CN108864235A - A kind of 1- halogen -2,3,5- oxygen -（Replace）The preparation method of benzyl-D- arabinofuranose and nelarabine - Google Patents
A kind of 1- halogen -2,3,5- oxygen -（Replace）The preparation method of benzyl-D- arabinofuranose and nelarabine Download PDFInfo
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Abstract
The invention discloses a kind of 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose preparation methods：1- oxygen-alkyl -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose obtains 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose through hydrogen halides substitution reaction.And a kind of preparation method of standby nelarabine, 1- halogen -2 according to claim 5,3,5- oxygen-(substitution) benzyl-D- arabinofuranose obtains 2- amino -6- methoxyl group -9- [2 ' through chemical synthesis with 2- amino -6- methoxypurine, 3 ', 5 '-three-oxygen-(substitution) benzyl-β-D- arabinofuranosidase glycosyl] purine, then 2 are sloughed by catalytic hydrogenation, 3,5- oxygen-(substitution) benzyl obtains nelarabine.Preparation method of the invention has merging step few, and raw material is cheap, and obtained finished product can obtain higher-quality intermediate product and target product convenient for purification, so that the present invention is more advantageous to the production of commercial running large-scale.
Description
Technical field
The present invention relates to the technical fields of medicine specifically to refer to a kind of 1- halogen -2,3,5- oxygen-(substitution) benzyl-D-
The preparation method of arabinofuranose and nelarabine.
Background technique
Acute T cell lymphocytic leukemia (T-ALL) and T- cell lymphoblastic lymthoma (T-LBL) are
The malignant tumour of rare T lymphocyte, speed of worsening quickly, seriously affect the hematopoiesis function of body.The cure rate in children
Reach 80%, but adult cure rate is lower, and patient's poor prognosis that is unresponsive to standard care or recurring, so it is clinical anxious
There need to be more highly selective and active drug to T- cell.
The entitled 9- β-D- arabinofuranosidase glycosyl -6- methoxyl group -9H- purine -2- amine of nelarabine (nelarabine) chemistry,
Trade name Arranon is by the water of the cytotoxin arabinoguanosine of plain (GlaxoSmithKline) the company research and development of Britain Ge Lan
Dissolubility prodrug is clinically used for treating the acute T cell lymph mother recurred again after or treatment reactionless at least two kinds of chemotherapy regimens
Cell leukemia (T-ALL) and T- cell lymphoblastic lymthoma (T-LBL).
Existing synthesis 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose preparation method, which usually exists, to be needed
More synthesis step, and 1- halogen -2,3 is prepared, the generated time of 5- oxygen-(substitution) benzyl-D- arabinofuranose is longer,
It is at high cost, be unfavorable for the technical issues of enterprise's industrialized production.
By 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose is synthesized in the synthetic method of nelarabine,
That there are synthetic routes is more, the reaction time is longer, and higher cost, is difficult to realize the technical issues of industrialized production.
Summary of the invention
The first purpose of this invention is to provide a kind of 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose
Preparation method, can effectively shorten synthesis step, reduce enterprise's production cost.
Second object of the present invention is to provide a kind of 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranosidase
Sugar.
Third object of the present invention is to provide a kind of preparation method of nelarabine, and synthetic route is short, high income, produces
Quality is high, and can be suitable for enterprise's industrialized production.
What the embodiment of the present invention was realized in：
A kind of preparation method of 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose：1- oxygen-alkyl -2,3,
5- oxygen-(substitution) benzyl-D- arabinofuranose obtains 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- through hydrogen halides substitution reaction
Arabinofuranose.
A kind of obtained 1- halogen -2,3,5- oxygen-of 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose preparation method
(substitution) benzyl-D- arabinofuranose.
A kind of preparation method of nelarabine：1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose and 2- amino -
6- methoxypurine obtains 2- amino -6- methoxyl group -9- [2 ', 3 ', 5 '-three-oxygen-(substitution) benzyl-β-d- Ah through chemical synthesis
Draw primary furyl glycosyl] purine, then 2,3,5- oxygen-(substitution) benzyl is sloughed by catalytic hydrogenation and obtains nelarabine.
