 hours, reaction finishes, and adds 156mL ethanol in solution, with the reaction solution evaporated under reduced pressure, add the 10L ethyl acetate again, again with 5% sodium hydrogen carbonate solution washing secondary, each 2L, water ethyl acetate back extraction, merge organic phase, anhydrous sodium sulfate drying filters, filtrate decompression concentrates, concentrate resulting colourless colloidal solid 251.2 grams in back, promptly 2 ', 3 ', 5 '-three-O-ethanoyl-6-O-methylguanosine, yield 90.4%, and TLC (ethyl acetate: methyl alcohol=6: 1), raw material Rf=0.4; Product Rf=0.8.
Embodiment 5:2 ', 3 ', the preparation of 5 '-three-O-ethanoyl-6-O-methylguanosine
2 '; 3 '; the preparation method of 5 '-three-O-ethanoyl-6-O-methylguanosine is: get 102.0 gram 6-O-methylguanosines and be dissolved in the 1000mL anhydrous pyridine; evaporated under reduced pressure, 60 ℃ of vacuum-drying 2 hours, repetitive operation is once; add the 2L acetonitrile then and mix stirring; get white opacity liquid, with 4gDMAP; the 40mL triethylamine adds in the white opacity liquid, adds the slow earlier back of 130mL diacetyl oxide in the reaction flask soon under the nitrogen protection; material dissolves gradually; the stirring at room reaction, reaction finishes, and adds ethanol 120mL in solution; with the reaction solution evaporated under reduced pressure; add ethyl acetate again, again with 5% sodium hydrogen carbonate solution washing secondary, water ethyl acetate back extraction; merge organic phase; anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; concentrate resulting colourless colloidal solid 131.2 grams in back; promptly 2 ', 3 ', 5 '-three-O-ethanoyl-6-O-methylguanosine.Yield 90.3%, and TLC (ethyl acetate: methyl alcohol=6: 1), raw material Rf=0.4; Product Rf=0.8.
Embodiment 6:2 ', 3 ', the preparation of 5 '-three-O-ethanoyl-6-O-methylguanosine
Getting 590 gram 6-O-methylguanosines is dissolved in the 6000mL anhydrous pyridine; evaporated under reduced pressure, 60 ℃ of vacuum-drying 2 hours, repetitive operation is once; add the 10L acetonitrile then and mix stirring; get white opacity liquid, with 25gDMAP; the 180mL triethylamine adds in the white opacity liquid, adds the slow earlier back of 600mL diacetyl oxide in the reaction flask soon under the nitrogen protection; material dissolves gradually; the stirring at room reaction, reaction finishes, and adds ethanol in solution; with the reaction solution evaporated under reduced pressure; add ethyl acetate again, again with 5% sodium hydrogen carbonate solution washing secondary, water ethyl acetate back extraction; merge organic phase; anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; concentrate resulting colourless colloidal solid 752 grams in back; promptly 2 ', 3 ', 5 '-three-O-ethanoyl-6-O-methylguanosine.Yield 89.5%, and TLC (ethyl acetate: methyl alcohol=6: 1), raw material Rf=0.4; Product Rf=0.8.
Embodiment 7:3 ', the preparation of 5 '-two-O-ethanoyl-6-O-methylguanosine
Get 150 gram sodium-acetates and 137.5 gram oxammonium hydrochlorides, be suspended in the 3L anhydrous pyridine, stir 30min, under the nitrogen protection with 250 grams 2 ', 3 ', 5 '-three-O-ethanoyl-6-O-methylguanosine adds, and stirring reaction is 7 hours under the room temperature, and the TLC detection reaction finishes, in system, add 2.5L acetone, the reaction solution concentrating under reduced pressure adds 10L acetone continuation underpressure distillation and takes remaining pyridine out of in the leftover materials, crude product is dissolved in the acetone after-filtration, insoluble filter residue washing with acetone, merge acetone solution, concentrating under reduced pressure gets an oily matter, silica gel column chromatography, with ethyl acetate is eluting solvent, collect the product phase, evaporated under reduced pressure gets colourless colloidal solid, gets white solid 112.4 grams with methylene dichloride-heptane recrystallization, promptly 3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine, yield 49.9%, mp:150-153 ℃; TLC (ethyl acetate), raw material Rf=0.6; Product Rf=0.45;
1HNMR. (DMSO): δ=8.09 (s, 1H, H-8); 6.52 (s, 2H, NH
2); (5.88 d, 1H, H-1 '); 5.81 (d, 1H, 2 '-OH); (5.23 m, 1H, H-3 '); (4.87 m, 1H, H-2 '); (4.31 m, 1H, H-4 '); (4.23 m, 2H, H-5 '); 3.97 (s, 3H, OCH
3); 2.12 (s, 3H, CH
3CO); 2.04 (s, 3H, CH
3CO).
