CN109134569B - A kind of production technology of Vidarabine Monophosphate - Google Patents
A kind of production technology of Vidarabine Monophosphate Download PDFInfo
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- CN109134569B CN109134569B CN201811080678.XA CN201811080678A CN109134569B CN 109134569 B CN109134569 B CN 109134569B CN 201811080678 A CN201811080678 A CN 201811080678A CN 109134569 B CN109134569 B CN 109134569B
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- vidarabine monophosphate
- production technology
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
Abstract
The invention belongs to Vidarabine Monophosphate preparation technical fields, and in particular to a kind of production technology of Vidarabine Monophosphate, the technique include the following steps: that arabinosy ladenosine is dissolved in organic solvent by S1, cooling；Phosphoryl chloride phosphorus oxychloride is added in S2, and insulation reaction to arabinosy ladenosine surplus stops when being no more than the 3% of additional amount；S3 is filtered after palladium catalyst catalysis reduction is added, and gained filtrate is removed solvent up to Vidarabine Monophosphate crude product；The Vidarabine Monophosphate crude product recrystallization purifying that S4 obtains step S3.It is reacted using the relatively low phosphoryl chloride phosphorus oxychloride of the production technology reference reactivity of Vidarabine Monophosphate provided by the invention with raw material arabinosy ladenosine, reaction is mild, and it is easy to control, the generation quantity of by-product is reduced from reaction source；And the ether of introducing is restored using novel palladium catalyst selectivity, purifying process is simple, target product yield and purity is high.
Description
Technical field
The invention belongs to Vidarabine Monophosphate preparation technical fields, and in particular to a kind of production of Vidarabine Monophosphate
Technique.
Background technique
Vidarabine Monophosphate (vidarabine monophosphate, AraAMP) is the list of arabinosy ladenosine (Ara-A)
Phosphate cpd is a kind of artificial synthesized adenosine class antiviral agent.It is mainly used for chronic viral in China at present
Hepatitis, herpes simplex virus, herpes zoster virus, vaccinia virus and many animals herpesviral and a small number of oncornavirus RNAs
Deng.Its pharmacological action be because it can be such that its activity reduces in conjunction with deoxyribonucleic acid polymerase, so that DNA be inhibited to synthesize,
After Vidarabine Monophosphate enters cell, arabinosy ladenosine diphosphonic acid and arabinosy ladenosine triphosphoric acid are generated by phosphorylation, and it is disease-resistant
Toxic action is mainly due to caused by Vidarabine Monophosphate triphosphoric acid, with deoxyadenosine triphosphate competitive binding to DNA
On, thus selective depression varial polymerases and reductase activity, DNA is inhibited to continue to synthesize.Vidarabine Monophosphate is to DNA
It significantly inhibits, has apparent inhibition activity to various DNA virus, it is viral B-mode to be widely used in treatment at home
Hepatitis, being in great demand clinically, the study on the synthesis for carrying out Vidarabine Monophosphate is of great significance.
The synthetic route reported at present for preparing Vidarabine Monophosphate includes following several: 1) with trialkyl phosphates
For solvent, phosphorus oxychloride is reacted or is hydrolyzed with arabinosy ladenosine, obtains crude product, but the purifying of product is using at ion exchange resin separation
Reason is not suitable for large-scale production.2) arabinosy ladenosine is suspended in triethyl phosphate, the dichloro of phosphorus oxychloride is added under low temperature
Dichloromethane reaction, after completion of the reaction, reaction solution is poured into ice water and is quenched, and is hydrolyzed, and solid is precipitated in extraction, pH value, filters slightly
Then crude product is suspended in water, with sodium hydroxide tune pH to 6, pH to 2.5 is adjusted after filtering, dehydrated alcohol is eventually adding and obtains by product
Sterling.The synthesis technology is relatively easy, and convenient for industrialization, but this method by-product is more, and purifying is difficult.3) in N, N- diisopropyl
For ethamine as acid binding agent, 4-dimethylaminopyridine is catalyst and phosphorus oxychloride reaction, hydrolysis adjust pH value be precipitated monophosphate Ah
Sugared adenosine.The wastewater treatment of n,N-diisopropylethylamine and 4-dimethylaminopyridine is difficult in the reaction, and environmental protection treatment is at high cost
The problem of.4) under conditions of being alkali as solvent and pyridine using acetonitrile, arabinosy ladenosine and phosphorus oxychloride carry out phosphorylation at low temperature
Reaction prepares Vidarabine Monophosphate.Solvent acetonitrile price used in this method is more expensive, and pyridine toxicity is big.
