CN103275158A - Methods for preparing decitabine - Google Patents
Methods for preparing decitabine Download PDFInfo
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- CN103275158A CN103275158A CN2013102391927A CN201310239192A CN103275158A CN 103275158 A CN103275158 A CN 103275158A CN 2013102391927 A CN2013102391927 A CN 2013102391927A CN 201310239192 A CN201310239192 A CN 201310239192A CN 103275158 A CN103275158 A CN 103275158A
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Abstract
The invention relates to a novel method for preparing decitabine. The technology comprises silylation of azacytosine in the presence of Bis (trimethylsilyl) sulfate or 1,3-Bis (trimethylsilyl) urea. The invention further relates to an another novel method for preparing the decitabine, in the method, an intermediate product is not required to be extracted, a coupled reaction is performed in the same solvent where a silylation reaction is performed, and the operation is simple. The methods are applicable to industrial scale production of the decitabine, and the decitabine can be produced conveniently, so that procedures of treatment and separation of an intermediate body are avoided, and accordingly, the duration time of the technology is reduced, and the production capacity is improved.
Description
Technical field
The present invention relates to the medical chemistry field, particularly, the present invention relates to a kind of method for preparing Decitabine.
Background technology
Decitabine (decitabine) is the medicine that is used for the treatment of primary and Secondary cases myelodysplastic syndrome (MDS) respectively at being gone on the market by European EMEA and drugs approved by FDA in April, 2006 and May.This medicine is by the exploitation of MGI Pharma company, and commodity are called Dacogen, are injection.
Decitabine is a class hypomethylation reagent, has unique mechanism of action.Decitabine directly is incorporated in the dnmt rna after phosphorylation, makes dna methylation, causes cytodifferentiation or apoptosis, thus the performance antitumor action.It can not suppress the synthetic of DNA external, and can cause hypomethylation in tumour cell, and the relevant cell differentiation of keeping gene and the function of breeding control are arranged.Non-proliferative cell is to this medicine relative insensitivity.
Decitabine is a kind of chemotherapeutics.Clinical report shows that it has broad-spectrum anti-tumor activity to the pernicious canceration of blood and solid tumor.This medicine is applicable to treatment MDS, be suitable for comprising that receive treatment and do not receive treatment, neopathy and the insecondary MDS patient of all France-U.S.-Britain (FAB) somatotype, and the MDS patient who is divided into high-risk, 2 grades of danger of moderate, 1 grade of danger of moderate by the IPSS system.In the III clinical trial phase of Decitabine injection liquid, 170 patients' (France-U.S.-Britain's hypotype is arranged and by the patient of 2 grades of 1 grade of middle danger, the middle danger of international prognosis integrating system prediction, high-risk myelodysplastic syndrome) overall response rate is 17%, comprises 9% reply fully with 8% part and reply.The overall improvement rate (reply fully add part reply and the hematology improver) of accepting the patient of Decitabine treatment is 30%, and the treatment that only receives backing account for 7%.All patients that Decitabine is replied do not rely on blood transfusion, in the patient through Decitabine treatment, have 35% patient to observe and cytologically reply fully.Decitabine modal untoward reaction in therapeutic process is neutrophil minimizing, thrombopenia and anaemia.
Decitabine be natural nucleus glycoside 2 '-the Deoxyribose cytidine analogue, its chemical name: 1-(β-D-2-ribodesose)-4-amino-1,3,5-triazines-2 (1H)-ketone; English name: 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2 (1H)-one; Molecular formula is C
8H
12N
4O
4Relative molecular weight is 228.2; The CAS registration number is 2353-33-5.
Known Decitabine is synthetic to mainly contain following 3 kinds of thinkings:
First kind of thinking is azacitidine deoxidation method, is raw material with the azacitidine, at first protects 3 ' and 5 ' position hydroxyl, sloughs the hydroxyl of 2 ' position then, slough 3 again ' and 5 ' position hydroxyl protecting group generate Decitabine.The starting raw material that this route uses is azacitidine, and uses special reagent 1,3-two chloro-1,1,3, and 3-tetra isopropyl disiloxane, sulfo-phenyl chloroformate and three-(trimethyl silicon based) silane etc., market supply is few, the cost height.
Second kind of thinking is the isocyanic ester method, and namely 1964 Pliml and Storm be the method for synthetic Decitabine the earliest, is that 2-deoxy-D-ribose and the urea cyclization of protection prepares Decitabine by deprotection.This method is used expensive isocyanic acid silver, cyclization again after the glucosidesization, and synthetic route is longer, and isomer separation difficulty, and operational condition harshness adopt less.
The third is the direct glucosidesization of 5-azepine cytosine(Cyt); the two silica-based protection things of 5-azepine cytosine(Cyt) and hexamethyldisilazane (HMDS) prepared in reaction; with 2-deoxidation-direct condensation of d-ribose of protecting, slough protecting group then, last isomer separation obtains Decitabine.The difference of different and 3,5 hydroxyl protecting groups of 1 leavings group of 2-deoxidation-d-ribose forms different synthetic routes.But this method sillylation reagent alternative is little, consumption is big, and the intermediate product that needs to obtain each step separates removal of impurities, and operation is comparatively complicated, is unsuitable for suitability for industrialized production.
Therefore, it is simple to develop a kind of technology, and can obtain high yield and highly purified method for preparing decitabine is the technical barrier in affiliated field.
Summary of the invention
At the deficiencies in the prior art, one of purpose of the present invention is to provide a kind of method for preparing Decitabine, and described method has been widened the range of choice of sillylation reagent.