Embodiment 8:3 ', the preparation of 5 '-two-O-ethanoyl-6-O-methylguanosine
Get 79 gram sodium-acetates and 69 gram oxammonium hydrochlorides; be suspended in the 1.5L anhydrous pyridine; stir; under the nitrogen protection with 130 grams 2 ', 3 ', 5 '-three-O-ethanoyl-6-O-methylguanosine adds; stirring reaction under the room temperature; the TLC detection reaction finishes, and adds 5L acetone, reaction solution concentrating under reduced pressure in system; add acetone continuation underpressure distillation in the leftover materials and take remaining pyridine out of; crude product is dissolved in the acetone after-filtration, and insoluble filter residue washing with acetone merges acetone solution; concentrating under reduced pressure gets an oily matter; silica gel column chromatography, eluent ethyl acetate is collected the product phase; evaporated under reduced pressure gets colourless colloidal solid; get white solid 62.8 gram with methylene dichloride-heptane recrystallization, promptly 3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine.Yield 53.6%, mp:150-153 ℃; TLC (ethyl acetate), raw material Rf=0.6; Product Rf=0.45;
1HNMR. (DMSO): δ=8.09 (s, 1H, H-8); 6.52 (s, 2H, NH
2); (5.88 d, 1H, H-1 '); 5.81 (d, 1H, 2 '-OH); (5.23 m, 1H, H-3 '); (4.87 m, 1H, H-2 '); (4.31 m, 1H, H-4 '); (4.23 m, 2H, H-5 '); 3.97 (s, 3H, OCH
3); 2.12 (s, 3H, CH
3CO); 2.04 (s, 3H, CH
3CO).
Embodiment 9:3 ', the preparation of 5 '-two-O-ethanoyl-6-O-methylguanosine
Get 450 gram sodium-acetates and 421.3 gram oxammonium hydrochlorides; be suspended in the 10L anhydrous pyridine; stir; under the nitrogen protection with 750 grams 2 ', 3 ', 5 '-three-O-ethanoyl-6-O-methylguanosine adds; stirring reaction under the room temperature; the TLC detection reaction finishes, and adds acetone in system, the reaction solution concentrating under reduced pressure; add acetone continuation underpressure distillation in the leftover materials and take remaining pyridine out of; crude product is dissolved in the acetone after-filtration, and insoluble filter residue washing with acetone merges acetone solution; concentrating under reduced pressure gets an oily matter; silica gel column chromatography, ethyl acetate are eluent, collect the product phase; evaporated under reduced pressure gets colourless colloidal solid; get white solid 329.8 gram with methylene dichloride-heptane recrystallization, promptly 3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine.Yield 48.8%, mp:150-153 ℃; TLC (ethyl acetate), raw material Rf=0.6; Product Rf=0.45;
1HNMR. (DMSO): δ=8.09 (s, 1H, H-8); 6.52 (s, 2H, NH
2); (5.88 d, 1H, H-1 '); 5.81 (d, 1H, 2 '-OH); (5.23 m, 1H, H-3 '); (4.87 m, 1H, H-2 '); (4.31 m, 1H, H-4 '); (4.23 m, 2H, H-5 '); 3.97 (s, 3H, OCH
3); 2.12 (s, 3H, CH
3CO); 2.04 (s, 3H, CH
3CO).
Embodiment 10:2 '-O-trifyl-3 ', the preparation of 5 '-two-O-ethanoyl-6-O-methylguanosine
Get 110 the gram 3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine, the N of 35.2g; N-dimethyl aminopyridine and 46mL triethylamine add in the 1650mL anhydrous pyridine, are cooled to-10 ℃ under stirring, and carefully drip trifluoromethanesulfanhydride anhydride 60ml; be full of white smoke in the reaction flask; slightly heat up, dropwise, reaction solution becomes red-brown; stirring at room 2 hours; the TLC detection reaction finishes, and reaction solution is carefully poured in the frozen water, uses chloroform extraction four times; the combined chloroform phase; washing, chloroform is used anhydrous magnesium sulfate drying mutually, filters; filtrate is concentrated into dried; sorrel solid 125 gram, promptly 2 '-O-trifyl-3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine.Yield 84.4%, TLC (ethyl acetate), raw material Rf=0.45; Product Rf=0.8.
