CN1583776A - Preparing method for cytarabine - Google Patents
Preparing method for cytarabine Download PDFInfo
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- CN1583776A CN1583776A CN 03153692 CN03153692A CN1583776A CN 1583776 A CN1583776 A CN 1583776A CN 03153692 CN03153692 CN 03153692 CN 03153692 A CN03153692 A CN 03153692A CN 1583776 A CN1583776 A CN 1583776A
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- Prior art keywords
- ara
- cytosine arabinoside
- triazole
- uridine
- ether
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Abstract
Cytosine arabinoside is prepared by: reacting uridine arabinoside and ethyl anhydride or acetyl chloride or acetyl bromine together in pyridine to get uridine arabinoside ethylester, reacting uridine arabinoside ethylester and triazoazole compound in presence of trichlorooxyphosphorus and inertia organic solvent to obtain triazoazole uridine, finally, aminolyzing triazoazole uridine to get cytosine arabinoside. Its advantages includes, cheaper and less solvent used, high yields on large scale production, cost low, and selecting strong acid cation exchange resin to separate and purify crude cytosine arabinoside to meet the standard of Europe and American pharmacopoeia.
Description
Invention field
The present invention relates to chemical pharmacy field, particularly, the present invention relates to a kind of preparation method of nucleotide drug cytosine arabinoside.
Background technology
The chemistry of cytosine arabinoside is by name: the Arabic glycosyl cytidine(C of 1-β-D-, and English Cytarabine by name is called for short Ara-C, and its chemical structure is as follows:
Cytosine arabinoside
Cytosine arabinoside is a kind of antiviral, also be used for antitumor, leukemia particularly.The preparation method of the cytosine arabinoside of bibliographical information has:
1. be the complete synthesizing process (DE2027305A and DE2601399A) of raw material with the pectinose:
The preparation process of this law cyanoacetylene is longer, and need use the propine acid amides of easily blasting, and is difficult to adapt to suitability for industrialized production;
2. be raw material with the cytidine, synthesize cytosine arabinoside through cyclotidine:
This route, the method for bibliographical information is a lot.But both made is nearest document (US5610292A), and the yield of cyclotidine also has only 29%, and yield is very low, the cost height.In addition, because the cyclotidine open loop unavoidably some cytidines can occur,, be difficult to the refining pharmacopeia requirement that reaches because its character and cytosine arabinoside are closely similar;
3. be the synthetic cytosine arabinoside of raw material with the ara U:
In this route, when X=Cl (DE2146733A) or SH (US3116282A), need in autoclave, to seal ammonia and separate, severe reaction conditions, facility investment is big; Work as X=
The time (US4754026A), in preparation process, can by-product Repone K and water because the Repone K moisture absorption very easily, reaction system is difficult to separation and purification, is not suitable for suitability for industrialized production;
4. the direct ammonia of ara U is separated synthetic cytosine arabinoside (EP757056A):
This method seems simply, and yield is also high, but has two weakness: 1., need high-temperature pressurizing (135 ℃, 15bar) ammonia is separated, to the equipment requirements height; 2., owing to used the two silicon amine of hexamethyl (22.42 gram ara Us need with the two silicon amine of 187.5ml hexamethyl) in a large number, not only to environment cause big dirty and also because of a large amount of silicon compound of by-product to the ion exchange resin infringement greatly, so the cost height is uneconomical;
It is the method for the synthetic cytosine arabinoside of starting raw material with the uridine that 5.1982 year KJ Divakar etc. has reported, wherein comprised following operational path (J.Chem.Soc.Perkin.Trans 1 1982,1171-1176):
But this method is applied to industrial production exists following shortcoming:
1., the document is when preparation compound VI I, be that ara U and acetic anhydride are reacted in pyridine, the pyridine consumption has surpassed 1: 10 with the ara U ratio (the 26.5g ara U need restrain pyridines with 275) herein, because pyridine costs an arm and a leg, be difficult to reclaim, use so a large amount of pyridines not only environment to be impacted, and cost is increased greatly;
2., the document is when preparation Compound I X, be with the 1.2.4-triazole, after phosphorus oxychloride and triethylamine react in acetonitrile, react with compound VI I again, this method acetonitrile consumption is 1: 22 with the ratio of compound VI I, acetonitrile also is an expensive solvent, is difficult to recovery set usefulness in the reaction of this step, and the same reason also can make production cost increase; Also have so many solvents also to be unfavorable for cytosine arabinoside scale operation; In addition, in this method, the large usage quantity of the reaction of this step triethylamine, phosphorus trichloride and 1.2.4-triazole;
3., the document is with Compound I X elder generation and ammoniacal liquor dioxane mixture reaction when in the end a step prepares Compound I, react with methanol ammonia again, directly crystallization in ethanol after concentrated, the preparation cytosine arabinoside, herein not only the dioxane consumption big (with the amount ratio of Compound I X be 1: 10), cost height, and owing to lack effective method for purifying and separating, the gained cytosine arabinoside is of poor quality, does not reach American-European pharmacopeia requirement.