The described method for preparing Decitabine comprises: adopt two (trimethyl silicon based) sulfuric esters and/or hexamethyl two silicon ureas as the sillylation reagent of 5-azepine cytosine(Cyt).
The described method for preparing Decitabine may further comprise the steps:
(1) adopt two (trimethyl silicon based) sulfuric esters and/or hexamethyl two silicon ureas in organic solvent, to carry out silylation reactive as sillylation reagent and 5-azepine cytosine(Cyt);
(2) derivative and the catalyst mix of the reaction mixture that step (1) is obtained and D-2-desoxyribofu-are carried out linked reaction;
(3) alternatively, change the solvent of the reaction mixture that step (2) obtains;
(4) carry out deprotection reaction, obtain Decitabine.
When the alkaline reagents that participates in the described deprotection reaction of step (4) is dissolved in the described organic solvent of step (1), do not carry out step (3); Otherwise, be insoluble to the described organic solvent of step (1) if participate in the alkaline reagents of the described deprotection reaction of step (4), then replace with new solvent, to dissolve the alkaline reagents of described deprotection reaction.
After step (1) silylation reactive finishes, needn't replace solvent, and needn't remove solvent, excessive sillylation reagent and byproduct of reaction, but with reaction mixture directly and sugar derivatives and catalyst mix carry out linked reaction and get final product, simple to operate; Simultaneously, because therefore described silylated 5-azepine cytosine(Cyt) instability when contacting with water and/or atmospheric water, minimizes by the aftertreatment that makes silylated nitrogen cytosine, avoided the conversion of silylated 5-azepine cytosine(Cyt).
After the described linked reaction of step (2) finishes, needn't the purified reaction product, can be directly and alkaline reagents carry out deprotection reaction; Perhaps after the described linked reaction of step (2) finishes; needn't the purified reaction product; but be the solvent that solubilized participates in the alkaline reagents of deprotection reaction with solvent replacing; carry out deprotection reaction with alkaline reagents then; therefore, described linked reaction is carried out in the solvent identical with described silylation reactive.
Multiple solvent can be used for described silylation reactive and linked reaction.Preferably, the described organic solvent of step (1) is aprotic organic solvent, non-silylated aprotic organic solvent more preferably, and more preferably a kind in methylene dichloride, ethylene dichloride or the acetonitrile or at least 2 kinds combination are preferably acetonitrile especially.
Preferably, the consumption of the described organic solvent of step (1) is 5～150L/ (kg5-azepine cytosine(Cyt)), 5.1L/ (kg5-azepine cytosine(Cyt)) for example, (5.4L/ kg5-azepine cytosine(Cyt)), (5.6L/ kg5-azepine cytosine(Cyt)), (5.9L/ kg5-azepine cytosine(Cyt)), (6.1L/ kg5-azepine cytosine(Cyt)), (6.5L/ kg5-azepine cytosine(Cyt)), 4L/ (kg5-azepine cytosine(Cyt)), 8L/ (kg5-azepine cytosine(Cyt)), 13L/ (kg5-azepine cytosine(Cyt)), 25L/ (kg5-azepine cytosine(Cyt)), 50L/ (kg5-azepine cytosine(Cyt)), 80L/ (kg5-azepine cytosine(Cyt)), 90L/ (kg5-azepine cytosine(Cyt)), 110L/ (kg5-azepine cytosine(Cyt)), 130L/ (kg5-azepine cytosine(Cyt)), 140L/ (kg5-azepine cytosine(Cyt)), 145L/ (kg5-azepine cytosine(Cyt)), 148L/ (kg5-azepine cytosine(Cyt)) or 149L/ (kg5-azepine cytosine(Cyt)) etc., more preferably 10～120L/ (kg5-azepine cytosine(Cyt)) is preferably 20～100L/ (kg5-azepine cytosine(Cyt)) especially; Described " L/ (kg5-azepine cytosine(Cyt)) " refers to the number that rises of the organic solvent required with respect to every kilogram of 5-azepine cytosine(Cyt).
Preferably, the described sillylation reagent of step (1) is (2～3) with the ratio of the molar weight of 5-azepine cytosine(Cyt): 1, be preferably (2.2～2.5) especially: 1; One of ordinary skill in the art should be appreciated that the molar weight of described sillylation reagent is both molar weight sums if described sillylation reagent is the mixture of two (trimethyl silicon based) sulfuric esters and hexamethyl two silicon ureas; When if described sillylation reagent is one of two (trimethyl silicon based) sulfuric esters or hexamethyl two silicon ureas, the molar weight of described sillylation reagent is the molar weight of two (trimethyl silicon based) sulfuric esters or hexamethyl two silicon ureas; The present invention only uses the sillylation reagent higher slightly than stoichiometry, has avoided a large amount of wastes of using sillylation reagent and causing in the prior art.
Preferably, the temperature of the described silylation reactive of step (1) is the reflux temperature of 0 ℃～silylation reactive mixture, and more preferably the reflux temperature of 20 ℃～silylation reactive mixture is preferably 20 ℃～100 ℃ especially.
Adopt the method for the invention, step (1) but described silylation reactive finish within a short period of time, generally be less than 4 hours.
Preferably, the derivative of the described D-2-desoxyribofu-of step (2) has leavings group at its 1, and is obtained by acidylate by the hydroxyl as the D-2-desoxyribofu-of precursor; Preferably, described leavings group is halogen, is preferably chlorine especially; Preferably, described acyl group preferentially is selected to toluyl or to chlorobenzene formacyl.
