CN101463034A - Preparation of triacetylganciclovir - Google Patents
Preparation of triacetylganciclovir Download PDFInfo
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- CN101463034A CN101463034A CNA2009100954095A CN200910095409A CN101463034A CN 101463034 A CN101463034 A CN 101463034A CN A2009100954095 A CNA2009100954095 A CN A2009100954095A CN 200910095409 A CN200910095409 A CN 200910095409A CN 101463034 A CN101463034 A CN 101463034A
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Abstract
The invention discloses a preparation method of triacetyl-ganciclovir with a structure as shown in formula (I). The preparation method comprises the following steps: monoacetyl guanine with the structure as shown in formula (II) and 1,3-diacetyloxy-2-(acetyloxymethoxy)propane with the structure as shown in formula (III) are taken as raw materials, then fully react at the temperature of 100-150 DEG C in an organic solvent and under the action of a catalyst, and a triacetyl-ganciclovir product is obtained by subsequent treatment. The preparation method has the advantages of reasonable process, high reaction yield, good product purity, low production cost and excellent industrial application value.
Description
(1) technical field
The present invention relates to the preparation method of a kind of triacetyl ganciclovir { chemical name is 9-[2-acetoxyl group-1-(acetoxy-methyl) oxyethyl group] methyl-2-acetamido-6-oxygen-purine }.
(2) background technology
About synthesizing of ganciclovir, reported method is a lot of in the document, but ultimate principle is as one man, and nineteen eighty-two so far, successively there are many companies to apply for a patent, but are that main raw material and various acetyl-o-methyl ether or monochloromethyl ether carry out condensation reaction with guanine and derivative thereof basically.U.S. Merck company (European patent EP 74306,1983) adopt diacetyl guanine and 1,3-diethyl acyl-oxygen-2-(acetoxyl group methoxyl group) propane condensation, isomer separation, hydrolysis obtains ganciclovir, this technology relates to the synthetic of an important intermediate, the triacetyl ganciclovir that the present invention just mentions, the triacetyl ganciclovir promptly gets ganciclovir through hydrolysis, the quality product of ganciclovir depends primarily on the quality of triacetyl ganciclovir, if the triacetyl ganciclovir is of poor quality, the ganciclovir that obtains of hydrolysis will be difficult to the quality that reaches qualified so, even the means by purifying reach specification of quality reluctantly, yield losses also is very huge.European patent EP 74306,1983 preparation method is the diacetyl guanine that has 7 isomeries owing to what adopt, therefore the triacetyl ganciclovir that obtains contains the 7-position isomer about 40%, this isomer stable existence, aftertreatment bothers very much, and the method for processing is mainly made with extra care by the methyl alcohol chloroform, in process of production, refinement treatment bothers very much, and solvent loss is huge, particularly uses shortcomings such as long yield of chloroform treatment time is low.And owing to adopt 2, reaction is difficult to fully 9 diacetyl guanines as starting raw material, by EP 74306, the triacetyl ganciclovir that 1983 post-treating method obtains contains than higher unreacted purine derivative, the ganciclovir guanine impurity for preparing is higher, need repeatedly crystal's system, yield is difficult to improve.
(3) summary of the invention
The objective of the invention is to overcome the shortcoming of prior art, provide one technology is reasonable, reaction yield is high, the preparation method of good product purity, triacetyl ganciclovir that production cost is low.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A kind of structure is suc as formula the preparation method of the triacetyl ganciclovir shown in (I), it is characterized in that described preparation method be with structure suc as formula the single acetyl guanine shown in (II) and structure suc as formula 1 shown in (III), 3-diethyl acyl-oxygen-2-(acetoxyl group methoxyl group) propane is raw material, fully react in 100～150 ℃ in organic solvent under catalyst action, aftertreatment obtains triacetyl ganciclovir product.