Embodiment 11:2 '-O-trifyl-3 ', the preparation of 5 '-two-O-ethanoyl-6-O-methylguanosine
Get 60 the gram 3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine, the N of 18g; N-dimethyl aminopyridine and 25mL triethylamine add in the 850mL anhydrous pyridine, are cooled to-10 ℃ under stirring, and carefully drip trifluoromethanesulfanhydride anhydride 33mL; be full of white smoke in the reaction flask; slightly heat up, dropwise, reaction solution becomes red-brown; stirring at room; the TLC detection reaction finishes, and reaction solution is carefully poured in the frozen water, uses chloroform extraction four times; the combined chloroform phase; washing, chloroform is used anhydrous magnesium sulfate drying mutually, filters; filtrate is concentrated into dried; sorrel solid 68 gram, promptly 2 '-O-trifyl-3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine.Yield 84.2%, TLC (ethyl acetate), raw material Rf=0.45; Product Rf=0.8.
Embodiment 12:2 '-O-trifyl-3 ', the preparation of 5 '-two-O-ethanoyl-6-O-methylguanosine
2 '-O-trifyl-3 '; the preparation method of 5 '-two-O-ethanoyl-6-O-methylguanosine is: get 320 the gram 3 '; 5 '-two-O-ethanoyl-6-O-methylguanosine, 35.2 gram N, N-dimethyl aminopyridine and triethylamine add in the anhydrous pyridine; be cooled to-10 ℃ under stirring; the careful trifluoromethanesulfanhydride anhydride 176mL that drips is full of white smoke in the reaction flask, slightly heat up; dropwise; reaction solution becomes red-brown, stirring at room, and the TLC detection reaction finishes; carefully pour into reaction solution in the frozen water; with chloroform extraction four times, combined chloroform phase, washing; chloroform is used anhydrous magnesium sulfate drying mutually; filter, filtrate is concentrated into dried, gets sorrel solid 365 grams; promptly 2 '-O-trifyl-3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine.Yield 84.7%, TLC (ethyl acetate), raw material Rf=0.45; Product Rf=0.8.
Embodiment 13:2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-three-O-ethanoyl arbinofuranose base) preparation of purine
Get 120 the gram 2 '-O-trifyl-3 '; 5 '-two-O-ethanoyl-6-O-methylguanosine adds in the 2500mL ethyl acetate; add 53mL acetate; the N that adds 120mL again; the N-diisopropyl ethyl amine; in the following 40 ℃ of reactions of nitrogen atmosphere, reflux then and stir, the TLC detection reaction finishes; add the ethyl acetate dilution again; solution with water after the dilution; sodium bicarbonate aqueous solution and saturated common salt water washing, underpressure distillation removes and desolvates gained crude product dehydrated alcohol recrystallization behind the anhydrous sodium sulfate drying; get white solid 85.3 grams; be 2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-three-O-ethanoyl arbinofuranose base) purine.Yield 86.2%, TLC (ethyl acetate), raw material Rf=0.8; Product Rf=0.6.
Embodiment 14:2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-three-O-ethanoyl arbinofuranose base) preparation of purine
Get 65 the gram 2 '-O-trifyl-3 '; 5 '-two-O-ethanoyl-6-O-methylguanosine adds in the 1300mL ethyl acetate; add 30mL acetate; add 68mLN again; the N-diisopropyl ethyl amine; in the following 40 ℃ of reactions of nitrogen atmosphere, reflux then and stir, the TLC detection reaction finishes; add the ethyl acetate dilution again; solution with water after the dilution; sodium bicarbonate aqueous solution and saturated common salt water washing, underpressure distillation removes and desolvates gained crude product dehydrated alcohol recrystallization behind the anhydrous sodium sulfate drying; get white solid 45.9 grams; be 2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-three-O-ethanoyl arbinofuranose base) purine.Yield 85.6%, TLC (ethyl acetate), raw material Rf=0.8; Product Rf=0.6.