Preferably, the derivative of the described D-2-desoxyribofu-of step (2) is 1-chloro-3, the toluyl of 5-two-O--2-deoxidation-D-ribofuranose and/or 1-chloro-3, the chlorobenzene formacyl of 5-two-O--2-deoxidation-D-ribofuranose.
Preferably, the described catalyzer of step (2) is Lewis acid, more preferably a kind or at least 2 kinds combination in tin tetrachloride, titanium tetrachloride, zinc chloride, boron-trifluoride etherate, trimethylsilyl triflate or the trimethyl silyl perfluoro butyl sulphonate is preferably trimethylsilyl triflate especially.
Preferably, the temperature of the described linked reaction of step (2) is the reflux temperature of 0 ℃～linked reaction mixture, and more preferably the reflux temperature of 25 ℃～linked reaction mixture is preferably 25 ℃～100 ℃ especially.
Adopt the method for the invention, the described linked reaction of step (2) is generally finished in the short period of time, and finishes in less than 4 hours usually.
Alternatively, when linked reaction finished, to be directly to last deprotection reaction be possible by replace reaction solvent for coupling simply with the solvent of de-acyl reaction; Preferably, the solvent for the described deprotection reaction of step (4) is alcohols, more preferably C
1-C
4Alcohol, for example methyl alcohol, ethanol, ethylene glycol, n-propyl alcohol, Virahol, 1,2-propylene glycol, 1, ammediol, 1,2,3-glycerol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, 1,2-butyleneglycol, 1,3-butyleneglycol or 1,1 kind or at least 2 kinds combination in the 4-butyleneglycol etc., the typical but non-limiting example of described combination comprises: the combination of methyl alcohol and ethanol, the combination of ethylene glycol and n-propyl alcohol, methyl alcohol, 1, the combination of 2,3-glycerol and propyl carbinol, the trimethyl carbinol, 1, the 2-butyleneglycol, 1, the combination of 3-butyleneglycol and 1,4-butyleneglycol, methyl alcohol, ethanol, Virahol, 1,2-propylene glycol and 1, the combination of ammediol etc.; Be preferably methyl alcohol especially.
Preferably, the described deprotection reaction of step (4) carries out in the presence of alkaline reagents, further preferably carries out in the presence of sodium alkoxide and/or ammonia, particularly preferably in carrying out under the existence of sodium methylate, sodium ethylate and/or ammonia.
A kind of embodiment of the method for preparing Decitabine of the present invention is as follows:
Wherein, R is methyl or chlorine atom.
One of purpose of the present invention also is to provide the another kind of described method for preparing Decitabine, described method can allow product separated with high yield and high purity, and needn't use a large amount of sillylation reagents, the excessive sillylation reagent that still exists in the time of also needn't finishing except dereaction; The all operations of described method is suitable for the industrial-scale production Decitabine, and can carry out easily, can avoid processing and the separation steps of intermediate, therefore reduces the time length of technology and improves throughput.
The described method for preparing Decitabine may further comprise the steps:
(1) adopt sillylation reagent and 5-azepine cytosine(Cyt) in organic solvent, to carry out silylation reactive;
(2) derivative and the catalyst mix of the reaction mixture that step (1) is obtained and D-2-desoxyribofu-are carried out linked reaction;
(3) alternatively, change the solvent of the reaction mixture that step (2) obtains;
(4) carry out deprotection reaction, obtain Decitabine.
When the alkaline reagents that participates in the described deprotection reaction of step (4) is dissolved in the described organic solvent of step (1), do not carry out step (3); Otherwise, be insoluble to the described organic solvent of step (1) if participate in the alkaline reagents of the described deprotection reaction of step (4), then replace with new solvent, to dissolve the alkaline reagents of described deprotection reaction.
After step (1) silylation reactive finishes, needn't replace solvent, and needn't remove solvent, excessive sillylation reagent and byproduct of reaction, but with reaction mixture directly and sugar derivatives and catalyst mix carry out linked reaction and get final product, simple to operate; Simultaneously, because therefore described silylated 5-azepine cytosine(Cyt) instability when contacting with water and/or atmospheric water, minimizes by the aftertreatment that makes silylated nitrogen cytosine, avoided the conversion of silylated 5-azepine cytosine(Cyt).
After the described linked reaction of step (2) finishes, needn't the purified reaction product, can be directly and alkaline reagents carry out deprotection reaction; Perhaps after the described linked reaction of step (2) finishes; needn't the purified reaction product; but be the solvent that solubilized participates in the alkaline reagents of deprotection reaction with solvent replacing; carry out deprotection reaction with alkaline reagents then; therefore, described linked reaction is carried out in the solvent identical with described silylation reactive.
Preferably, the described sillylation reagent of step (1) is two (trimethyl silicon based) sulfuric esters and/or hexamethyl two silicon ureas.
Multiple solvent can be used for described silylation reactive and linked reaction.Preferably, the described organic solvent of step (1) is aprotic organic solvent, non-silylated aprotic organic solvent more preferably, and more preferably a kind in methylene dichloride, ethylene dichloride or the acetonitrile or at least 2 kinds combination are preferably acetonitrile especially.