Reaction formula is as follows:
Described catalyzer is selected from mineral acid, Lewis acid, the straight or branched alkyl acid of 1-8 carbon atom, the straight or branched alkylsulphonic acid of 1～8 carbon atom or the aromatic hydrocarbon sulfonic acid of 6-8 carbon atom, described mineral acid and Lewis acid can be selected from mineral acid commonly used and Lewis acid, mineral acid commonly used has hydrochloric acid, the vitriol oil etc., Lewis acid commonly used has aluminum chloride, iron(ic) chloride, boron trifluoride, the fluoroform sulphonate of columbium pentachloride and lanthanon etc., the preferred vitriol oil of catalyzer of the present invention, hydrochloric acid, formic acid, methylsulfonic acid, ethyl sulfonic acid or tosic acid, the most preferably tosic acid or the vitriol oil.
Described organic solvent is selected from the aromatic hydrocarbon of dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), diethylformamide (DEF), tetramethylene sulfone or boiling point 80-150 ℃, most preferably DMF.
Described single acetyl guanine and 1, the molar ratio of 3-diethyl acyl-oxygen-2-(acetoxyl group methoxyl group) propane is 1:1.0～5.0, preferred 1:1.1～3.0, more preferably 1:1.2～2.0.
The molar ratio of described single acetyl guanine and catalyzer is 1:0.01～0.3, preferred 1:0.02～0.2, more preferably 1:0.03～0.1.Be described single acetyl guanine, 1, the molar ratio of 3-diethyl acyl-oxygen-2-(acetoxyl group methoxyl group) propane and catalyzer is 1:1.0～5.0:0.01～0.3, more preferably 1:1.1～3.0:0.02～0.2.
The mass ratio of described single acetyl guanine and organic solvent is 1:1～10, most preferably 1:2.
Preferred 110～140 ℃ of temperature of reaction of the present invention, more preferably 120～130 ℃.
The present invention can adopt TLC tracking monitor extent of reaction, and the general reaction times was at 6-72 hour.
Preparation method of the present invention can adopt existing method to carry out aftertreatment, such as European patent EP 74306,1983 described post-treating methods.
The present invention recommends a kind of post-treating method as follows: single acetyl guanine and 1,3-diethyl acyl-oxygen-2-(acetoxyl group methoxyl group) propane fully reacts the reaction mixture that obtains and steams solvent earlier, resistates extracts with extraction solvent then, separate organic layer, organic layer is through concentrated, crystallisation by cooling, the centrifugal crude product that obtains, crude product is carried out recrystallizing and refining, obtain triacetyl ganciclovir product; Described extraction solvent is selected from the mixed solvent that one of water and following organic solvent are formed: ethyl acetate, toluene, dimethylbenzene, chloroform, and water and volume of organic solvent ratio do not have special requirement in the general extraction solvent, and proportioning all is suitable for the present invention arbitrarily; It is one of following that described recrystallization solvent is selected from: methyl alcohol, chloroform, ethyl acetate, ethanol, acetone, water.This treatment process once can obtain purity at the triacetyl ganciclovir product more than 98% as long as make with extra care.
The present invention recommends another kind of post-treating method as follows: single acetyl guanine and 1,3-diethyl acyl-oxygen-2-(acetoxyl group methoxyl group) propane fully reacts the reaction mixture that obtains and steams solvent earlier, adding ethyl acetate then in the resistates stirs, crystallisation by cooling obtains crude product, the gained crude product carries out recrystallizing and refining, obtains triacetyl ganciclovir product; It is one of following that described recrystallization solvent is selected from: methyl alcohol, chloroform, ethyl acetate, ethanol, acetone, water.Use this post-treating method, those skilled in the art can determine the recrystallizing and refining number of times according to practical situation, and generally speaking, this post-treating method can obtain purity at the triacetyl ganciclovir product more than 98% after making with extra care two to three times.
Compared with prior art, beneficial effect of the present invention is embodied in following several respects:
1, the weight yield that adopts the single acetyl guanine is than diacetyl guanine height, and the single acetyl guanine of identical weight is more than the triacetyl ganciclovir quantity that diacetyl guanine prepares;
2, single acetyl guanine and diacetyl guanine all are to adopt with guanine and aceticanhydride reaction to obtain, but the aceticanhydride of single acetyl guanine consumption will be lower than the aceticanhydride that diacetyl guanine consumes, so will have superiority on the cost;
3, owing to do not have ethanoyl on 9 of the single acetyl guanines, do not hinder 1,3-diethyl acyl-oxygen-2-(acetoxyl group methoxyl group) propane and 9 bit amino condensations, so selectivity will get well, it is also far better to react the degree of finishing.
