CN105566424B - A kind of preparation method of Calcium Dibutyryladenosine Cyclophosph-ate - Google Patents
A kind of preparation method of Calcium Dibutyryladenosine Cyclophosph-ate Download PDFInfo
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- CN105566424B CN105566424B CN201410552985.9A CN201410552985A CN105566424B CN 105566424 B CN105566424 B CN 105566424B CN 201410552985 A CN201410552985 A CN 201410552985A CN 105566424 B CN105566424 B CN 105566424B
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- RCFZVVHQICKFQW-NGVPHMJWSA-L calcium;[(4ar,6r,7r,7ar)-6-[6-(butanoylamino)purin-9-yl]-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4h-furo[3,2-d][1,3,2]dioxaphosphinin-7-yl] butanoate Chemical compound [Ca+2].C([C@H]1O2)OP([O-])(=O)O[C@H]1[C@@H](OC(=O)CCC)[C@@H]2N1C(N=CN=C2NC(=O)CCC)=C2N=C1.C([C@H]1O2)OP([O-])(=O)O[C@H]1[C@@H](OC(=O)CCC)[C@@H]2N1C(N=CN=C2NC(=O)CCC)=C2N=C1 RCFZVVHQICKFQW-NGVPHMJWSA-L 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- YBPWNFMPWVRSOD-QDEZUTFSSA-N 5-[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]-5-hydroxynonane-4,6-dione Chemical compound C(CCC)(=O)C([C@@H]1[C@H]([C@H]([C@@H](O1)N1C=NC=2C(N)=NC=NC1=2)O)O)(O)C(CCC)=O YBPWNFMPWVRSOD-QDEZUTFSSA-N 0.000 claims abstract description 29
- -1 adenosine cyclophosphate triethylamine salt Chemical class 0.000 claims abstract description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 17
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 14
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- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 claims abstract description 11
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000007787 solid Substances 0.000 claims description 19
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- OBUXYLWNUXTQDT-FRJWGUMJSA-N 1-[(2s,3r,4s,5r)-2-(6-aminopurin-9-yl)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]butan-1-one Chemical compound C1=NC2=C(N)N=CN=C2N1[C@]1(C(=O)CCC)O[C@H](CO)[C@@H](O)[C@H]1O OBUXYLWNUXTQDT-FRJWGUMJSA-N 0.000 claims 1
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- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 2
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 2
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
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Abstract
The present invention relates to technical field of medicine synthesis, more particularly to a kind of preparation method of Calcium Dibutyryladenosine Cyclophosph-ate.The preparation method is with adenosine cyclophosphate as raw material; adenosine cyclophosphate triethylamine salt is prepared under aprotic solvent with triethylamine; then with butyryl oxide. as acylating agent; synthesize dibutyryl adenosine cyclophosphate in organic non-protonic solvent; compared with traditional handicraft, the production cycle was foreshortened to 34 days the method by original 9～10 days, and crude yield is improved to 78～82%; yield is improved to 90～94% after purification, and overall yield of reaction is improved to 70～75%.Method of the present invention using continuous washing, then through reversed phase extraction, dibutyryl adenosine cyclophosphate its liquid chromatograph purity of acquisition reach 98～98.5%.
Description
Technical field
The present invention relates to technical field of medicine synthesis, more particularly to a kind of preparation method of Calcium Dibutyryladenosine Cyclophosph-ate.
Background technology
Derivant of the Calcium Dibutyryladenosine Cyclophosph-ate for adenosine cyclophosphate (cAMP).As cAMP is difficult to pass through cell membrane, and
Into intracellular cAMP soon by intracellular di-phosphate ester enzyme hydrolysiss, therefore make the derivant of cyclic adenosine monophosphate.Ring phosphorus
Adenosine monophosphate Ramulus Uncariae Cum Uncis acyl ester is stronger than cAMP to the permeability of cell, and can resist the destruction of phosphodiesterase in body, therefore its
Action time and speed are lasting and rapid than cAMP, are with the distribution of more preferably vivo medicine concentration and dynamic metabolism characteristic
New generation product.Calcium Dibutyryladenosine Cyclophosph-ate can participate in cellular energy metabolism and protein synthesis in vivo, be on the point of so as to protect
Dead cell, accelerates repair process, is protected the integrity of renal tubules, and then improve hemodynamics and circulation in kidney,
Increase renal blood flow, reach the effect of protection renal function.Calcium Dibutyryladenosine Cyclophosph-ate has extensive cell activation function, can
Sugar, fat, the regulation of three big metabolism of protein in participant's body, to expansion of blood vessels, diastole smooth muscle, improve myocardial ischemia and lack
Oxygen, the damage of the especially injury repairing to myocardial cell and mitigation ischemic region Reperfu- sion have highly important effect.Two butyryl
The cardiovascular preparation that adenosine cyclophosphate calcium is taken into account with nutrition as a kind for the treatment of, applies in old stable angina pectoris crowd, treats
Effect affirmative, can improve the quality of living.Pharmaceutical research shows there are cAMP regulation and control in g protein coupled receptor signal path in the recent period
Effect, therefore Calcium Dibutyryladenosine Cyclophosph-ate also likely to be applicable to the disease treatment related to apoptosis and inherited immunity etc..