Preferably, the consumption of the described organic solvent of step (1) is 5～150L/ (kg5-azepine cytosine(Cyt)), 5.1L/ (kg5-azepine cytosine(Cyt)) for example, (5.4L/ kg5-azepine cytosine(Cyt)), (5.6L/ kg5-azepine cytosine(Cyt)), (5.9L/ kg5-azepine cytosine(Cyt)), (6.1L/ kg5-azepine cytosine(Cyt)), (6.5L/ kg5-azepine cytosine(Cyt)), 7L/ (kg5-azepine cytosine(Cyt)), 8L/ (kg5-azepine cytosine(Cyt)), 15L/ (kg5-azepine cytosine(Cyt)), 20L/ (kg5-azepine cytosine(Cyt)), 50L/ (kg5-azepine cytosine(Cyt)), 80L/ (kg5-azepine cytosine(Cyt)), 90L/ (kg5-azepine cytosine(Cyt)), 110L/ (kg5-azepine cytosine(Cyt)), 130L/ (kg5-azepine cytosine(Cyt)), 140L/ (kg5-azepine cytosine(Cyt)), 145L/ (kg5-azepine cytosine(Cyt)), 148L/ (kg5-azepine cytosine(Cyt)) or 149L/ (kg5-azepine cytosine(Cyt)) etc., more preferably 10～120L/ (kg5-azepine cytosine(Cyt)) is preferably 20～100L/ (kg5-azepine cytosine(Cyt)) especially; Described " L/ (kg5-azepine cytosine(Cyt)) " refers to the number that rises of the organic solvent required with respect to every kilogram of 5-azepine cytosine(Cyt).
Preferably, the described sillylation reagent of step (1) is (2～3) with the ratio of the molar weight of 5-azepine cytosine(Cyt): 1, be preferably (2.2～2.5) especially: 1; The present invention only uses the sillylation reagent higher slightly than stoichiometry, has avoided a large amount of wastes of using sillylation reagent and causing in the prior art.
Preferably, the temperature of the described silylation reactive of step (1) is the reflux temperature of 0 ℃～silylation reactive mixture, and more preferably the reflux temperature of 20 ℃～silylation reactive mixture is preferably 20 ℃～100 ℃ especially.
Adopt the method for the invention, step (1) but described silylation reactive finish within a short period of time, generally be less than 4 hours.
Preferably, the derivative of the described D-2-desoxyribofu-of step (2) has leavings group at its 1, and is obtained by acidylate by the hydroxyl as the D-2-desoxyribofu-of precursor; Preferably, described leavings group is halogen, is preferably chlorine especially; Preferably, described acyl group preferentially is selected to toluyl or to chlorobenzene formacyl.
Preferably, the derivative of the described D-2-desoxyribofu-of step (2) is 1-chloro-3, the toluyl of 5-two-O--2-deoxidation-D-ribofuranose and/or 1-chloro-3, the chlorobenzene formacyl of 5-two-O--2-deoxidation-D-ribofuranose.
Preferably, the described catalyzer of step (2) is Lewis acid, more preferably a kind or at least 2 kinds combination in tin tetrachloride, titanium tetrachloride, zinc chloride, boron-trifluoride etherate, trimethylsilyl triflate or the trimethyl silyl perfluoro butyl sulphonate is preferably trimethylsilyl triflate especially.
Preferably, the temperature of the described linked reaction of step (2) is the reflux temperature of 0 ℃～linked reaction mixture, and more preferably the reflux temperature of 25 ℃～linked reaction mixture is preferably 25 ℃～100 ℃ especially.
Adopt the method for the invention, the described linked reaction of step (2) is generally finished in the short period of time, and finishes in less than 4 hours usually.
Alternatively, when linked reaction finished, to be directly to last deprotection reaction be possible by replace reaction solvent for coupling simply with the solvent of de-acyl reaction; Preferably, the solvent for the described deprotection reaction of step (4) is alcohols, more preferably C
1-C
4Alcohol, for example methyl alcohol, ethanol, ethylene glycol, n-propyl alcohol, Virahol, 1,2-propylene glycol, 1, ammediol, 1,2,3-glycerol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, 1,2-butyleneglycol, 1,3-butyleneglycol or 1,1 kind or at least 2 kinds combination in the 4-butyleneglycol etc., the typical but non-limiting example of described combination comprises: the combination of methyl alcohol and ethanol, the combination of ethylene glycol and n-propyl alcohol, methyl alcohol, 1, the combination of 2,3-glycerol and propyl carbinol, the trimethyl carbinol, 1, the 2-butyleneglycol, 1, the combination of 3-butyleneglycol and 1,4-butyleneglycol, methyl alcohol, ethanol, Virahol, 1,2-propylene glycol and 1, the combination of ammediol etc.; Be preferably methyl alcohol especially.
Preferably, the described deprotection reaction of step (4) carries out in the presence of alkaline reagents, further preferably carries out in the presence of sodium alkoxide and/or ammonia, particularly preferably in carrying out under the existence of sodium methylate, sodium ethylate and/or ammonia.
Adopt described method can obtain the higher Decitabine of purity; and yield is higher; when for example using methyl alcohol as the solvent in the deprotection reaction, the direct crystallization of product during reaction takes place and obtain high quality Decitabine (HPLC purity＞99%), the crude product yield surpasses 30%.
The simplicity of technology makes that with the combination that obtains high quality product and high technology yield the present invention is particularly advantageous to prepare Decitabine with technical scale.
One of purpose of the present invention also is to provide the another kind of method for preparing Decitabine, may further comprise the steps:
(1) adopt two (trimethyl silicon based) sulfuric esters and/or hexamethyl two silicon ureas in consumption is the aprotic organic solvent of 5～150L/ (kg5-azepine cytosine(Cyt)), to carry out silylation reactive as sillylation reagent and 5-azepine cytosine(Cyt), wherein, described sillylation reagent is (2～3) with the ratio of the molar weight of 5-azepine cytosine(Cyt): 1;
(2) derivative of the reaction mixture that step (1) is obtained and D-2-desoxyribofu-and Lewis acid mix and carry out linked reaction, wherein, the derivative of described D-2-desoxyribofu-is 1-chloro-3, the toluyl of 5-two-O--2-deoxidation-D-ribofuranose and/or 1-chloro-3, the chlorobenzene formacyl of 5-two-O--2-deoxidation-D-ribofuranose;
(3) aprotic organic solvent of the reaction mixture that step (2) is obtained replaces with alcoholic solvent;
(4) in the presence of sodium alkoxide and/or ammonia, carry out deprotection reaction, obtain Decitabine.