4, the present invention adopts method of extraction in last handling process, effectively unreacted single acetyl guanine and triacetyl ganciclovir are separated, the triacetyl ganciclovir single acetyl guanine content that obtains is very low, helps the ganciclovir quality product and improves.
5, the present invention makes impurity effectively be separated with product owing to adopted extraction, so the product purity raising, helps refining postprocessing working procedures, and the product that is is crystallization, centrifugal easily in treating process, and yield and quality improve synchronously.
6, the present invention extracts with ethyl acetate earlier in last handling process, makes product can separate with impurity, has improved product purity, the easy crystallization of handling by ethyl acetate of product, centrifugal and dry.
(4) embodiment
The invention will be further described below in conjunction with embodiment, but protection scope of the present invention is not limited to this.
Embodiment 1
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, catalyzer is a tosic acid, organic solvent is DMF, its consumption is 2 times of single acetyl guanine quality, and the used tosic acid of the embodiment of the invention is the tosic acid hydrate.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 130 ℃, and 130 ℃ of reactions 24 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 20ML and the ethyl acetate temperature rising reflux of 200ML and stirred 1 hour to syrupy shape, separate water layer behind the non-shock chilling to 40 ℃, with method extraction 1 time, combined ethyl acetate steams the about 250ML of ethyl acetate to water layer with ethyl acetate 200ML, solution is cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 20.7 of oven dry.
Crude product adds the methyl alcohol heating makes dissolving, and crystallisation by cooling gets 18.2 gram triacetyl ganciclovirs, content 98.5%.Total recovery is pressed the single acetyl guanine and is calculated 47.7%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 2
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.1:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 27.3g (110mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 130 ℃, and 130 ℃ of reactions 24 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 20ML and the ethyl acetate temperature rising reflux of 200ML and stirred 1 hour to syrupy shape, separate water layer behind the non-shock chilling to 40 ℃, with method extraction 1 time, combined ethyl acetate steams the about 250ML of ethyl acetate to water layer with ethyl acetate 200ML, solution is cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 19.3 of oven dry.
Crude product adds the methyl alcohol heating makes dissolving, and crystallisation by cooling gets 15.1 gram triacetyl ganciclovirs, content 98.5%.Total recovery is pressed the single acetyl guanine and is calculated 39.6%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 3
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.1:0.1, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 27.3g (110mmol), DMF40.0g and catalyzer 1.9g.Finish, be warming up to 130 ℃, and 130 ℃ of reactions 24 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 20ML and the ethyl acetate temperature rising reflux of 200ML and stirred 1 hour to syrupy shape, separate water layer behind the non-shock chilling to 40 ℃, with method extraction 1 time, combined ethyl acetate steams the about 250ML of ethyl acetate to water layer with ethyl acetate 200ML, solution is cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 14.3 of oven dry.
Crude product adds the methyl alcohol heating makes dissolving, and crystallisation by cooling gets 10.1 gram triacetyl ganciclovirs, content 98.5%.Total recovery is pressed the single acetyl guanine and is calculated 26.5%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 4
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is the vitriol oil, and organic solvent is DMSO, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMSO40.0g and catalyzer 0.29g.Finish, be warming up to 120 ℃, and 120 ℃ of reactions 14 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 20ML and the ethyl acetate temperature rising reflux of 200ML and stirred 1 hour to syrupy shape, separate water layer behind the non-shock chilling to 40 ℃, with method extraction 1 time, combined ethyl acetate steams the about 250ML of ethyl acetate to water layer with ethyl acetate 200ML, solution is cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 20.1 of oven dry.