The beneficial effect of the embodiment of the present invention is：1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose, is logical
1- oxygen-alkyl -2,3 is crossed, 5- oxygen-(substitution) benzyl-D- arabinofuranose is reacted through hydrogen halides to be made, which can
Effectively shorten synthesis step, and easy to operate, while yield is higher, and can effectively reduce enterprise's production cost, it is more suitable
Large-scale production is industrialized for enterprise.
It the series reactions such as is chemically synthesized by 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose to obtain
To the method for nelarabine, this method preparation process is simple, and intermediate product in the step and target product are convenient for purifying,
Be conducive to obtain the nelarabine of high quality, which can effectively reduce the production cost of enterprise, and the preparation side
Method can be suitable for the production of large-scale.
Detailed description of the invention
In order to illustrate the technical solution of the embodiments of the present invention more clearly, below will be to needed in the embodiment attached
Figure is briefly described, it should be understood that the following drawings illustrates only certain embodiments of the present invention, therefore is not construed as pair
The restriction of range for those of ordinary skill in the art without creative efforts, can also be according to this
A little attached drawings obtain other relevant attached drawings.
Fig. 1 is that the nuclear-magnetism of the bromo- 2,3,5- oxygen-of 1- of the embodiment of the present invention (2,4- dichloro benzyl)-D- arabinofuranose is total
The hydrogen that shakes is composed；
Fig. 2 is 2- of embodiment of the present invention amino -6- methoxyl group -9- [2 ', 3 ', 5 '-three-oxygen-(2,4- dichloro benzyl)-β -
D- arabinofuranosidase glycosyl] purine nuclear magnetic resonance spectroscopy；
Fig. 3 is 2- of embodiment of the present invention amino -6- methoxyl group -9- [2 ', 3 ', 5 '-three-oxygen-(2,4- dichloro benzyl)-β -
D- arabinofuranosidase glycosyl] purine carbon-13 nmr spectra；
Fig. 4 is the nuclear magnetic resonance spectroscopy of nelarabine of the embodiment of the present invention；
Fig. 5 is the carbon-13 nmr spectra of nelarabine of the embodiment of the present invention.
Specific embodiment
It in order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below will be in the embodiment of the present invention
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, according to normal conditions or manufacturer builds
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
Below to a kind of 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose provided in an embodiment of the present invention
Preparation method and the preparation method of nelarabine are specifically described.
The embodiment of the present invention provides a kind of preparation side of 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose
Method, 1- oxygen-alkyl -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose obtain 1- halogen -2,3 through hydrogen halides substitution reaction,
5- oxygen-(substitution) benzyl-D- arabinofuranose.
1- halogen -2,3 prepared by the present invention, 5- oxygen-(substitution) benzyl-D- arabinofuranose are by 1- oxygen-alkyl -
2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose is reacted through hydrogen halides to be made.
The preparation method can effectively shorten obtained 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose step
Suddenly.
Further, the hydrogen halides is excellent can choose as at least one of hydrogen bromide, hydrogen chloride, hydrogen fluoride or hydrogen iodide,
It is further preferably hydrogen bromide or hydrogen chloride, still further preferably hydrogen bromide.
Wherein hydrogen halides, herein it should be strongly noted that if it is hydrogen bromide or hydrogen chloride and 1- oxygen-is passed directly into
Alkyl -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose reaction, in the reaction process, because be passed directly into hydrogen bromide or
The amount of person's hydrogen chloride is not easy to control, and is not easy to control entire synthesis process, while influencing synthetic effect, therefore in the present embodiment
In, the preparation method of further preferred hydrogen bromide or hydrogen chloride is then to instill acetyl bromide by the way that alcohol is added in organic solvent
Or chloroacetic chloride, reaction are made after a certain period of time, this method can effectively control the amount of hydrogen bromide or hydrogen chloride, and then convenient for control
Entire synthesis process improves synthesis quality to reduce error.
After hydrogen bromide made from the above method or hydrogen chloride, then 1- oxygen-alkyl -2,3,5- oxygen-are added thereto
The reaction was continued disappears to raw material for (substitution) benzyl-D- arabinofuranose, and ice water extraction is added and goes out reaction, reaction temperature for -20~
100 DEG C, the reaction time is 1~24 hour, and liquid separation, organic phase uses dilute alkaline aqueous solution and water washing respectively, is dried, filtered, and is depressurized
Concentration and recovery solvent, residue are 1- bromine (chlorine) -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose.