Compared with prior art, advantage of the present invention is:
(1) adopts two (trimethyl silicon based) sulfuric esters and/or hexamethyl two silicon ureas as sillylation reagent innovatively, widened the range of choice of sillylation reagent;
(2) in entire synthesis process, avoid the use of the aqueous solution, thereby the quick degraded when having avoided the triazine ring in the building-up process to contact with water has improved yield;
(3) needn't carry out separation that intermediate is shielded nucleosides and purifying thereof (for example by chromatography and/or pass through crystallization process), but with reaction solution concentrate do after, by at C
1-C
4Finish synthetic, simple to operate in the alcohol with the deprotection of sodium alkoxide;
(4) adopt described method can obtain the higher Decitabine of purity; and yield is higher; when for example using methyl alcohol as the solvent in the deprotection reaction, the direct crystallization of product during reaction takes place and obtain high quality Decitabine (HPLC purity＞99%), the crude product yield surpasses 30%.
Embodiment
For ease of understanding the present invention, it is as follows that the present invention enumerates embodiment.Those skilled in the art should understand that described embodiment helps to understand the present invention, should not be considered as concrete restriction of the present invention.
Embodiment 1
The 4600mL acetonitrile is joined in the 115.3g5-azepine cytosine(Cyt), be warming up to 50 ℃, stir two (trimethyl silicon based) sulfuric esters reactions of adding 573.6g down 90 minutes.Cool to 25 ℃ then, add 139.4mL three silyl triflate and 200g1-chloro-3, the toluyl of 5-two-O--2-deoxidation-D-ribofuranose; behind the stirring reaction 120 minutes; cool to 0 ℃, drip the 660mL anhydrous methanol, be added dropwise to complete the concentrated dope that obtains in back.Add anhydrous methanol and stirring to it, added the 2.0g activated carbon decolorizing afterwards 3 hours, filter, drip the methanol solution of 657mL30% sodium methylate in the filtrate, 50 ℃ of stirring reactions 80 minutes are cooled to 0 ℃ then, being stirred to no solid separates out, filter, the solid drying under reduced pressure gets Decitabine crude product (HPLC purity is 99.4%, and the detection wavelength is 220nm).Crude product behind the recrystallization, obtains the pure product 32.8g of Decitabine from methyl alcohol, HPLC purity is that 99.9%(detection wavelength is 220nm).
1HNMR(DMSO-d
6) δ 8.50(s, 1, H-6), 7.49 (d, 2, NH
2), 6.03 (t, 1, H-1 '), 5.22 (d, 1, OH-3 '), 5.02 (t, 1, OH-5 '), 4.22 (m, 1, H-3 '), 3.81 (m, 1, H-4 '), 3.58 (m, 2, H-5 '), 2.16 (m, 2, H-2 '), LC-MS (ESI): 229.0[M+H]
+, 247.0[M+H
2O+H]
+, illustrate that the material of the present invention's preparation is Decitabine.
Embodiment 2
The 4650mL acetonitrile is joined in the 121.1g5-azepine cytosine(Cyt), be warming up to 50 ℃, stir adding 530.0g hexamethyl two silicon ureas reaction down 80 minutes.Cool to 25 ℃ then, add 156.1mL three silyl triflate and 210g1-chloro-3, the toluyl of 5-two-O--2-deoxidation-D-ribofuranose; behind the stirring reaction 130 minutes; cool to 0 ℃, drip the 690mL anhydrous methanol, be added dropwise to complete the concentrated dope that obtains in back.Add anhydrous methanol and stirring to it, added the 2.1g activated carbon decolorizing afterwards 2.5 hours, filter, drip the methanol solution of 670mL30% sodium methylate in the filtrate, 50 ℃ of stirring reactions 90 minutes are cooled to 0 ℃ then, being stirred to no solid separates out, filter, the solid drying under reduced pressure gets Decitabine crude product (HPLC purity is 99.3%, and the detection wavelength is 220nm).Crude product behind the recrystallization, obtains the pure product 29.5g of Decitabine from methyl alcohol, HPLC purity is that 99.9%(detection wavelength is 220nm).
LC-MS (ESI): 229.1[M+H]
+, 247.1[M+H
2O+H]
+, illustrate that the material of the present invention's preparation is Decitabine
Embodiment 3
The 4500mL acetonitrile is joined in the 101.7g5-azepine cytosine(Cyt), be warming up to 50 ℃, stir two (trimethyl silicon based) sulfuric esters reactions of adding 516.9g down 95 minutes.Cool to 25 ℃ then, add 123.0mL three silyl triflate and 195g1-chloro-3, the chlorobenzene formacyl of 5-two-O--2-deoxidation-D-ribofuranose; behind the stirring reaction 125 minutes; cool to 0 ℃, drip the 670mL anhydrous methanol, be added dropwise to complete the concentrated dope that obtains in back.Add anhydrous methanol and stirring to it, added the 1.9g activated carbon decolorizing afterwards 2.5 hours, filter, drip the methanol solution of 650mL30% sodium methylate in the filtrate, 50 ℃ of stirring reactions 85 minutes are cooled to 0 ℃ then, being stirred to no solid separates out, filter, the solid drying under reduced pressure gets Decitabine crude product (HPLC purity is 99.2%, and the detection wavelength is 220nm).Crude product behind the recrystallization, obtains the pure product 26.6g of Decitabine from methyl alcohol, HPLC purity is that 99.9%(detection wavelength is 220nm).