Embodiment 15:2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-three-O-ethanoyl arbinofuranose base) preparation of purine
Get 350 the gram 2 '-O-trifyl-3 '; 5 '-two-O-ethanoyl-6-O-methylguanosine adds in the ethyl acetate; add acetate; add N again; the N-diisopropyl ethyl amine; in the following 40 ℃ of reactions of nitrogen atmosphere, reflux then and stir, the TLC detection reaction finishes; add the ethyl acetate dilution again; solution with water after the dilution; sodium bicarbonate aqueous solution and saturated common salt water washing, underpressure distillation removes and desolvates gained crude product dehydrated alcohol recrystallization behind the anhydrous sodium sulfate drying; get white solid 243 grams; be 2-amino-6-methoxy-9-β-D-(2 ', 3 ', 5 '-three-O-ethanoyl arbinofuranose base) purine.Yield 84.2%, TLC (ethyl acetate), raw material Rf=0.8; Product Rf=0.6.
Embodiment 16: the preparation of Nelzarabine
With 80 gram 2-amino-6-methoxyl group-9-β-D-(2 '; 3 ', 5 '-three-O-ethanoyl arbinofuranose base) purine adds in the 16L dehydrated alcohol, places ice-water bath to cool off; air in the logical nitrogen purge system; feed anhydrous ammonia gas then until the system homogeneous phase in system, products therefrom is placed in refrigerator, then concentrating under reduced pressure; the enriched product ethyl alcohol recrystallization; drying obtains Nelzarabine 50.9 grams, yield 90.6%.
1H-NMR(DMSO)：δ3.61-3.67(m，2H)，3.96(s，3H)，4.02-4.14(m，3H)，5.05(t，1H)，5.49(d，1H)，5.61(d，1H)，6.12(d，1H)，6.41(br，2H)，7.92(s，1H).
Embodiment 17: the preparation of Nelzarabine
With 45 gram 2-amino-6-methoxyl group-9-β-D-(2 '; 3 ', 5 '-three-O-ethanoyl arbinofuranose base) purine adds in the dehydrated alcohol, places ice-water bath to cool off; air in the logical nitrogen purge system; feed anhydrous ammonia gas then until the system homogeneous phase in system, products therefrom is placed in refrigerator, then concentrating under reduced pressure; the enriched product ethyl alcohol recrystallization; drying obtains Nelzarabine 27.3 grams, yield 86.4%.
Embodiment 18: the preparation of Nelzarabine
The preparation method of Nelzarabine is: with 240 gram 2-amino-6-methoxyl group-9-β-D-(2 '; 3 ', 5 '-three-O-ethanoyl arbinofuranose base) purine adds in the dehydrated alcohol, places ice-water bath to cool off; air in the logical nitrogen purge system; feed anhydrous ammonia gas then until the system homogeneous phase in system, products therefrom is placed in refrigerator, then concentrating under reduced pressure; the enriched product ethyl alcohol recrystallization; drying obtains Nelzarabine 152.0 grams, yield 90.2%.
Embodiment 19: the refinement treatment of Nelzarabine
50.0g Nelzarabine adds, and 1500ml methyl alcohol is mixed to be heated to backflow, stirs after 1 hour, material dissolves substantially, filters while hot, filtrate is concentrated into about 750ml, stirs down to add 1500ml dehydrated alcohol and 500ml ether, places cooling, 0 ℃ of crystallization 12h, filter, use absolute ethanol washing, drying.Obtain purified Nelzarabine crystallization 45.3g.
Embodiment 20: Nelzarabine crystalline X-ray powder diffraction is analyzed
Use Japanese Rigaku D/max-2400X ray powder diffraction instrument of science, with Cu-k α radiation, pipe stream 150mA, pipe press 40Kv, 8 degree/minute under with the step-length of 0.02 degree the sample of embodiment 19 is analyzed, it demonstrates X-ray powder diffraction collection of illustrative plates as illustrated in fig. 1 and 2.Its diffraction data is as shown in the table:
Embodiment 21: Nelzarabine crystalline differential scanning calorimetric analysis
Sample to embodiment 19 on the U.S. DSC-7 of PE company type differential scanning calorimeter carries out DSC mensuration, 250 ℃ of ceiling temperatures, 50 ℃ of lower limit temperatures, 10 ℃/min of temperature rise rate.