Further, the organic solvent is chloroform, methylene chloride, 1,2- dichloroethanes, tetrahydrofuran, 2- methyl tetrahydro furan
It mutters, at least one of dioxane, ether, the tertiary ether of first or diisopropyl ether.
Further, the alcohol be methanol, ethyl alcohol, trifluoroethanol, propyl alcohol, isopropanol, butanol, sec-butyl alcohol or the tert-butyl alcohol in extremely
Few one kind.
Further, alcohol, acetyl bromide or chloroacetic chloride and 1- oxygen-alkyl -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranosidase
The optional range 1.5 of molar ratio of sugar：1.2：1~2.5：2.2：1；It is reacted 1~24 hour in -20~100 DEG C of temperature ranges.
At this it should be strongly noted that 1- oxygen-alkyl -2,3,5- oxygen-(substitution) benzyl-D- are Arabic in the present embodiment
Furanose is by obtaining 1- oxygen-alkyl -2,3,5- oxygen-(substitution) benzyl-D- through chemical synthesis using D-arabinose as raw material
Arabinofuranose, then again by 1- oxygen-alkyl -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose is through chemical synthesis
Obtain 1- bromine (chlorine) -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose.
Specific reaction equation：
Specific preparation process is as follows：
(1) D-arabinose (I) is dissolved in alcoholic solvent, acid catalyst is added, end of reaction is added inorganic base and is neutralized to
Recycling design is concentrated under reduced pressure in neutrality, filtering, and residue is 1- oxygen-alkyl-D- arabinofuranose (II)；
Wherein alcoholic solvent is preferably at least one of methanol, ethyl alcohol, trifluoroethanol, propyl alcohol or isopropanol, in this alcoholic solvent
Solvent is also used as reactant.
Wherein acid catalyst is preferably at least one of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoromethayl sulfonic acid or trifluoroacetic acid；
Further, inorganic base includes lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, hydroxide
Calcium, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, saleratus, potassium phosphate, dipotassium hydrogen phosphate, sodium acetate or
At least one of potassium acetate is 1~50mol% in the dosage of this acid catalyst.
At -20~100 DEG C, the reaction time is 2~24 hours for the reaction temperature control of this step.
(2) 1- oxygen-alkyl-D- arabinofuranose is dissolved in solvent, sodium hydride is added, reaction is added after 1 hour and (taken
Generation) benzyl chloride or (substitution) bromobenzyl, ice water and organic solvent, liquid separation are added after the reaction was continued, organic phase is done with water washing
Dry, recycling design is concentrated under reduced pressure in filtering, and residue is 1- oxygen-alkyl -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranosidase
Sugar.
Wherein (replace) benzyl chloride or (substitution) bromobenzyl includes benzyl chloride, bromobenzyl, 4- chlorobenzyl chloride, 4- chlorine bromobenzyl, 4- bromine benzyl chloride, 4-
Bromine bromobenzyl, 4- methoxyl group benzyl chloride, 4- methoxyl group bromobenzyl, 4- nitro benzyl chloride, 4- nitro bromobenzyl, 2,4 dichloro benzyl chloride or 2,4- dichloro
At least one of bromobenzyl.
Wherein organic solvent includes N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrofuran, 2- methyl tetrahydro
The tertiary ether of furans, dioxane, ether, first, diisopropyl ether, glycol dimethyl ether, acetonitrile, acetone, butanone, dimethyl sulfoxide or N- first
At least one of base pyrrolidones.
In the reaction process, 1- oxygen-alkyl-D-arabinose, sodium hydride and (substitution) benzyl chloride or (substitution) bromobenzyl
The optional range 1 of molar ratio：3.3：3.3~1：6.6：6.6.
Range of reaction temperature is controlled at 0~100 DEG C, the reaction time 2~24 hours
The step of present invention prepares 1- oxygen-alkyl -2,3, and 5- oxygen-(substitution) benzyl-D- arabinofuranose synthesizes is few, and
It is easy to operate, it is higher by yield, and enterprise's production cost can be effectively reduced, it is extensive to be more suitable for enterprise's industrialization
Production.