LC-MS (ESI): 229.0[M+H]
+, 247.0[M+H
2O+H]
+, illustrate that the material of the present invention's preparation is Decitabine.
Embodiment 4
The 4700mL acetonitrile is joined in the 112.2g5-azepine cytosine(Cyt), be warming up to 50 ℃, stir adding 491.1g hexamethyl two silicon ureas reaction down 85 minutes.Cool to 25 ℃ then, add 135.6mL three silyl triflate and 215g1-chloro-3, the chlorobenzene formacyl of 5-two-O--2-deoxidation-D-ribofuranose; behind the stirring reaction 130 minutes; cool to 0 ℃, drip the 690mL anhydrous methanol, be added dropwise to complete the concentrated dope that obtains in back.Add anhydrous methanol and stirring to it, added the 2.2g activated carbon decolorizing afterwards 2 hours, filter, drip the methanol solution of 680mL30% sodium methylate in the filtrate, 50 ℃ of stirring reactions 95 minutes are cooled to 0 ℃ then, being stirred to no solid separates out, filter, the solid drying under reduced pressure gets Decitabine crude product (HPLC purity is 99.4%, and the detection wavelength is 220nm).Crude product behind the recrystallization, obtains the pure product 30.1g of Decitabine from methyl alcohol, HPLC purity is that 99.9%(detection wavelength is 220nm).
LC-MS (ESI): 229.0[M+H]
+, 247.0[M+H
2O+H]
+, illustrate that the material of the present invention's preparation is Decitabine.
Embodiment 5
The 16.8L ethylene dichloride is joined in the 112.2g5-azepine cytosine(Cyt), be warming up to 100 ℃, stir adding 484g hexamethyldisilazane reaction down 92 minutes.Cool to 85 ℃ then, add 102g zinc chloride and 215g1-chloro-3, the chlorobenzene formacyl of 5-two-O--2-deoxidation-D-ribofuranose, stirring reaction cooled to 0 ℃ after 150 minutes, dripped the 730mL anhydrous methanol, were added dropwise to complete the concentrated dope that obtains in back.Add anhydrous methanol and stirring to it, added the 2.2g activated carbon decolorizing afterwards 2 hours, filter, drip the methanol solution of 720mL30% sodium ethylate in the filtrate, 50 ℃ of stirring reactions 95 minutes are cooled to 0 ℃ then, being stirred to no solid separates out, filter, the solid drying under reduced pressure gets Decitabine crude product (HPLC purity is 99.1%, and the detection wavelength is 220nm).Crude product behind the recrystallization, obtains the pure product 28.4g of Decitabine from methyl alcohol, HPLC purity is that 99.8%(detection wavelength is 220nm).
LC-MS (ESI): 229.1[M+H]
+, 247.1[M+H
2O+H]
+, illustrate that the material of the present invention's preparation is Decitabine.
By present embodiment as can be known, as sillylation reagent, adopt the method for the invention with hexamethyldisilazane, under the condition of intermediate that do not need to purify, still can obtain the Decitabine of high quality, high yield.
Embodiment 6
101.7g5-azepine cytosine(Cyt), two (trimethyl silicon based) sulfuric esters of 505.9g and 4700ml acetonitrile are mixed, be heated to 100 ℃ of reactions 6 hours, filter, 80 ℃ of evaporated under reduced pressure get white solid.Then with this white solid, 123.0mL three silyl triflate, 195g1-chloro-3; the chlorobenzene formacyl of 5-two-O--2-deoxidation-D-ribofuranose and 4000g methylene dichloride are at 25 ℃ of following stirring reactions after 12 hours; add 1000mL water washing reaction solution; standing demix; take off a layer dichloromethane layer; use anhydrous sodium sulfate drying; filter and remove siccative; filtrate is carried out concentrating under reduced pressure; being concentrated at 1/5 o'clock stops to concentrate; filter to remove the solid of separating out, continue to be concentrated into dried, get faint yellow solid.Described faint yellow solid is added in the normal hexane, and stirring and forming concentration is the suspension of 0.2g/ml, in 22 ℃ of stirring 1h, filters, and 40 ℃ of forced air drying 6h of filter cake get the solid of off-white color.
Described off-white color solid is mixed with the methanol solution of 650mL30% sodium methylate, 25 ℃ of stirring reactions 8 hours, filter, filtrate is concentrated into 1/10 volume, separate out solid, filter the filter cake methanol wash, 40 ℃ of dryings of filter cake got Decitabine crude product (HPLC purity is 99.5%, and the detection wavelength is 220nm) in 6 hours.Crude product behind the recrystallization, obtains the pure product 20.6g of Decitabine from methyl alcohol, HPLC purity is that 99.8%(detection wavelength is 220nm).
LC-MS (ESI): 229.0[M+H]
+, 247.0[M+H
2O+H]
+, illustrate that the material of the present invention's preparation is Decitabine.
By present embodiment as can be known, two (trimethyl silicon based) sulfuric esters of the present invention are used for prior art, still can make the Decitabine of high quality, high yield, the present invention has opened up the selectable range of sillylation reagent.