Summary of the invention
In order to solve the above problem in the prior art, present invention is designed to provide that a kind of by-product is few, system
The preparation process of the Vidarabine Monophosphate of standby simple process, easy purification.
In order to achieve the above-mentioned object of the invention, the present invention provides the following technical scheme that
A kind of production technology of Vidarabine Monophosphate comprising following steps:
Arabinosy ladenosine is dissolved in organic solvent by S1, cooling；
Phosphoryl chloride phosphorus oxychloride is added into the system after step S1 cooling by S2, and insulation reaction to arabinosy ladenosine surplus, which is no more than, to be added
Amount 3% when stop；
S3 is filtered after palladium catalyst catalysis reduction being added in the system after step S2 reaction stopping, and gained filtrate is removed
Solvent is up to Vidarabine Monophosphate crude product；
Sterling Vidarabine Monophosphate is obtained after the Vidarabine Monophosphate crude product recrystallization purifying that S4 obtains step S3.
Preferably, the organic solvent is tetrahydrofuran, dioxane, acetone, butanone or cyclohexanone.
Preferably, -5 DEG C to 15 DEG C are cooled in step S1.
Preferably, the mass volume ratio of step S1 arabinosy ladenosine and organic solvent is 8-20g/mL.
Preferably, the molar ratio of arabinosy ladenosine and phosphoryl chloride phosphorus oxychloride is 1:1-2.5 in step S1.
Preferably, the phosphoryl chloride phosphorus oxychloride is to be free of or the C2-C10 alkyl phosphinylidyne optionally containing one to three substituent group
Chlorine, C6-C10 diphenylphosphoryl chlorine；The substituent group is halogen or nitro.
It is further preferred that the substituent group is chlorine, bromine or nitro.
It is further preferred that the phosphoryl chloride phosphorus oxychloride is to be free of or the C2-C10 alkyl phosphinylidyne optionally containing one to two chlorine
Base.
It is further preferred that the phosphoryl chloride phosphorus oxychloride is to be free of or the phenyl of the C6-C10 optionally containing one to two nitro
Phosphoryl chloride phosphorus oxychloride.
Preferably, the preparation method of palladium catalyst described in step S3 includes the following steps:
Dissolve in ammonia water by palladium chloride and magnesium chloride hexahydrate, it adds aluminum fluoride to be reacted, filter after the reaction was completed,
By gained Washing of Filter Cake, drying, catalyst co-precipitate is obtained；
The heating roasting of catalyst co-precipitate, crushes after cooling, obtains target palladium catalyst.
Preferably, the preparation method of palladium catalyst described in step S3 includes the following steps:
By palladium chloride and magnesium chloride hexahydrate dissolve in ammonia water after, add aluminum fluoride, add ammonia under stirring conditions
Aqueous solution adjusts pH value between 7.0-9.0, after reacting 20-40min, filters, by Washing of Filter Cake to neutrality, at 100-120 DEG C
Under the conditions of dry 8-10h, obtain catalyst co-precipitate.
Further include following steps:
Under the conditions of by the catalyst co-precipitate, electric heating is to 250-300 DEG C in nitrogen environment, after roasting 16-18h,
Cooling, crushes to obtain target palladium catalyst.
Preferably, in step S3 palladium catalyst dosage be arabinosy ladenosine 3-10 mass %；It is still more preferably 5-8
Quality %.
Preferably, the molar ratio of the palladium chloride and magnesium chloride hexahydrate is 1:1-10.