Halogen -2,3 1- are made by preparation 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose preparation method,
5- oxygen-(substitution) benzyl-D- arabinofuranose product, which can be effectively reduced enterprise's production cost, more real
It is produced on a large scale with enterprise.
The embodiment of the present invention provides a kind of nelarabine preparation method, 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- I
Primary furanose obtains 2- amino -6- methoxyl group -9- [2 ', 3 ', 5 '-three-oxygen-through chemical synthesis with 2- amino -6- methoxypurine
(2,4- dichloro benzyl)-β-D- arabinofuranosidase glycosyl] purine, then 2,3,5- oxygen-(substitution) benzyl is sloughed by catalytic hydrogenation
Obtain nelarabine.
Nelarabine is obtained through the above steps, the preparation method synthetic route is short, and it is low in cost, it is extensive to be conducive to enterprise
Metaplasia produces, while according to above-mentioned a series of preparation method, intermediate product and target product can be pure by recrystallization progress
Change, isomers is effectively removed, so that final goal product quality is effectively guaranteed.
Further, the chemical synthesis includes：2- amino -6- methoxypurine is dissolved in organic solvent, alkali, reaction is added
After a certain period of time, 1- halogen -2,3 is added, 5- oxygen-(substitution) benzyl-D- arabinofuranose reacts certain time, obtains 2-
Amino -6- methoxyl group -9- [2 ', 3 ', 5 '-three-oxygen-(substitution) benzyl-β-D- arabinofuranosidase glycosyl] purine, the chemical synthesis
Specially glycosylation reaction.
Further, the organic solvent be acetonitrile, n,N-Dimethylformamide, n,N-dimethylacetamide, tetrahydrofuran,
The tertiary ether of 2- methyltetrahydrofuran, dioxane, ether, first, diisopropyl ether, glycol dimethyl ether, acetonitrile, acetone, butanone, diformazan
At least one of sulfoxide or N-Methyl pyrrolidone.
Further, the alkali is sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrogen
At least one of cesium oxide, magnesium hydroxide, calcium hydroxide or barium hydroxide.
Further, 2- amino -6- methoxypurine, alkali and 1- bromo- 2,3,5- oxygen-(substitution) benzyl-D-arabinose
The optional range 1.5 of molar ratio：1.2：1~5.5：5.2：1.
Further, at 0~100 DEG C, the reaction time is 1~24 hour for the rhEndostatin control of the reaction.
Further, the catalytic dehydrogenation includes：By 2- amino -6- methoxyl group -9- [2 ', 3 ', 5 '-three-oxygen-(substitution) benzyl
Base-β-D- arabinofuranosidase glycosyl] purine is dissolved in solvent, addition catalyst, and is passed through hydrogen or ammonium formate is added, and reaction obtains
Target product nelarabine.
Further, the solvent is in methanol, ethyl alcohol, trifluoroethanol, propyl alcohol, isopropanol, butanol, sec-butyl alcohol or the tert-butyl alcohol
At least one.
Further, the catalyst is Pd/C, Pd (OH)2At least one of/C or Raney Ni, wherein the catalysis
The optional range of the dosage of agent is 10mol%~100mol%, and temperature is controlled at 0~100 DEG C, and the reaction time was at 1~48 hour.
By the above-mentioned method for preparing nelarabine, this method preparation process is simple, and the intermediate product in the step and
Target product is convenient for purifying, and is conducive to the nelarabine for obtaining high quality, which can effectively reduce the life of enterprise
Cost is produced, and the preparation method can be suitable for the production of large-scale.
Embodiment 1：
A kind of 1- bromo- 2, the preparation method of 3,5- tri--oxygen-(2,4- dichloro benzyl)-D-arabinose,
Specific steps：
(1)：Prepare 1- oxygen-methyl D-arabinofuranose
It in 2L flask, is added D-arabinose (100g, 0.67mol), 1500 milliliters of methanol, 10 milli of the concentrated sulfuric acid is added
It rises, is warming up to 40 DEG C and stirs 24 hours.Be cooled to room temperature, be added sodium hydroxide (10g, 0.25mol), stirring, adjust pH value be 7~
8, it filters, is concentrated under reduced pressure, residue need not purify and be directly used in the next step.