Embodiment 7
The 606mL methylene dichloride is joined in the 121.1g5-azepine cytosine(Cyt), be warming up to 10 ℃, stir adding 442g hexamethyl two silicon ureas reaction down 150 minutes.Be warmed up to 65 ℃ then, add 142g titanium tetrachloride and 210g1-chloro-3, the toluyl of 5-two-O--2-deoxidation-D-ribofuranose, stirring reaction cooled to 0 ℃ after 90 minutes, dripped the 650mL dehydrated alcohol, were added dropwise to complete the concentrated dope that obtains in back.Add dehydrated alcohol and stirring to it, added the 2.1g activated carbon decolorizing afterwards 2.5 hours, filter, drip the ethanolic soln of 600mL20% ammoniacal liquor sodium in the filtrate, 30 ℃ of stirring reactions 120 minutes are cooled to 0 ℃ then, being stirred to no solid separates out, filter, the solid drying under reduced pressure gets Decitabine crude product (HPLC purity is 99.4%, and the detection wavelength is 220nm).Crude product behind the recrystallization, obtains the pure product 21.2g of Decitabine from ethanol, HPLC purity is that 99.9%(detection wavelength is 220nm).
LC-MS (ESI): 229.0[M+H]
+, 247.0[M+H
2O+H]
+, illustrate that the material of the present invention's preparation is Decitabine.
As seen from the above embodiment, the method of the invention has been expanded the optional scope of sillylation reagent on the one hand, by need not separation of intermediates in the preparation process, simplify method for preparing decitabine on the other hand, prepared the Decitabine of high quality, high yield simultaneously.
Applicant's statement, the present invention illustrates detailed process equipment of the present invention and technical process by above-described embodiment, but the present invention is not limited to above-mentioned detailed process equipment and technical process, does not mean that namely the present invention must rely on above-mentioned detailed process equipment and technical process could be implemented.The person of ordinary skill in the field should understand, any improvement in the present invention to the interpolation of the equivalence replacement of each raw material of product of the present invention and ancillary component, the selection of concrete mode etc., all drops within protection scope of the present invention and the open scope.
Claims (10)
1. a method for preparing Decitabine comprises: adopt two (trimethyl silicon based) sulfuric esters and/or hexamethyl two silicon ureas as the sillylation reagent of 5-azepine cytosine(Cyt).
2. the method for claim 1 is characterized in that, said method comprising the steps of:
(1) adopt two (trimethyl silicon based) sulfuric esters and/or hexamethyl two silicon ureas in organic solvent, to carry out silylation reactive as sillylation reagent and 5-azepine cytosine(Cyt);
(2) derivative and the catalyst mix of the reaction mixture that step (1) is obtained and D-2-desoxyribofu-are carried out linked reaction;
(3) alternatively, change the solvent of the reaction mixture that step (2) obtains;
(4) carry out deprotection reaction, obtain Decitabine;
Preferably, described sillylation reagent is (2～3) with the ratio of the molar weight of 5-azepine cytosine(Cyt): 1, be preferably (2.2～2.5) especially: 1.
3. method as claimed in claim 2, it is characterized in that, the described organic solvent of step (1) is aprotic organic solvent, non-silylated aprotic organic solvent more preferably, more preferably a kind in methylene dichloride, ethylene dichloride or the acetonitrile or at least 2 kinds combination are preferably acetonitrile especially;
Preferably, the consumption of the described organic solvent of step (1) is 5～150L/ (kg5-azepine cytosine(Cyt)), and more preferably 10～120L/ (kg5-azepine cytosine(Cyt)) is preferably 20～100L/ (kg5-azepine cytosine(Cyt)) especially;
Preferably, the temperature of the described silylation reactive of step (1) is the reflux temperature of 0 ℃～silylation reactive mixture, and more preferably the reflux temperature of 20 ℃～silylation reactive mixture is preferably 20 ℃～100 ℃ especially.
4. as claim 2 or 3 described methods, it is characterized in that the derivative of the described D-2-desoxyribofu-of step (2) has leavings group at its 1, and obtained by acidylate by the hydroxyl as the D-2-desoxyribofu-of precursor; Preferably, described leavings group is halogen, is preferably chlorine especially; Preferably, described acyl group preferentially is selected to toluyl or to chlorobenzene formacyl;
Preferably, the derivative of the described D-2-desoxyribofu-of step (2) is 1-chloro-3, the toluyl of 5-two-O--2-deoxidation-D-ribofuranose and/or 1-chloro-3, the chlorobenzene formacyl of 5-two-O--2-deoxidation-D-ribofuranose;
Preferably, the described catalyzer of step (2) is Lewis acid, more preferably a kind or at least 2 kinds combination in tin tetrachloride, titanium tetrachloride, zinc chloride, boron-trifluoride etherate, trimethylsilyl triflate or the trimethyl silyl perfluoro butyl sulphonate is preferably trimethylsilyl triflate especially;
Preferably, the temperature of the described linked reaction of step (2) is the reflux temperature of 0 ℃～linked reaction mixture, and more preferably the reflux temperature of 25 ℃～linked reaction mixture is preferably 25 ℃～100 ℃ especially.
5. as each described method of claim 2-4, it is characterized in that the solvent that is used for the described deprotection reaction of step (4) is alcohols, more preferably C
1-C
4Alcohol is preferably methyl alcohol especially;
Preferably, the described deprotection reaction of step (4) carries out in the presence of alkaline reagents, further preferably carries out in the presence of sodium alkoxide and/or ammonia, particularly preferably in carrying out under the existence of sodium methylate, sodium ethylate and/or ammonia.
6. method for preparing Decitabine may further comprise the steps:
(1) adopt sillylation reagent and 5-azepine cytosine(Cyt) in organic solvent, to carry out silylation reactive;
(2) derivative and the catalyst mix of the reaction mixture that step (1) is obtained and D-2-desoxyribofu-are carried out linked reaction;
(3) alternatively, change the solvent of the reaction mixture that step (2) obtains;
(4) carry out deprotection reaction, obtain Decitabine.