Goal of the invention
The objective of the invention is to overcome the deficiencies in the prior art, provide one be suitable for suitability for industrialized production easy, prepare the method for high quality cytosine arabinoside economically and reasonably.
Summary of the invention
The present invention is raw material with the ara U, by following reactions steps, prepares synthetic cytosine arabinoside:
Concrete steps are:
1, the former glycosides of arabinose is suspended in the pyridine, with acetic anhydride or Acetyl Chloride 98Min. or acetyl bromide reaction, concentrate the back refining compound VI I.Herein, the mole number of acetic anhydride or Acetyl Chloride 98Min. or acetyl bromide is 1 with the ratio of ara U: 1.25-1: 9, be preferably 1: 3-1: and 6, be preferably 1: 3-1: 45; The weight ratio of pyridine and cytosine arabinoside is 1: 1-1: 10, be preferably 1: 2-1: 4; Temperature of reaction is 0-100 ℃;
2,1.2.4-triazole (R=H) or 3-nitro-1.2.4-triazole (R=NO2) and phosphorus oxychloride are dissolved in the inert organic solvent, cooling drips triethylamine, behind the adding compound VI that the finishes I, 0-60 ℃ of reaction 1-20 hour, after washing concentrates, get compounds X; The inert organic solvent is meant C herein
1-C
4Halogenated alkane or the ester that forms of the alcohol of the acid of the ether of the ketone of C3-C10 or C4-C12 or tetrahydrofuran (THF) or dioxane or C1-C8 and C1-C8.The halogenated alkane of C1-C4 is meant but is not limited only to methylene dichloride, chloroform, 1.1.1-trichloroethane etc. herein; The ketone of C3-C10 is meant but is not limited only to acetone, butanone, hexone etc.; The ether of C4-C12 is meant but is not limited only to ether, dipropyl ether, diisopropyl ether, methyl tertiary butyl ether etc.The ester that the acid of C1-C8 and the alcohol of C1-C8 form is meant but is not limited only to ethyl acetate, butylacetate, tert.-butyl acetate etc.Inert organic solvent total amount (volume ml) is 1 with the ratio of compound VI I (weight g): 5-15.
3, with after compounds X and ammoniacal liquor dioxane or the reaction of ammoniacal liquor tetrahydrofuran compound, concentrate, react with methanol ammonia again, reconcentration, after the residue water dissolution, last Zeo-karb, wash the removal of impurity earlier with water, use the alkaline eluant wash-out again, after elutriant concentrated, water-acetone or water-ethanol were refining as to meet American-European officinal ara U.Zeo-karb is meant on vinylbenzene-divinylbenzene interpolymer and has sulfonic Zeo-karb herein, and its degree of crosslinking is between 2%-10%, and granular size is between the 50-1000 order.As domestic resin 001X2,001X4,001X8; Import resin such as DOWEX50W series, Amberlite IR-120, Lewatit-100, Diaion SK-1 etc.Alkaline eluant is meant the organic amine aqueous solution of the C1-C9 of the ammoniacal liquor of 0.1%-10% or 0.1%-10%.Wherein the organic amine of C1-C9 is meant but is not limited only to methylamine, ethamine, dimethylamine, triethylamine, thanomin or their mixture etc.