(2)：Prepare 1- oxygen-three-oxygen of methyl -2,3,5--(2,4- dichloro benzyl)-D- arabinofuranose
In 100 milliliters of three-necked flasks, sodium hydride (60%, 3.47g, 87mmol) and 30 milliliters of DMF are added, stir, delay
The slow solution that 1- oxygen-methyl D-arabinofuranose (IIa) (3.72g, 17mmol) is added dropwise and is dissolved in 20 milliliters of DMF, there is a large amount of gas
Bubble generates.After being added dropwise, continue stirring 30 minutes.It is added at one time 2,4- dichlorobenzyl chloride (13.6g, 70mmol), water is cooling
Under, it quickly stirs, heat release is obvious, and has bubble formation.Temperature is no more than 40 degree in control, continues stirring 3 hours, and a small amount of water is added to extract
It goes out reaction.Reaction mixture is transferred in beaker, 300 milliliters of water are added, is stirred, white solid is precipitated in bottom of a cup, is placed in refrigerator-freezer
Middle cooling 30 minutes.Incline upper layer aqueous, 100 milliliters of methylene chloride dissolved solids is added, organic layer is washed with water three times, with sulphur
Sour magnesium dries, filters, and is concentrated under reduced pressure.Thick white solid is precipitated with Diethyl ether recrystallization in residue, refrigerates 1 hour, filtering, Gu
Body obtains white solid (9.36g, yield 86%) with cold ether, drying.1H NMR(300MHz,CDCl3)δ7.46-7.33
(m, 6H), 4.93 (d, J=4.1Hz, 1H), 4.75-4.66 (m, 6H), 4.21-4.14 (m, 3H), 3.67 (d, J=5.6Hz,
2H),3.41(s,3H)。
(3)：Prepare the bromo- tri--oxygen of 2,3,5--of 1- (2,4- dichloro benzyl)-D arabinofuranose
In 100 milliliters of three-necked flasks, 75 milliliters of methylene chloride, methanol (1mL, 24mmol) is added, ice water is cooling, is added
After 30 minutes, 1- oxygen-methyl -2,3, tri--oxygen of 5--(2,4- dichloro benzyl)-is added in acetyl bromide (3.6mL, 48mmol), stirring
D-arabinose (IIIa) (7.7g, 12mmol), is stirred at room temperature 8 hours.Extract reaction of going out, liquid separation with ice water, organic layer is used
NaHCO3Saturated solution washed once, and be washed with water 2 times, and magnesium sulfate dries, filters, and be concentrated under reduced pressure, and residue need not purify straight
It connects for the next step.
Comparative example：
A kind of 1- chloro- 2, the preparation method of 3,5- oxygen-(substitution) benzyl-D- arabinofuranose, by glycosylation precursor 1-
Chloro- 2,3,5- oxygen-benzyl-D- arabinofuranose (X) and 2- amino -6- methoxypurine are condensed to yield glycosylation product, and
Glycosylation precursor 1- chloro- 2,3,5- oxygen-benzyl-D- arabinofuranose (X) are to react to obtain through five steps by D-arabinose, tool
Body chemical equation is as follows：
The preparation method step is complicated, and obtained product yield is lower.
Description of test：
Illustrated by experimental example 1 and the Experimental Comparison of comparative example, a kind of 1- halogen -2,3 provided by the present invention, 5- oxygen-(take
Generation) benzyl-D- arabinofuranose preparation method, using D-arabinose as raw material, it is only necessary to can be obtained by by 4 steps,
And existing preparation method then needs 6 steps to few, so that it is few to obtain this method synthesis step, while adopting during this preparation method
Raw material is cheap, is more advantageous to the production of enterprise's large-scale, further, by a process for preparing 1- halogen -2,3,5-
Oxygen-(substitution) benzyl-D- arabinofuranose and subsequently through 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranosidase
Sugar prepares nelarabine and intermediate product, can be conducive to purify, obtain higher-quality product, is enterprise's large-scale production
More favorable condition is provided.