7. method as claimed in claim 6 is characterized in that, the described sillylation reagent of step (1) is two (trimethyl silicon based) sulfuric esters and/or hexamethyl two silicon ureas;
Preferably, the described organic solvent of step (1) is aprotic organic solvent, non-silylated aprotic organic solvent more preferably, and more preferably a kind in methylene dichloride, ethylene dichloride or the acetonitrile or at least 2 kinds combination are preferably acetonitrile especially;
Preferably, the consumption of the described organic solvent of step (1) is 5～150L/ (kg5-azepine cytosine(Cyt)), and more preferably 10～120L/ (kg5-azepine cytosine(Cyt)) is preferably 20～100L/ (kg5-azepine cytosine(Cyt)) especially;
Preferably, the described sillylation reagent of step (1) is (2～3) with the ratio of the molar weight of 5-azepine cytosine(Cyt): 1, be preferably (2.2～2.5) especially: 1;
Preferably, the temperature of the described silylation reactive of step (1) is the reflux temperature of 0 ℃～silylation reactive mixture, and more preferably the reflux temperature of 20 ℃～silylation reactive mixture is preferably 20 ℃～100 ℃ especially.
8. as claim 6 or 7 described methods, it is characterized in that the derivative of the described D-2-desoxyribofu-of step (2) has leavings group at its 1, and obtained by acidylate by the hydroxyl as the D-2-desoxyribofu-of precursor; Preferably, described leavings group is halogen, is preferably chlorine especially; Preferably, described acyl group preferentially is selected to toluyl or to chlorobenzene formacyl;
Preferably, the derivative of the described D-2-desoxyribofu-of step (2) is 1-chloro-3, the toluyl of 5-two-O--2-deoxidation-D-ribofuranose and/or 1-chloro-3, the chlorobenzene formacyl of 5-two-O--2-deoxidation-D-ribofuranose;
Preferably, the described catalyzer of step (2) is Lewis acid, more preferably a kind or at least 2 kinds combination in tin tetrachloride, titanium tetrachloride, zinc chloride, boron-trifluoride etherate, trimethylsilyl triflate or the trimethyl silyl perfluoro butyl sulphonate is preferably trimethylsilyl triflate especially;
Preferably, the temperature of the described linked reaction of step (2) is the reflux temperature of 0 ℃～linked reaction mixture, and more preferably the reflux temperature of 25 ℃～linked reaction mixture is preferably 25 ℃～100 ℃ especially.
9. as each described method of claim 6-8, it is characterized in that the solvent that is used for the described deprotection reaction of step (4) is alcohols, more preferably C
1-C
4Alcohol is preferably methyl alcohol especially;
Preferably, the described deprotection reaction of step (4) carries out in the presence of alkaline reagents, further preferably carries out in the presence of sodium alkoxide and/or ammonia, particularly preferably in carrying out under the existence of sodium methylate, sodium ethylate and/or ammonia.
10. method for preparing Decitabine may further comprise the steps:
(1) adopt two (trimethyl silicon based) sulfuric esters and/or hexamethyl two silicon ureas in consumption is the aprotic organic solvent of 5～150L/ (kg5-azepine cytosine(Cyt)), to carry out silylation reactive as sillylation reagent and 5-azepine cytosine(Cyt), wherein, described sillylation reagent is (2～3) with the ratio of the molar weight of 5-azepine cytosine(Cyt): 1;
(2) derivative of the reaction mixture that step (1) is obtained and D-2-desoxyribofu-and Lewis acid mix and carry out linked reaction, wherein, the derivative of described D-2-desoxyribofu-is 1-chloro-3, the toluyl of 5-two-O--2-deoxidation-D-ribofuranose and/or 1-chloro-3, the chlorobenzene formacyl of 5-two-O--2-deoxidation-D-ribofuranose;
(3) aprotic organic solvent of the reaction mixture that step (2) is obtained replaces with alcoholic solvent;
(4) in the presence of sodium alkoxide and/or ammonia, carry out deprotection reaction, obtain Decitabine.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030036023A1 (en) * | 2000-12-12 | 2003-02-20 | Moreau Wayne M. | Supercritical fluid(SCF) silylation process |
| CN102206240A (en) * | 2010-03-30 | 2011-10-05 | 凯米股份公司 | Process for the synthesis of azacitidine and decitabine |
| CN102216315A (en) * | 2008-08-08 | 2011-10-12 | 台湾神隆股份有限公司 | Process for making 5-azacytosine nucleosides and their derivatives |
-
2013
- 2013-06-17 CN CN2013102391927A patent/CN103275158A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030036023A1 (en) * | 2000-12-12 | 2003-02-20 | Moreau Wayne M. | Supercritical fluid(SCF) silylation process |
| CN102216315A (en) * | 2008-08-08 | 2011-10-12 | 台湾神隆股份有限公司 | Process for making 5-azacytosine nucleosides and their derivatives |
| CN102206240A (en) * | 2010-03-30 | 2011-10-05 | 凯米股份公司 | Process for the synthesis of azacitidine and decitabine |
Non-Patent Citations (3)
| Title |
|---|
| 中国化工信息中心，等: "《中国化工产品目录》", 31 January 2004, 化学工业出版社 * |
| 李宗磊: "地西他滨的合成研究", 《南京理工大学硕士学位论文》 * |
| 李谢，等: "地西他滨的合成研究", 《化工时刊》 * |
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