Preferably, the recrystallization operation of step S4 includes the following steps:
After the Vidarabine Monophosphate crude product that step S3 is obtained is completely dissolved in water, it is molten that organic mixing is added thereto
Agent and cooling crystallization filter, dry, obtain target product；Wherein, organic mixed solvent is ethyl acetate, triethylamine, positive second
The combination of one of alkane and ether, methanol.
It is further preferred that the Vidarabine Monophosphate crude product completely dissolves in water under the conditions of 40-60 DEG C.
Reaction route of the invention is as follows:
Compared with prior art, the beneficial effects of the present invention are:
Utilize the relatively low phosphoryl chloride phosphorus oxychloride of the production technology reference reactivity of Vidarabine Monophosphate provided by the invention
It is reacted with raw material arabinosy ladenosine, reaction is mild, and it is easy to control, the quantity of by-product is reduced from reaction source；And utilize novelty
Palladium catalyst selectivity the ether of introducing is restored, purifying process is simple, target product yield and purity is high.
Specific embodiment
To keep purpose and the technical solution of the embodiment of the present invention clearer, below in conjunction with the embodiment of the present invention, to this
The technical solution of invention is clearly and completely described.Can be commercially available for the raw material phosphoryl chloride phosphorus oxychloride in the embodiment of the present invention, it can also
Be made with reference to published preparation method, such as bibliography " phosphoryl chloride phosphorus oxychloride Study of synthesis method progress ", Liu Bo etc., chemical engineering and
Equipment, the 12nd phase in 2010, the 133-134 pages.
Embodiment 1
A kind of production technology of Vidarabine Monophosphate comprising following steps:
Arabinosy ladenosine 30g is mixed in 3mL tetrahydrofuran by S1, and stirring is cooled to 0 DEG C；
Di-n-butyl phosphoryl chloride phosphorus oxychloride 30.83g is added portionwise into the system after step S1 cooling in S2, in 10 DEG C of conditions after adding
Descend the reaction was continued to stop when being no more than the 3% of additional amount to arabinosy ladenosine surplus；
1.5g palladium catalyst is added into the reaction system after step S2 stopping and is warming up to 50 DEG C by S3 is stirred to react 8h, mistake
Filter, and ethanol washing filter cake is used, collection filtrate removes solvent under reduced pressure, obtains Vidarabine Monophosphate crude product；
The preparation method of the palladium catalyst includes the following steps:
Palladium chloride 17.7g and magnesium chloride hexahydrate 203.3g are added into 20mL saturation ammonia spirit, stirred to completely molten
Solution；Aluminum fluoride is added, slowly adds the ammonia spirit of a small amount of mass concentration 15% under stirring conditions, adjusts pH value to 8,
After reacting 30min, filtering, by Washing of Filter Cake to neutrality, drying dries 10h under the conditions of 120 DEG C, obtains catalyst co-precipitate,
Then under the conditions of electric heating is to 260 DEG C in nitrogen environment by above-mentioned catalyst co-precipitate, 18h is roasted, cooling crushes to obtain palladium
Catalyst granules；
The Vidarabine Monophosphate crude product that S4 obtains step S3 under the conditions of 40 DEG C just it is soluble in water after, thereto by
The mixed solution (ether: methanol: ethyl acetate volume ratio 1:5:0.5) of ether, methanol, ethyl acetate is gradually added to just having not
Molten object occurs, and is cooled to 0 DEG C or so crystallization, filters, 40 DEG C of vacuum drying, and obtaining white crystalline powder 38.95g, (yield is
95%, purity 99.3%).
After measured, the molten point of product is 211.5 DEG C, UV λ max=259.2nm, m/z:[M-H]-=346.1.