Crude product adds the methyl alcohol heating makes dissolving, and crystallisation by cooling gets 17.2 gram triacetyl ganciclovirs, content 98.5%.Total recovery is pressed the single acetyl guanine and is calculated 45.1%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 5
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.01, and catalyzer is the vitriol oil, and organic solvent is DMSO, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMSO40.0g and catalyzer 0.1g.Finish, be warming up to 120 ℃, and 120 ℃ of reactions 14 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 20ML and the ethyl acetate temperature rising reflux of 200ML and stirred 1 hour to syrupy shape, separate water layer behind the non-shock chilling to 40 ℃, with method extraction 1 time, combined ethyl acetate steams the about 250ML of ethyl acetate to water layer with ethyl acetate 200ML, solution is cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 15.1 of oven dry.
Crude product adds the methyl alcohol heating makes dissolving, and crystallisation by cooling gets 10.2 gram triacetyl ganciclovirs, content 98.5%.Total recovery is pressed the single acetyl guanine and is calculated 26.7%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 6
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is the vitriol oil, and organic solvent is a toluene, its consumption is 5 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), toluene 100.0g and catalyzer 0.29g.Finish, be warming up to backflow, reacted 14 hours, (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes the TLC tracking monitor, stops heating, add the water of 20ML and the toluene temperature rising reflux of 100ML and stirred 0.3 hour, separate water layer behind the non-shock chilling to 40 ℃, water layer with toluene 100ML with method extraction 1 time, combining methylbenzene, steam the about 150ML of toluene, solution is cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 15.1 of oven dry.
Crude product adds the methyl alcohol heating makes dissolving, and crystallisation by cooling gets 11.2 gram triacetyl ganciclovirs, content 98.5%.Total recovery is pressed the single acetyl guanine and is calculated 29.4%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 7
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is the vitriol oil, and organic solvent is DMF, its consumption is 1 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF20.0g and catalyzer 0.29g.Finish, be warming up to 120 ℃, and 120 ℃ of reactions 19 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 20ML and the ethyl acetate temperature rising reflux of 200ML and stirred 1 hour to syrupy shape, separate water layer behind the non-shock chilling to 40 ℃, with method extraction 1 time, combined ethyl acetate steams the about 250ML of ethyl acetate to water layer with ethyl acetate 200ML, solution is cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 19.1 of oven dry.
Crude product adds the methyl alcohol heating makes dissolving, and crystallisation by cooling gets 16.2 gram triacetyl ganciclovirs, content 98.5%.Total recovery is pressed the single acetyl guanine and is calculated 42.5%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 8
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 100 ℃, and 100 ℃ of reactions 72 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 20ML and the ethyl acetate temperature rising reflux of 200ML and stirred 0.3 hour to syrupy shape, separate water layer behind the non-shock chilling to 50 ℃, with method extraction 1 time, combined ethyl acetate steams the about 250ML of ethyl acetate to water layer with ethyl acetate 200ML, solution is cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 21.7 of oven dry.
Crude product adds the methyl alcohol heating makes dissolving, and crystallisation by cooling gets 18.6 gram triacetyl ganciclovirs, content 98.3%.Total recovery is pressed the single acetyl guanine and is calculated 48.7%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 9
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 150 ℃, and 150 ℃ of reactions 6 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 20ML and the ethyl acetate temperature rising reflux of 200ML and stirred 0.3 hour to syrupy shape, separate water layer behind the non-shock chilling to 50 ℃, with method extraction 1 time, combined ethyl acetate steams the about 250ML of ethyl acetate to water layer with ethyl acetate 200ML, solution is cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 15.7 of oven dry.
Crude product adds the methyl alcohol heating makes dissolving, and crystallisation by cooling gets 12.6 gram triacetyl ganciclovirs, content 98.1%.Total recovery is pressed the single acetyl guanine and is calculated 33.0%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 10
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 130 ℃, and 130 ℃ of reactions 24 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 20ML and the ethyl acetate temperature rising reflux of 200ML and stirred 0.3 hour to syrupy shape, separate water layer behind the non-shock chilling to 50 ℃, with method extraction 1 time, combined ethyl acetate steams the about 250ML of ethyl acetate to water layer with ethyl acetate 200ML, solution is cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 21.0 of oven dry.