Adenosine diphosphate (ADP) calcium is clinically mainly used in treating cardiovascular disease such as heart strand as protease activator at present
Bitterly, the auxiliary treatment of acute myocardial infarction, also can be used for myocarditiss, cardiogenic shock, Post operation nethike embrane bleed bottom and psoriasises,
And other anticancer drug therapy leukemia can be aided in.
It is many at present that Calcium Dibutyryladenosine Cyclophosph-ate is prepared using chemical synthesis process, but suffer from the drawback that：(1) it is acylated anti-
Very long, yield relatively low (60% or so) between seasonable, production efficiency relatively low (8～10 days)；(2) extraction process is coarse, causes product
Purity relatively low (liquid phase purity 85%), affects product curative effect.
Therefore it provides a kind of high income, purity are good, with short production cycle, beneficial to the dibutyryl adenosine cyclophosphate of industrialized production
The preparation method of calcium has realistic meaning.
The content of the invention
In view of this, the present invention provides a kind of preparation method of Calcium Dibutyryladenosine Cyclophosph-ate.The method and traditional handicraft phase
Relatively, the production cycle foreshortened to 3-4 days by original 9～10 days, crude yield is improved to 78～82%, and yield is improved after purification
To 90～94%, overall yield of reaction is improved to 70～75%.Method of the present invention using continuous washing, then through reversed phase extraction,
The dibutyryl adenosine cyclophosphate of acquisition its liquid chromatograph purity reaches 98～98.5%.
In order to realize foregoing invention purpose, the present invention provides technical scheme below：
The invention provides a kind of preparation method of Calcium Dibutyryladenosine Cyclophosph-ate, comprises the following steps：
Step 1：Obtain adenosine cyclophosphate triethylamine salt；
Step 2：The adenosine cyclophosphate triethylamine salt is mixed with n butanoic anhydride in aprotic solvent, in organic base catalytic
Lower generation acylation reaction, hydrolysis collect dibutyryl adenosine cyclophosphate；
The acylation reaction is that lucifuge reacts 20～36h at 30 DEG C～80 DEG C；
Step 3：The dibutyryl adenosine cyclophosphate is taken into salt, is obtained final product.
In some embodiments of the invention, preferably there is acylation reaction in step 2 under conditions of nitrogen protection.
In some embodiments of the invention, in terms of g/mL/mL, adenosine cyclophosphate three described in acylation reaction described in step 2
Ethylamine salt, the n butanoic anhydride, the mass volume ratio of the aprotic solvent are 1：4～10：50～60.
In some embodiments of the invention, aprotic solvent described in step 2 be tetrahydrofuran, Isosorbide-5-Nitrae-dioxane,
Mixture more than one or both of DMF, acetonitrile or pyridine.It is all suitable for the non-of acylation reaction
Proton solvent is all within the scope of the present invention, is not limited thereto.
In technical solutions according to the invention, described organic base is DMAP, triethylamine or diisopropyl
Ethylamine.
Preferably, step 1 is specially：After triethylamine salt is mixed with water, then mix with adenosine cyclophosphate, ring phosphorus gland is obtained
Glycosides triethylamine salt.
Preferably, the step of also including the first purification after mixing with adenosine cyclophosphate described in step 1 again.
In some embodiments of the invention, first purification is specially the vacuum drying at 50 DEG C and obtains solid, will
Aprotic solvent dissolves the solid, concentrates, is dried.Every operation that can reach purification effect is in the protection model of the present invention
In enclosing, the present invention is not limited thereto.
In some embodiments of the invention, it is specially into salt described in step 3 and calcium salt is mixed with alcohol-water mixed solution
Afterwards, mix generation salt-forming reaction with the alcohol of the dibutyryl adenosine cyclophosphate.
Preferably, the step of also including the second purification into after salt described in step 3.
In some embodiments of the invention, second purification is specially the solution filtration for taking the salt-forming reaction, receives
After collection filtering residue is mixed with alcohol, mix with ether, filter in 0 DEG C, collecting filtering residue, being dried.Every operation that can reach purification effect
Within the scope of the present invention, the present invention is not limited thereto.