1HNMR(D2O, 400MHz) δ ppm:8.25 (1H, s), 7.93 (1H, s), 6.36 (1H, s), 4.31 (1H, t),
4.12-4.10(1H,t)。
Embodiment 2
A kind of production technology of Vidarabine Monophosphate comprising following steps:
Arabinosy ladenosine 30g is mixed in 3mL acetone by S1, and stirring is cooled to -5 DEG C；
Bis- (4- nitrobenzene) phosphoryl chloride phosphorus oxychloride 52.12g are added portionwise into the system after step S1 cooling in S2, in 5 DEG C after adding
Under the conditions of the reaction was continued to arabinosy ladenosine surplus be no more than additional amount 3% when stop；
1.5g palladium catalyst is added into the reaction system after step S2 stopping and is warming up to 50 DEG C by S3 is stirred to react 8h, mistake
Filter, and ethanol washing filter cake is used, collection filtrate removes solvent under reduced pressure, obtains Vidarabine Monophosphate crude product；The palladium is urged
The preparation method is the same as that of Example 1 for agent；
The Vidarabine Monophosphate crude product that S4 obtains step S3 under the conditions of 40 DEG C just it is soluble in water after, thereto by
It is insoluble to just having that ether, methanol, the mixed solution (ether: methanol: triethylamine volume ratio is 1:3:0.05) of triethylamine is gradually added
Object occur, be cooled to 0 DEG C or so crystallization, filter, 40 DEG C vacuum drying, obtain white crystalline powder 39.77g (yield 97%,
99.9%) purity is.
Embodiment 3
A kind of production technology of Vidarabine Monophosphate comprising following steps:
Arabinosy ladenosine 30g is mixed in 3mL dioxane by S1, and stirring is cooled to 8 DEG C；
Bis- (2- chloroethyl) phosphoryl chloride phosphorus oxychloride 32.54g are added portionwise into the system after step S1 cooling in S2, in 15 DEG C after adding
Under the conditions of the reaction was continued to arabinosy ladenosine surplus be no more than additional amount 1% when stop；
1.5g palladium catalyst is added into the reaction system after step S2 stopping and is warming up to 50 DEG C by S3 is stirred to react 8h, mistake
Filter, and ethanol washing filter cake is used, collection filtrate removes solvent under reduced pressure, obtains Vidarabine Monophosphate crude product；
The preparation method is the same as that of Example 1 for the palladium catalyst；
The Vidarabine Monophosphate crude product that S4 obtains step S3 under the conditions of 40 DEG C just it is soluble in water after, thereto by
It is insoluble to just having that ether, methanol, the mixed solution (ether: methanol: ethyl acetate volume ratio 1:2:5) of ethyl acetate is gradually added
Object occur, be cooled to 0 DEG C or so crystallization, filter, 40 DEG C vacuum drying, obtain white crystalline powder 38.13g (yield 97%,
99.85%) purity is.
Embodiment 4
A kind of production technology of Vidarabine Monophosphate, the difference with embodiment 1 are only that palladium described in step S3 is urged
The preparation method of agent includes the following steps:
Palladium chloride 17.7g and magnesium chloride hexahydrate 304.95g are added into 30mL saturation ammonia spirit, stirred to completely molten
Solution；Aluminum fluoride is added, slowly adds the ammonia spirit of a small amount of mass concentration 15% under stirring conditions, adjusts pH value to 8,
After reacting 30min, filtering, by Washing of Filter Cake to neutrality, drying dries 10h under the conditions of 120 DEG C, obtains catalyst co-precipitate,
Then under the conditions of electric heating is to 260 DEG C in nitrogen environment by above-mentioned catalyst co-precipitate, 18h is roasted, cooling crushes to obtain palladium
Catalyst granules.
In the present embodiment, it is made white crystalline powder 37.72g (yield 92%, purity 81%).