Crude product adds the chloroform heating makes dissolving, and crystallisation by cooling gets 15.6 gram triacetyl ganciclovirs, content 98.3%.Total recovery is pressed the single acetyl guanine and is calculated 40.9%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 11
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 130 ℃, and 130 ℃ of reactions 20 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 50ML and the chloroform temperature rising reflux of 200ML and stirred 0.3 hour to syrupy shape, separate water layer behind the non-shock chilling to 50 ℃, with method extraction 1 time, combined chloroform steams the about 250ML of chloroform to water layer with chloroform 200ML, solution is cooled to-5 ℃ of crystallizations, suction filtration, filter cake restrains with chloroform washing three times, the triacetyl ganciclovir crude product 17.9 of oven dry.
Crude product adds the methyl alcohol heating makes dissolving, and crystallisation by cooling gets 14.6 gram triacetyl ganciclovirs, content 98.3%.Total recovery is pressed the single acetyl guanine and is calculated 38.2%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 12
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 130 ℃, and 130 ℃ of reactions 20 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 20ML and the ethyl acetate temperature rising reflux of 200ML and stirred 0.3 hour to syrupy shape, separate water layer behind the non-shock chilling to 50 ℃, with method extraction 1 time, combined ethyl acetate steams the about 250ML of ethyl acetate to water layer with ethyl acetate 200ML, solution is cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 21.0 of oven dry.
Crude product adds the chloroform heating makes dissolving, and crystallisation by cooling gets 15.6 gram triacetyl ganciclovirs, content 98.3%.Total recovery is pressed the single acetyl guanine and is calculated 40.9%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 13
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 130 ℃, and 130 ℃ of reactions 25 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 50ML and the chloroform temperature rising reflux of 200ML and stirred 0.3 hour to syrupy shape, separate water layer behind the non-shock chilling to 50 ℃, with method extraction 1 time, combined chloroform steams the about 250ML of chloroform to water layer with chloroform 200ML, solution is cooled to-5 ℃ of crystallizations, suction filtration, filter cake restrains with chloroform washing three times, the triacetyl ganciclovir crude product 17.9 of oven dry.
Crude product adds the methyl alcohol heating makes dissolving, and crystallisation by cooling gets 14.6 gram triacetyl ganciclovirs, content 98.3%.Total recovery is pressed the single acetyl guanine and is calculated 38.2%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 14
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 130 ℃, and 130 ℃ of reactions 25 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 20ML and the toluene of 100ML and is warming up to 70 ℃ of stirrings 0.3 hour to syrupy shape, separate water layer behind the non-shock chilling to 50 ℃, with method extraction 1 time, combining methylbenzene steams the about 100ML of toluene to water layer with toluene 100ML, solution is cooled to-5 ℃ of crystallizations, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 20.9 of oven dry.
Crude product adds the methyl alcohol heating makes dissolving, and crystallisation by cooling gets 18.1 gram triacetyl ganciclovirs, content 98.3%.Total recovery is pressed the single acetyl guanine and is calculated 47.6%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 15
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 130 ℃, and at 130 ℃ of reactions 23 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF is to syrupy shape, and the ethyl acetate that adds 60ML stirred 1 hour, non-shock chilling to 0 ℃ crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 18.7 of oven dry.
Crude product methyl alcohol reflux, dissolving, crystallisation by cooling, suction filtration, oven dry, add in the there-necked flask,, get 17.2 gram triacetyl ganciclovirs with chloroform reflux, dissolving, crystallisation by cooling, content 98.5%, total recovery are pressed the single acetyl guanine and are calculated 45.1%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 16
Molar ratio single acetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add single acetyl guanine 19.3g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 130 ℃, and at 130 ℃ of reactions 20 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the ethyl acetate of 60ML to syrupy shape, be cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 20.7 of oven dry.
Crude product methyl alcohol reflux, dissolving, crystallisation by cooling, suction filtration, oven dry, the product that obtains adds in the there-necked flask, and water is heated to 80 ℃, dissolving, and crystallisation by cooling gets 15.2 gram triacetyl ganciclovirs, content 98.2%, total recovery are pressed the single acetyl guanine and are calculated 39.9%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 17
The molar ratio diacetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add diacetyl guanine 23.5g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 130 ℃, and at 130 ℃ of reactions 22 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the ethyl acetate of 60ML to syrupy shape, be cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 19.7 of oven dry.