Embodiment 2：
A kind of preparation method preparing nelarabine：
Whole specific reaction equation is as follows：
(1)：Prepare 1- oxygen-methyl D-arabinofuranose
It in 2L flask, is added D-arabinose (100g, 0.67mol), 1500 milliliters of methanol, 10 milli of the concentrated sulfuric acid is added
It rises, is warming up to 40 DEG C and stirs 24 hours.Be cooled to room temperature, be added sodium hydroxide (10g, 0.25mol), stirring, adjust pH value be 7~
8, it filters, is concentrated under reduced pressure, residue need not purify and be directly used in the next step.
(2)：Prepare 1- oxygen-three-oxygen of methyl -2,3,5--(2,4- dichloro benzyl)-D- arabinofuranose
In 100 milliliters of three-necked flasks, sodium hydride (60%, 3.47g, 87mmol) and 30 milliliters of DMF are added, stir, delay
The slow solution that 1- oxygen-methyl D-arabinofuranose (3.72g, 17mmol) is added dropwise and is dissolved in 20 milliliters of DMF, has a large amount of bubbles raw
At.After being added dropwise, continue stirring 30 minutes.It is added at one time 2,4- dichlorobenzyl chloride (13.6g, 70mmol), under water is cooling, fastly
Speed stirring, heat release is obvious, and has bubble formation.Temperature is no more than 40 degree in control, continues stirring 3 hours, adds a small amount of water extraction to go out anti-
It answers.Reaction mixture is transferred in beaker, 300 milliliters of water are added, is stirred, white solid is precipitated in bottom of a cup, is placed in cold in refrigerator-freezer
But 30 minutes.Incline upper layer aqueous, 100 milliliters of methylene chloride dissolved solids is added, organic layer is washed with water three times, with magnesium sulfate
It dries, filters, is concentrated under reduced pressure.Thick white solid is precipitated with Diethyl ether recrystallization in residue, refrigerates 1 hour, filtering, solid with
Cold ether, it is dry, obtain white solid (9.36g, yield 86%).1H NMR(300MHz,CDCl3)δ7.46-7.33(m,
6H), 4.93 (d, J=4.1Hz, 1H), 4.75-4.66 (m, 6H), 4.21-4.14 (m, 3H), 3.67 (d, J=5.6Hz, 2H),
3.41(s,3H)。
(3)：Prepare the bromo- tri--oxygen of 2,3,5--of 1- (2,4- dichloro benzyl)-D arabinofuranose
In 100 milliliters of three-necked flasks, 75 milliliters of methylene chloride, methanol (1mL, 24mmol) is added, ice water is cooling, is added
After 30 minutes, 1- oxygen-methyl -2,3, tri--oxygen of 5--(2,4- dichloro benzyl)-is added in acetyl bromide (3.6mL, 48mmol), stirring
D-arabinose (IIIa) (7.7g, 12mmol), is stirred at room temperature 8 hours.Extract reaction of going out, liquid separation with ice water, organic layer is used
NaHCO3Saturated solution washed once, and be washed with water 2 times, and magnesium sulfate dries, filters, and be concentrated under reduced pressure, and residue need not purify straight
It connects for the next step.