Embodiment 5
A kind of production technology of Vidarabine Monophosphate comprising following steps:
Arabinosy ladenosine 30g is mixed in 5mL cyclohexanone by S1, and stirring is cooled to 3 DEG C；
Dibenzyl phosphoryl chlorine 32.64g is added portionwise into the system after step S1 cooling in S2, in 15 DEG C of conditions after adding
Descend the reaction was continued to stop when being no more than the 3% of additional amount to arabinosy ladenosine surplus；
2g palladium catalyst is added into the reaction system after step S2 stopping and is warming up to 70 DEG C by S3 is stirred to react 6h, mistake
Filter, and ethanol washing filter cake is used, collection filtrate removes solvent under reduced pressure, obtains Vidarabine Monophosphate crude product；
The preparation method is the same as that of Example 1 for the palladium catalyst；
The Vidarabine Monophosphate crude product that S4 obtains step S3 under the conditions of 40 DEG C just it is soluble in water after, thereto by
The mixed solution (ether: methanol: ethyl acetate volume ratio 1:1:1) of ether, methanol, n-hexane is gradually added to just having an insoluble matter
Occur, be cooled to 0 DEG C or so crystallization, filter, 40 DEG C vacuum drying, obtain white crystalline powder 38.54g (yield 94%, it is pure
99%) degree is.
The above is only embodiments of the present invention, and the description thereof is more specific and detailed, and but it cannot be understood as right
The limitation of the invention patent range.It should be pointed out that for those of ordinary skill in the art, not departing from the present invention
Under the premise of design, various modifications and improvements can be made, these are all belonged to the scope of protection of the present invention.
Claims (5)
1. a kind of production technology of Vidarabine Monophosphate comprising following steps:
Arabinosy ladenosine is dissolved in organic solvent by S1, cooling；
Phosphoryl chloride phosphorus oxychloride is added into the system after step S1 cooling by S2, and insulation reaction to arabinosy ladenosine surplus is no more than additional amount
Stop when 3%；
S3 is filtered after palladium catalyst catalysis reduction being added in the reaction system after step S2 stopping, and gained filtrate is removed solvent
Up to Vidarabine Monophosphate crude product；
Sterling Vidarabine Monophosphate is obtained after the Vidarabine Monophosphate crude product recrystallization purifying that S4 obtains step S3；Step S1
Middle cooling, which refers to, is cooled to -5 DEG C to 15 DEG C；The organic solvent is tetrahydrofuran, dioxane, acetone, butanone or cyclohexanone；
The preparation method of palladium catalyst described in step S3 includes the following steps:
Dissolve in ammonia water by palladium chloride and magnesium chloride hexahydrate, it adds aluminum fluoride to be reacted, filter after the reaction was completed, by institute
Washing of Filter Cake, drying are obtained, catalyst co-precipitate is obtained；
The heating roasting of catalyst co-precipitate, crushes after cooling, obtains target palladium catalyst；
The molar ratio of the palladium chloride and magnesium chloride hexahydrate is 1:1-10.
2. production technology according to claim 1, the phosphoryl chloride phosphorus oxychloride is to be free of or optionally containing one to three substitution
C2-C10 alkyl phosphoryl chloride phosphorus oxychloride, the C6-C10 diphenylphosphoryl chlorine of base, the substituent group are halogen atom or nitro.
3. production technology according to claim 1, the molar ratio of arabinosy ladenosine and phosphoryl chloride phosphorus oxychloride is 1:1-2.5 in step S1.
4. production technology according to claim 1, the dosage of palladium catalyst is the 3-10 matter of arabinosy ladenosine in step S3
Measure %.
5. the recrystallization operation of production technology according to claim 1, step S4 includes the following steps:
After the Vidarabine Monophosphate crude product that step S3 is obtained is dissolved with water, organic mixed solvent and cooling analysis are added thereto
Crystalline substance filters, dry, obtains target product；Wherein, organic mixed solvent be ethyl acetate or triethylamine one kind and ether,
The combination of methanol.
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| CN102079766A (en) * | 2009-11-29 | 2011-06-01 | 海南中化联合制药工业股份有限公司 | Preparation method of vidarabine monophosphate |
| CN103204890B (en) * | 2013-02-22 | 2016-03-09 | 广东先强药业有限公司 | A kind of phosphorylation prepares the method for vidarabine phosphate |
| CN104860994A (en) * | 2014-02-20 | 2015-08-26 | 中国药科大学 | Preparation and medical uses of 3-quinuclidinone phosphorus-containing compounds |
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