Compare the following advantage of the inventive method tool with method of the prior art:
1, the inexpensive amount of solvent selected for use of the present invention is few, and preparation of industrialization yield height can effectively be controlled production cost;
2, the present invention selects for use storng-acid cation exchange resin separation and purification cytosine arabinoside crude product can obtain meeting the cytosine arabinoside finished product of American Pharmacopeia.
The invention will be further described below by embodiment.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.
Embodiment 1: the preparation of ara U ethyl ester (compound VI I):
Pyridine 26.2kg is added in the retort, stir, add ara U 11.5kg, acetic anhydride 18.6kg successively, stirring at room reaction 3 hours.Reaction is finished, and adds 11.5 liters of methyl alcohol, stirs 0.5 hour, is evaporated to pyridine and can steam.Add the dissolving of ethanol stirring heating.Be chilled to below 0 ℃ and spend the night.Discharging, suction filtration, oven dry get compound VI I 15.8kg, yield 91%.
Embodiment 2: the preparation of triazole uridine (Compound I X):
Chloroform 150L is added retort, stir, add triazole 15kg.Be chilled to below 5 ℃, add phosphorus oxychloride 9.225kg.Finish phosphorus oxychloride, continue to be stirred to below 5 ℃, drip triethylamine 33.75L.The control rate of addition makes the highest intensification be no more than 8 ℃.15kg adds in the above-mentioned retort with ara U ethyl ester (compound VI I).Stirred overnight at room temperature.React completely, add entry 150L, stir, emit chloroform layer.Water chloroform 60L * 2, extracting twice merges anhydrous magnesium sulfate drying with organic phase and preceding chloroform layer.Suction filtration, filtering sal epsom, filtrate adds dehydrated alcohol after concentrating dried chloroform, the stirring and refluxing dissolving.Be chilled to below 0 ℃ and spend the night.Suction filtration leaches solid, and after solid washed with small amount of ethanol, oven dry (70 ℃) got triazole uridine (Compound I X) 14.3kg, yield 84%.
Embodiment 3: the preparation of cytosine arabinoside:
Dioxane 68.5kg is added retort, open stirring and be chilled to 15 ℃, logical ammonia 5～6 hours.Add triazole uridine (compounds X) 13.7kg and ammoniacal liquor 9.6kg, stirred overnight at room temperature.The concentrating under reduced pressure dioxane distillates to no longer including liquid.Add methanol ammonia 54.8kg, reaction is spent the night.Reaction is finished, and is evaporated to dried.Residue is dissolved in deionized water 60L, last 001X4 ion exchange resin.Use earlier deionized water drip washing, the back contains the product elutriant with 5% weak ammonia wash-out, collection, and reduced vacuum is concentrated into to do and is crude product.Crude product water alcohol reflux is dissolved.Filtered while hot, filtrate are advanced smart baking bag crystallizer.Crystallization is spent the night.Suction filtration leaches crystallization, and crystallization is with after the small amount of ethanol washing, dry cytosine arabinoside 5.75kg, yield 70%, the full inspection of product meets the American Pharmacopeia requirement.
Claims (10)
1. a method for preparing cytosine arabinoside comprises the following steps:
A. with ara U Yu Yi Wu or Acetyl Chloride 98Min. or acetyl bromide react in pyridine, obtain the ara U ethyl ester
Ara U ara U ethyl ester
B. ara U ethyl ester and 3-triazole compounds are reacted under phosphorus oxychloride and the effect of inert organic solvent, obtain the triazole uridine;
Ara U ethyl ester triazole uridine
C. the triazole uridine being carried out ammonia separates and obtains cytosine arabinoside;
Triazole uridine cytosine arabinoside
It is characterized in that:
Among the step a, the mole number of acetic anhydride or Acetyl Chloride 98Min. or acetyl bromide is 1 with the ratio of the mole number of ara U: 1.25-1: 9; The weight ratio of pyridine and cytosine arabinoside is 1: 1-1: 10;
Among the step b, inert volume of organic solvent (ml) is 1 with the ratio of the weight (g) of ara U second: 5-15,3-triazole compounds are 1.2.4-triazole or 3-nitro-1.2.4-triazole;
Among the step c, after reaction solution concentrates, go up Zeo-karb, wash out impurity with water, obtain cytosine arabinoside with alkaline eluent wash-out again with the less water dissolving.