Crude product methyl alcohol reflux, dissolving, crystallisation by cooling, suction filtration, oven dry, add in the there-necked flask, with chloroform reflux, dissolving, crystallisation by cooling, suction filtration, filter cake is directly re-refined once with method with chloroform, gets 11.2 gram triacetyl ganciclovirs, content 98.3%, total recovery is pressed the di-acetyl guanine and is calculated 29.4%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 18
The molar ratio diacetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add diacetyl guanine 23.5g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 130 ℃, and 130 ℃ of reactions 25 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF adds the water of 20ML and the ethyl acetate temperature rising reflux of 200ML and stirred 1 hour to syrupy shape, separate water layer behind the non-shock chilling to 40 ℃, with method extraction 1 time, combined ethyl acetate steams the about 250ML of ethyl acetate to water layer with ethyl acetate 200ML, solution is cooled to 0 ℃ of crystallization, suction filtration, filter cake restrains with ethyl acetate washing three times, the triacetyl ganciclovir crude product 20.2 of oven dry.
Crude product methyl alcohol reflux, dissolving, crystallisation by cooling, suction filtration, oven dry, product adds in the there-necked flask, with chloroform reflux, dissolving, crystallisation by cooling, suction filtration, filter cake is directly re-refined once with method with chloroform, gets 13.2 gram triacetyl ganciclovirs, content 98.3%, total recovery is pressed the di-acetyl guanine and is calculated 34.6%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)
Embodiment 19
The molar ratio diacetyl guanine: 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane: catalyzer is 1:1.5:0.03, and catalyzer is a tosic acid, and organic solvent is DMF, its consumption is 2 times of single acetyl guanine weight.
In thermometer, reflux condensing tube, constant pressure funnel and churned mechanically 250mL four-hole boiling flask are housed, add diacetyl guanine 23.5g (100mmol), 1,3-diacetyl-2-(acetoxyl group methoxyl group) propane 37.2g (150mmol), DMF40.0g and catalyzer 0.58g.Finish, be warming up to 130 ℃, and at 130 ℃ of reactions 48 hours, TLC tracking monitor (developping agent: chloroform-methanol-ammoniacal liquor (8:2:0.2)), reaction finishes, stop heating, underpressure distillation DMF is to syrupy shape, and the chloroform that adds 60ML stirred 1 hour, non-shock chilling is to-5 ℃ of crystallizations, suction filtration, filter cake restrains with chloroform washing three times, the triacetyl ganciclovir crude product 15.6 of oven dry.
Crude product methyl alcohol reflux, dissolving, crystallisation by cooling, suction filtration, oven dry, product add in the there-necked flask, with chloroform reflux, dissolving, crystallisation by cooling, suction filtration, filter cake oven dry, the product that obtains need be with the methyl alcohol reflux, dissolve recrystallization once again, get 9.2 gram triacetyl ganciclovirs, content 98.5%, total recovery is pressed the di-acetyl guanine and is calculated 24.1%, mp172-173 ℃
Molecular formula C
15H
19N
5O
7, molecular weight 381.35
Ultimate analysis:
Measured value: C:47.21% H:4.98% N:29.48%
Calculated value: 47.24% H:5.02% N29.37%
Mass spectroscopy: m/e:381,151
Nuclear magnetic spectrum:
H’NMR(DMSO-d6)δ(ppm)
1.92(S，6H，AcO)
2.22(S，3H，AcN)
3.96(S，5H，H-3’，H-4’)
5.52(S，2H，H-1’)
8.16(S，1H，H-8’)。
Claims (10)
1, a kind of structure is suc as formula the preparation method of the triacetyl ganciclovir shown in (I), it is characterized in that described preparation method be with structure suc as formula the single acetyl guanine shown in (II) and structure suc as formula 1 shown in (III), 3-diethyl acyl-oxygen-2-(acetoxyl group methoxyl group) propane is raw material, fully react in 100～150 ℃ in organic solvent under catalyst action, the reaction mixture aftertreatment obtains triacetyl ganciclovir product; Described catalyzer is selected from the straight or branched alkylsulphonic acid of mineral acid, Lewis acid, the straight or branched alkyl acid of a 1-8 carbon atom, 1～8 carbon atom or the aromatic hydrocarbon sulfonic acid of 6-8 carbon atom; Described organic solvent is selected from dimethyl formamide, dimethyl sulfoxide (DMSO), diethylformamide, tetramethylene sulfone or boiling point 80-150 ℃ aromatic hydrocarbon;
2, the preparation method of triacetyl ganciclovir as claimed in claim 1 is characterized in that described catalyzer is the vitriol oil, hydrochloric acid, formic acid, methylsulfonic acid, ethyl sulfonic acid or tosic acid.