It has DSC collection of illustrative plates substantially as shown in Figure 3.The result shows that the initial fusing point of Nelzarabine crystalline of the present invention is 199.3 ℃, and summit temperature is 201.7 ℃.
Claims (10)
1. the crystallization of Nelzarabine, in the X-ray powder diffraction is analyzed, be about 8.9996,8.4665,5.4137,4.3838,4.1992,3.7667,3.4556,3.3682,3.2384,3.0702 places at lattice apart from the d value peak is arranged, its differential scanning calorimetric analysis is under the condition of 10 ℃/min of temperature rise rate, and peak temperature is 202 ℃.
2. the crystallization of the described Nelzarabine of claim 1, in the X-ray powder diffraction was analyzed, being about 13.3409,8.9996,8.4665,7.8517,6.5924,5.7564,5.4137,4.4713,4.3838,4.1992,4.1183,3.7667,3.5957,3.5201,3.4556,3.3682,3.2384,3.0702,3.0016 places at lattice apart from the d value had the peak.
3. claim 1 or 2 described Nelzarabine crystalline preparation methods, it comprises: Nelzarabine adds methanol mixed and is heated to backflow, dissolving back filtered while hot, filtrate concentrates, stir and add ethanol or ether down, placement cooling crystallization, filtration, use absolute ethanol washing, drying obtains the Nelzarabine crystallization.
4. the crystal composition of a Nelzarabine, its crystallization that contains claim 1 or 2 described Nelzarabines is more than 50%.
5. the described Nelzarabine crystal composition of claim 4, its crystallization that contains claim 1 or 2 described Nelzarabines is more than 70%.
6. the preparation method of a Nelzarabine comprises: formula III compound
Obtain the formula IV compound of 2 ' configuration reversal with the nucleophilic substitution reagent react
Then obtain Nelzarabine with deacylated tRNA base reagent react;
R wherein
1Be C
1-3The alkyl of atom; Phenyl; By 1-3 phenyl that is selected from the group replacement of methyl, halogen, nitro or methoxyl group;
R
3Be C
1-4Perfluoroalkyl;
R
2Be C
1-4The alkyl of atom; Phenyl; By 1-3 phenyl that is selected from the group replacement of methyl, halogen, nitro or methoxyl group.
7. the preparation method of the described Nelzarabine of claim 6, it comprises: the whole hydroxyl of 6-O-methylguanosine and acylating reagent reaction protection obtains formula I compound
Then obtain formula II compound with regioselective deacylation base reagent react
The reaction of formula II compound and sulfonylation agent obtains formula III compound then;
R wherein
1Be C
1-3The alkyl of atom; Phenyl; By 1-3 phenyl that is selected from the group replacement of methyl, halogen, nitro or methoxyl group.
8. the preparation method of the described Nelzarabine of claim 7, it comprises:
(1) 6-chlorine guanosine and methoxylation reagent react replace generation 6-O-methylguanosine;
(2) reaction of 6-O-methylguanosine and acetylation reagent obtain 2 ', 3 ', 5 '-three-O-ethanoyl-6-O-methylguanosine;
(3) 2 ', 3 ', 5 '-three-O-ethanoyl-6-O-methylguanosine under the protectant effect of selectively removing, slough 2 ' ethanoyl of position obtains 3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine;
(4) 3 ', the reaction of 5 '-two-O-ethanoyl-6-O-methylguanosine and sulfonylation agent obtains 2 '-O-trifyl-3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine;
(5) 2 '-O-trifyl-3 ', 5 '-two-O-ethanoyl-6-O-methylguanosine and nucleophilic substitution reagent react, obtain 2 ' configuration reversal 2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-three-O-ethanoyl arbinofuranose base) purine;
(6) remove compound 2-amino-6-methoxyl group-9-β-D-(2 ', 3 ', 5 '-three-O-ethanoyl arbinofuranose base) whole acyl groups of purine, obtain Nelzarabine.
9. new compound, structural formula is as follows:
R wherein
1Can be selected from C
1-3The alkyl of atom; Phenyl; By 1-3 phenyl that is selected from the group replacement of methyl, halogen, nitro or methoxyl group.