2. according to the process of claim 1 wherein, the inert organic solvent among the step b is C
1-C
4Halogenated alkane, C
3-C
10Ketone, C
4-C
12Ether, tetrahydrofuran (THF), dioxane, or C
1-C
8Acid and C
1-C
8The ester that alcohol forms.
3. according to the method for claim 2, the C among the step b wherein
1-C
4Halogenated alkane is methylene dichloride, chloroform or 1.1.1-trichloroethane, C
3-C
10Ketone is acetone, butanone or hexone, C
4-C
12Ether is ether, dipropyl ether, diisopropyl ether or methyl tertiary butyl ether, C
1-C
8Acid and C
1-C
8The ester that alcohol forms is ethyl acetate, butylacetate or tert.-butyl acetate.
4. according to the process of claim 1 wherein that the Zeo-karb among the step c is to have sulfonic Zeo-karb on vinylbenzene-divinylbenzene interpolymer, its degree of crosslinking is between 2%-10%, and granular size is between the 50-1000 order.
5. according to the process of claim 1 wherein that the temperature of reaction of step a is 0-100 ℃.
6. according to the process of claim 1 wherein that the weight ratio of pyridine and cytosine arabinoside is 1 among the step a: 2-1: 4.
7. according to the method for claim 6, wherein the ratio of the mole number of acetic anhydride or Acetyl Chloride 98Min. or acetyl bromide and the mole number of ara U is 1 among the step a: 3-1: 6.
8. according to the method for claim 7, wherein the mole number of acetic anhydride or Acetyl Chloride 98Min. or acetyl bromide is 1 with the ratio of the mole number of ara U: 3-1: 4.5.
9. according to the method for one of claim 1-8, wherein in step 3), alkaline eluent is the ammoniacal liquor of 0.1%-10% or the C of 0.1%-10%
1-C
9The organic amine aqueous solution.
10. require 9 method according to power, wherein C
1-C
9Organic amine be methylamine, ethamine, dimethylamine, triethylamine, thanomin or their mixture.
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| CNB031536921A CN1302004C (en) | 2003-08-22 | 2003-08-22 | Preparing method for cytarabine |
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| CNB031536921A CN1302004C (en) | 2003-08-22 | 2003-08-22 | Preparing method for cytarabine |
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| CN101948492A (en) * | 2010-08-20 | 2011-01-19 | 河南师范大学 | Technology for producing cytarabine through chemical synthesis method |
| CN101240002B (en) * | 2007-02-07 | 2011-01-26 | 首都医科大学 | Fatty acylaminoacylcytarabine conjugate, preparation method and application thereof |
| CN103694279A (en) * | 2013-12-23 | 2014-04-02 | 江西苏克尔新材料有限公司 | Preparation method of 2-deoxy-L-ribose |
| CN104086612A (en) * | 2013-07-17 | 2014-10-08 | 郑州大学 | 4-substituted amido-2'-deoxo-2'-fluoro-4'-azido-beta-D-cytidine compounds and preparation method and application thereof |
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| US3116282A (en) * | 1960-04-27 | 1963-12-31 | Upjohn Co | Pyrimidine nucleosides and process |
| TW225525B (en) * | 1991-11-23 | 1994-06-21 | Hoechst Ag | |
| IT1277425B1 (en) * | 1995-08-03 | 1997-11-10 | Pro Bio Sint Srl | METHOD FOR THE PREPARATION OF 1-B-D-ARABINOFURANOSILCITOSINA |
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| CN101240002B (en) * | 2007-02-07 | 2011-01-26 | 首都医科大学 | Fatty acylaminoacylcytarabine conjugate, preparation method and application thereof |
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