(4) 2- amino -6- methoxyl group -9- [2 ', 3 ', 5 '-three-oxygen-(2,4- dichloro benzyl)-β-D-arabinose is prepared
Base] purine
16.96 grams of 2- amido-6-chloropurines (V) (16.96g, 0.1mol) are dissolved in 250 milliliters of anhydrous acetonitriles, room temperature is stirred
4.00 grams of sodium hydrides (60%, 4.00g, 0.1mol) of lower addition are mixed, are reacted at room temperature 3 hours.By the bromo- tri--oxygen of 2,3,5--of 1- (2,
4- dichloro benzyl)-D-arabinose (IVa) (34.50g, 0.05mol) be dissolved in 250 milliliters of acetonitriles solution instill reaction flask in,
Reaction about 24 hours is stirred at room temperature, filters, is concentrated under reduced pressure, residue obtains white solid with ether/petroleum ether (1/5) recrystallization
(24.21g, yield 25%).1H NMR(300MHz,CDCl3) δ 7.96 (s, 1H), 7.38-7.30 (m, 4H), 7.27 (d, J=
2.1Hz,1H),7.24-7.18(m,2H),7.40(dd,J 1=2.1Hz, J2=8.3Hz, 1H), 6.85 (d, J=8.3Hz,
1H), 6.39 (d, J=3.6Hz, 1H), 4.96 (s, 2H), 4.73 (d, J=12.9Hz, 1H), 4.65 (d, J=12.7Hz, 1H),
4.61 (s, 2H), 4.49 (d, J=12.3Hz, 1H), 4.38-4.30 (m, 3H), 4.19 (dd, J1=4.6Hz, J2=9.5Hz,
1H), 4.07 (s, 3H), 3.78 (d, J=4.6Hz, 2H)13C NMR(75MHz,CDCl3)δ161.1,159.2,153.1,
138.6,134.0,133.9,133.8,133.6,133.3,133.2,132.5,129.8,129.7,129.6,128.9,
128.8,128.7,126.9,126.8,114.6,82.5,82.2,81.3,79.8,69.7,69.2,69.1,53.6。
(5) 2- amino -6- methoxyl group -9- (β-D-arabinose base) purine
In 100 milliliters of flasks, 2- amino -6- methoxyl group -9- [2 ', 3 ', 5 '-three-oxygen-(2,4- dichloro benzyl)-are added
β-d- aralino] purine (VIa) (2.31g, 2.98mmol), Pd-C (10%, 1.14g, 0.54mmol) and 100 milliliters
Methanol is passed through hydrogen, flows back 2 hours.Filtering is concentrated under reduced pressure, and residue is obtained white with ethyl acetate/methanol (1/5) recrystallization
Solid (0.49g, yield 57%).1H NMR (300MHz, D6-DMSO) δ 7.92 (s, 1H), 6.46 (s, 2H), 6.12 (d, J=
4.1Hz, 1H), 5.63 (d, J=5.1Hz, 1H), 5.52 (d, J=3.9Hz, 1H), 5.08 (t, J=5.5Hz, 1H), 4.09-
4.03(m,2H),3.95(s,2H),3.80-3.70(m,1H),3.69-3.56(m,2H).13C NMR(75MHz,D6-DMSO)δ
160.6,159.8,154.0,139.1,113.2,84.2,83.4,75.5,75.3,61.0,53.2。
The existing synthetic method for preparing nelarabine mainly has：
1, using 2- amino -6- methoxypurine and uracil arabinose glycosides as raw material, nelarabine is obtained using enzymatic process,
There are invertases that expensive, strain is difficult to obtains for this method, the reaction time too long (nearly one month), stringent to equipment requirement
The problems such as, therefore, which is difficult to realize industrialize.
2, it reacts to obtain 2- amino -6- methoxypurine, 1- oxygen-right by raw material and sodium methoxide of 2- amido-6-chloropurine
Nitro benzoyl -2,3,5- oxygen-benzyl-D- arabinofuranose is through chlorination, the condensation both under heavy metal catalyst effect
Glycoside products are obtained, most obtain nelarabine, the oxygen of 1- used in this method-p-nitrophenyl formoxyl -2,3,5- oxygen-through deprotection afterwards
Benzyl-D- arabinofuranose is to be obtained by D-arabinose through four-step reaction, and cost of material is high, reaction yield is low, therefore should
The nelarabine cost that method synthesizes is higher.
3, it using 6- chlorine guanosine as raw material, is converted by configuration and D-RIBOSE segment is changed into D- arabinofuranosidase sugar-tablet
Section is to obtain nelarabine, and there is also raw materials for this method costly, the longer problem of route.
4, using arabinoguanosine as raw material, by protection, chlorination, deprotection, methoxy substitution three-step reaction obtains naira simultaneously
Shore, the route steps are short, high income, but arabinoguanosine price or more expensive.
By the preparation method that the existing method for preparing nelarabine and the present embodiment prepare nelarabine compares：
What the present invention used is that the relatively existing raw material for preparing nelarabine of raw material is cheap compared to more crying with D-arabinose etc.,
It is more advantageous to the production development demand of enterprise.
The present invention prepares nelarabine synthetic route and is obviously shortened relative to existing preparation method synthesis step, can be effective
The throughput rate for improving synthesis nelarabine is more advantageous to the large-scale production of commercial running.