10. new compound, structural formula is as follows:
R wherein
1Can be selected from C
1-3The alkyl of atom; Phenyl; By 1-3 phenyl that is selected from the group replacement of methyl, halogen, nitro or methoxyl group;
R wherein
3Can be selected from C
1-4Perfluoroalkyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101543707A CN102250178A (en) | 2007-07-17 | 2008-01-28 | Synthesis of nelarabine |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710119140.0 | 2007-07-17 | ||
| CN 200710119140 CN101092441A (en) | 2007-07-17 | 2007-07-17 | Method for synthesizing nelarabine |
| CN2011101543707A CN102250178A (en) | 2007-07-17 | 2008-01-28 | Synthesis of nelarabine |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008100091467A Division CN101348511B (en) | 2007-07-17 | 2008-01-28 | Synthesis and refinement of nelarabine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102250178A true CN102250178A (en) | 2011-11-23 |
Family
ID=38990894
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710119140 Pending CN101092441A (en) | 2007-07-17 | 2007-07-17 | Method for synthesizing nelarabine |
| CN2008100091467A Active CN101348511B (en) | 2007-07-17 | 2008-01-28 | Synthesis and refinement of nelarabine |
| CN2011101543707A Pending CN102250178A (en) | 2007-07-17 | 2008-01-28 | Synthesis of nelarabine |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710119140 Pending CN101092441A (en) | 2007-07-17 | 2007-07-17 | Method for synthesizing nelarabine |
| CN2008100091467A Active CN101348511B (en) | 2007-07-17 | 2008-01-28 | Synthesis and refinement of nelarabine |
Country Status (1)
| Country | Link |
|---|---|
| CN (3) | CN101092441A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106317150A (en) * | 2016-08-22 | 2017-01-11 | 山东罗欣药业集团股份有限公司 | Crystalline compound for antitumor medicines and method for preparing crystalline compound |
| CN106397517A (en) * | 2016-08-22 | 2017-02-15 | 山东罗欣药业集团股份有限公司 | Compound for treating leukemia and preparation method thereof |
| CN115279891A (en) * | 2021-06-09 | 2022-11-01 | 正大天晴药业集团股份有限公司 | Recombinant gene engineering bacterium for preparing nelarabine and application thereof |
| WO2022258014A1 (en) * | 2021-06-09 | 2022-12-15 | 正大天晴药业集团股份有限公司 | Recombinant genetically engineered bacteria for preparing nelarabine, and application thereof |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101092441A (en) * | 2007-07-17 | 2007-12-26 | 北京本草天源药物研究院 | Method for synthesizing nelarabine |
| CN101683321B (en) * | 2008-09-27 | 2012-07-04 | 北京福瑞康正医药技术研究所 | Nelarabine parenteral solution and method for preparing same |
| CN101402662B (en) * | 2008-11-07 | 2011-06-15 | 江苏奥赛康药业有限公司 | Process for producing nelarabine |
| CN101768197A (en) * | 2008-12-29 | 2010-07-07 | 北京德众万全药物技术开发有限公司 | Preparation method for nelarabine |
| CN102313780B (en) * | 2010-07-07 | 2014-07-02 | 北京本草天源药物研究院 | Method for detecting and analyzing arranon |
| CN102002043B (en) * | 2010-11-16 | 2012-10-24 | 江苏科技大学 | Method for synthesizing 6-methoxy group purine derivative in presence of 4-aminopyridine as catalyst |
| CN103665076B (en) * | 2012-08-30 | 2018-01-09 | 上海阳帆医药科技有限公司 | The preparation method of nelarabine |
| CN103172687B (en) * | 2013-03-28 | 2015-07-08 | 山东罗欣药业集团股份有限公司 | Nelarabine crystalline compound and preparation method thereof |
| CN104892709B (en) * | 2015-06-04 | 2018-01-19 | 新乡学院 | A kind of method for synthesizing nelarabine |
| CN107556356B (en) * | 2017-09-27 | 2020-07-10 | 新乡拓新药业股份有限公司 | Method for synthesizing vidarabine |
| CN108373491B (en) * | 2018-04-18 | 2020-05-01 | 浙江诚意药业股份有限公司 | Preparation method of nelarabine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5602246A (en) * | 1992-11-25 | 1997-02-11 | Schering Aktiengesellschaft | Process for the preparation of fludarabine or fludarabine phosphate from guanosine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8712745D0 (en) * | 1987-05-30 | 1987-07-01 | Wellcome Found | Antiviral compounds |
| CN101092441A (en) * | 2007-07-17 | 2007-12-26 | 北京本草天源药物研究院 | Method for synthesizing nelarabine |
-
2007
- 2007-07-17 CN CN 200710119140 patent/CN101092441A/en active Pending
-
2008