3, the preparation method of triacetyl ganciclovir as claimed in claim 1 is characterized in that described catalyzer is the tosic acid or the vitriol oil.
4, the preparation method of triacetyl ganciclovir as claimed in claim 1 is characterized in that described organic solvent is a dimethyl formamide.
5, as the preparation method of the described triacetyl ganciclovir of one of claim 1～4, it is characterized in that described single acetyl guanine, 1, the molar ratio of 3-diethyl acyl-oxygen-2-(acetoxyl group methoxyl group) propane and catalyzer is 1:1.0～5.0:0.01～0.3.
6, the preparation method of triacetyl ganciclovir as claimed in claim 5 is characterized in that described single acetyl guanine and organic solvent mass ratio are 1:1～10.
7, the preparation method of triacetyl ganciclovir as claimed in claim 1 is characterized in that described being reflected under 110～140 ℃ carry out.
8, the preparation method of triacetyl ganciclovir as claimed in claim 1, it is characterized in that described aftertreatment adopts following method: fully the reaction mixture that obtains of reaction steams solvent earlier, resistates extracts with extraction solvent then, separate organic layer, organic layer is through concentrated, crystallisation by cooling, the centrifugal crude product that obtains, crude product is carried out recrystallizing and refining, obtain triacetyl ganciclovir product; Described extraction solvent is selected from the mixed solvent that one of water and following organic solvent are formed with arbitrary proportion: ethyl acetate, toluene, dimethylbenzene, chloroform.
9, the preparation method of triacetyl ganciclovir as claimed in claim 1, it is characterized in that described aftertreatment adopts following method: fully the reaction mixture that obtains of reaction steams solvent earlier, adding ethyl acetate then in the resistates stirs, crystallisation by cooling obtains crude product, the gained crude product carries out recrystallizing and refining, obtains triacetyl ganciclovir product.
10, the preparation method of triacetyl ganciclovir as claimed in claim 8 or 9, it is one of following to it is characterized in that recrystallization solvent is selected from: methyl alcohol, chloroform, ethyl acetate, ethanol, acetone, water.
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| CNA2009100954095A CN101463034A (en) | 2009-01-09 | 2009-01-09 | Preparation of triacetylganciclovir |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103467469A (en) * | 2013-08-13 | 2013-12-25 | 浙江车头制药股份有限公司 | Separation method of triacetyl ganciclovir isomer |
| CN113149988A (en) * | 2021-04-23 | 2021-07-23 | 海南锦瑞制药有限公司 | Ganciclovir preparation method and application |
-
2009
- 2009-01-09 CN CNA2009100954095A patent/CN101463034A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103467469A (en) * | 2013-08-13 | 2013-12-25 | 浙江车头制药股份有限公司 | Separation method of triacetyl ganciclovir isomer |
| CN103467469B (en) * | 2013-08-13 | 2016-03-30 | 浙江车头制药股份有限公司 | A kind of separation method of triacetyl ganciclovir isomer |
| CN113149988A (en) * | 2021-04-23 | 2021-07-23 | 海南锦瑞制药有限公司 | Ganciclovir preparation method and application |
| CN113149988B (en) * | 2021-04-23 | 2023-04-28 | 海南锦瑞制药有限公司 | Preparation method and application of ganciclovir |
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