For the nelarabine that the relatively existing preparation method of quality that the present invention prepares nelarabine obtains, this method preparation process
In be more convenient for purification, optimized product performance, higher-quality nelarabine can be obtained, thus improve enterprise society competition
Power.
Although an embodiment of the present invention has been shown and described, it will be understood by those skilled in the art that being：?
A variety of change, modification, replacement and modification, the present invention can be carried out to these embodiments by not departing under the principle of the present invention and objective
Range be defined by the claims and their equivalents.
Claims (10)
1. a kind of 1- halogen -2,3, the preparation method of 5- oxygen-(substitution) benzyl-D- arabinofuranose, it is characterised in that：1- oxygen-
Alkyl -2,3,5- oxygen-(substitution) benzyl-D- arabinofuranose obtains 1- halogen -2,3,5- oxygen through hydrogen halides substitution reaction-(takes
Generation) benzyl-D- arabinofuranose.
2. preparation method according to claim 1, it is characterised in that：The hydrogen halides is by being added in organic solvent
Alcohol, then instill acetyl halide and react to obtain.
3. preparation method according to claim 2, it is characterised in that：The organic solvent is chloroform, methylene chloride, 1,2-
At least one of dichloroethanes, tetrahydrofuran, 2- methyltetrahydrofuran, dioxane, ether, the tertiary ether of first or diisopropyl ether；Institute
Stating alcohol is at least one of methanol, ethyl alcohol, trifluoroethanol, propyl alcohol, isopropanol, butanol, sec-butyl alcohol or tert-butyl alcohol.
4. preparation method according to claim 1, it is characterised in that：The hydrogen halides be in hydrogen bromide or hydrogen chloride at least
It is a kind of.
5. preparation method according to any one of claims 1 to 4 be made 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- I
Primary furanose.
6. a kind of preparation method of standby nelarabine, it is characterised in that：1- halogen -2,3,5- oxygen-according to claim 5 (takes
Generation) benzyl-D- arabinofuranose and 2- amino -6- methoxypurine through chemical synthesis obtain 2- amino -6- methoxyl group -9-
[2 ', 3 ', 5 '-three-oxygen-(substitution) benzyl-β-D- arabinofuranosidase glycosyl] purine, then 2,3,5- are sloughed by catalytic hydrogenation
Oxygen-(substitution) benzyl obtains nelarabine.
7. preparation method according to claim 6, it is characterised in that：The chemical synthesis includes：By 2- amino -6- methoxy
Base purine is dissolved in organic solvent, and alkali is added, and reaction after a certain period of time, adds 1- halogen -2,3,5- oxygen-(substitution) benzyl-D- Ah
Primary furanose is drawn, certain time is reacted, obtains 2- amino -6- methoxyl group -9- [2 ', 3 ', 5 '-three-oxygen-(substitution) benzyl-β-D-
Arabinofuranosidase glycosyl] purine.
8. preparation method according to claim 7, it is characterised in that：The organic solvent is acetonitrile, N, N- dimethyl methyl
Amide, DMAC N,N' dimethyl acetamide, tetrahydrofuran, 2- methyltetrahydrofuran, dioxane, ether, the tertiary ether of first, diisopropyl ether,
At least one of glycol dimethyl ether, acetonitrile, acetone, butanone, dimethyl sulfoxide or N-Methyl pyrrolidone；The alkali is hydrogenation
Sodium, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide or
At least one of barium hydroxide.
9. preparation method according to claim 6, it is characterised in that：The catalytic dehydrogenation includes：By 2- amino -6- methoxy
Base -9- [2 ', 3 ', 5 '-three-oxygen-(substitution) benzyl-β-D- arabinofuranosidase glycosyl] purine is dissolved in solvent, and catalyst is added, and
It is passed through hydrogen or ammonium formate is added, reaction obtains target product nelarabine.
10. preparation method according to claim 8, it is characterised in that：The solvent is methanol, ethyl alcohol, trifluoroethanol, third
At least one of alcohol, isopropanol, butanol, sec-butyl alcohol or tert-butyl alcohol；The catalyst is Pd/C, Pd (OH)2/ C or Raney
At least one of Ni.
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