- 2008-01-28 CN CN2008100091467A patent/CN101348511B/en active Active
- 2008-01-28 CN CN2011101543707A patent/CN102250178A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5602246A (en) * | 1992-11-25 | 1997-02-11 | Schering Aktiengesellschaft | Process for the preparation of fludarabine or fludarabine phosphate from guanosine |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106317150A (en) * | 2016-08-22 | 2017-01-11 | 山东罗欣药业集团股份有限公司 | Crystalline compound for antitumor medicines and method for preparing crystalline compound |
| CN106397517A (en) * | 2016-08-22 | 2017-02-15 | 山东罗欣药业集团股份有限公司 | Compound for treating leukemia and preparation method thereof |
| CN106317150B (en) * | 2016-08-22 | 2019-02-15 | 山东罗欣药业集团股份有限公司 | A kind of crystal-form compound of anti-tumor drug and preparation method thereof |
| CN106397517B (en) * | 2016-08-22 | 2019-02-15 | 山东罗欣药业集团股份有限公司 | A kind of compound and preparation method thereof for treating leukaemia |
| CN115279891A (en) * | 2021-06-09 | 2022-11-01 | 正大天晴药业集团股份有限公司 | Recombinant gene engineering bacterium for preparing nelarabine and application thereof |
| WO2022258014A1 (en) * | 2021-06-09 | 2022-12-15 | 正大天晴药业集团股份有限公司 | Recombinant genetically engineered bacteria for preparing nelarabine, and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101092441A (en) | 2007-12-26 |
| CN101348511A (en) | 2009-01-21 |
| CN101348511B (en) | 2011-10-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101348511B (en) | Synthesis and refinement of nelarabine | |
| ES2207403A1 (en) | Preparation of non-crystalline and crystalline dihydrate forms of azithromycin | |
| CN111925381B (en) | Synthesis method of baroxavir key intermediate | |
| CN102219817A (en) | Method for carrying out carbalkoxylation acylation on fluorouracil compound with active coupling agent | |
| CN100425617C (en) | Fluoropyrimidine compound carbalkoxylation method | |
| CN114105978A (en) | Oxindole compound and preparation method and application thereof | |
| JPS63107994A (en) | Erythromycin derivative | |
| CN101302207A (en) | Preparation of 3-o-alkyl-5,6-o-(1-methyl ethylidine)-l-ascorbic acid and preparation of 5,6-o-(1- methyl ethylidine)-l- ascorbic acid | |
| JPWO2008093853A1 (en) | Macrolide compound solid, process for producing the same, and pharmaceutical composition thereof | |
| CN107216361B (en) | The preparation method of rope Citropten | |
| CN109053839A (en) | The novel processing step of 3 '-O-CH2N3-2 '-O-Me- cytidine of nucleosides modifier | |
| CA2292754C (en) | Process for the preparation of a deoxyuridine derivative | |
| CN107216360B (en) | A method of preparing rope Citropten | |
| CN108101881A (en) | It is used to prepare the method and its intermediate of tributidine | |
| CN117624044A (en) | Preparation method of lenvatinib | |
| CN111233751B (en) | Preparation method of 3, 3-difluoro-4-aminopiperidine compound and derivative thereof | |
| EP1258489B1 (en) | Method for purifying 5'-protected thymidines | |
| CN109776639B (en) | Synthetic method of arabinoside compound impurity | |
| CN100334101C (en) | Method for synthesizing 2',3'-dideoxy cytidine | |
| CN103665076B (en) | The preparation method of nelarabine | |
| CN106146573A (en) | Leonurine metabolite and preparation method thereof | |
| CN116947865A (en) | Synthesis method of risperidone intermediate and Li Sipu blue intermediate | |
| JP5192807B2 (en) | Stable crystals of protected pseudouridine | |
| CN116239531A (en) | Preparation method of lenvatinib | |
| JP3983085B2 (en) | Method for producing inclusion compounds of 5'-protected 2'-deoxypurine nucleosides |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| CB02 | Change of applicant information |
Address after: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Applicant after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address before: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Applicant before: Jiangsu Chiatai Tianqing Pharmaceutical Co., Ltd. |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: JIANGSU ZHENGDA TIANQING PHARMACEUTICAL CO., LTD. TO: CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD. |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20111123 |