In some embodiments of the invention, collect dibutyryl adenosine cyclophosphate to be specially in 25 DEG C～45 described in step 2
After DEG C concentrating under reduced pressure removes solvent, plus the water of 30-50 times of volume, with ether washings phase 2 times, 40 DEG C～60 DEG C vacuum distillations, then
Remaining water phase is extracted with dichloromethane, merges organic faciess, vacuum distillation removes dichloromethane, obtains dibutyryl adenosine cyclophosphate.
In technical solutions according to the invention, described alcohol is ethanol, propanol, butanol or isobutanol.
In technical solutions according to the invention, described ether is ether, diisopropyl ether or methyl tertiary butyl ether(MTBE).
Specifically, the preparation method of the Calcium Dibutyryladenosine Cyclophosph-ate that the present invention is provided can be：
The first step, the preparation of adenosine cyclophosphate triethylamine salt：
Triethylamine salt is stirred with purified water, adenosine cyclophosphate is put into, stirring is completely dissolved, mixed liquor is true at 50 DEG C
It is empty to be dried, obtain solid.Above-mentioned solid is dissolved with aprotic solvent, then this concentration is spin-dried for, and obtains adenosine cyclophosphate triethylamine salt.
Second step, the preparation of dibutyryl adenosine cyclophosphate：
A certain amount of adenosine cyclophosphate and n butanoic anhydride are taken, with aprotic solvent as solvent, lucifuge reaction one under uniform temperature
The section time, add water 1～3h of hydrolysis, and 25 DEG C～45 DEG C concentrating under reduced pressure remove solvent, and add water certain volume, organic solvent washing water
Phase, the 50 DEG C of vacuum distillations of water phase, then remaining water phase is extracted with dichloromethane, merge organic faciess, dichloromethane is removed under reduced pressure, obtains
Micro- viscous faint yellow dibutyryl adenosine cyclophosphate solid；
3rd step, the preparation of Calcium Dibutyryladenosine Cyclophosph-ate：
Take a certain amount of dibutyryl adenosine cyclophosphate to be dissolved in the alcohols solvent of certain volume；Take a certain amount of calcium chloride to be dissolved in
In the mixed liquor of alcohols solvent and water；Two solution are mixed, 15～35 DEG C of reaction 10min of room temperature are filtered, and alcohols are removed under reduced pressure molten
Agent and water, then dissolved with identical alcohols solvent, low temperature adds ether solvent, filters, obtains final product High-purity dibutyryladenosine cyclophosphate calcium
White powder or off-white powder；
The present invention has following features：
1. with short production cycle, high income.
2., using multistep washing and reversed phase extraction technique, the purity of dibutyryl adenosine cyclophosphate and its calcium salt is substantially increased.
A kind of preparation method of Calcium Dibutyryladenosine Cyclophosph-ate that the present invention is provided, comprises the following steps：Obtain adenosine cyclophosphate
Triethylamine salt；The adenosine cyclophosphate triethylamine salt is mixed with n butanoic anhydride in aprotic solvent, issued in organic base catalytic
Raw acylation reaction, hydrolysis collect dibutyryl adenosine cyclophosphate；The acylation reaction is that lucifuge reacts 20～36h at 30 DEG C～80 DEG C；
The dibutyryl adenosine cyclophosphate is taken into salt, is obtained final product.The present invention is made with adenosine cyclophosphate as raw material under aprotic solvent with triethylamine
Standby adenosine cyclophosphate triethylamine salt, then with butyryl oxide. as acylating agent, synthesizes two butyryl ring phosphorus glands in organic non-protonic solvent
Glycosides, compared with traditional handicraft, the production cycle was foreshortened to 3-4 days the method by original 9～10 days, and crude yield is improved to 78
～82%, after purification yield improve to 90～94%, overall yield of reaction is improved to 70～75%.The present invention is using continuous washing
Method, then through reversed phase extraction, dibutyryl adenosine cyclophosphate its liquid chromatograph purity of acquisition reach 98～98.5%.With high-purity
Dibutyryl adenosine cyclophosphate be raw material, Jing and inorganic salt calcium chloride react, and a step obtains highly purified dibutyryl adenosine cyclophosphate
Calcium, indices meet standards of pharmacopoeia, while simplifying preparation technology, are suitable to industrialized production.
Description of the drawings
Fig. 1 shows the preparation technology of the Calcium Dibutyryladenosine Cyclophosph-ate of present invention offer；
Fig. 2 shows Calcium Dibutyryladenosine Cyclophosph-ate mass spectrum prepared by embodiment 1；
Fig. 3 shows the HPLC spectrograms of Calcium Dibutyryladenosine Cyclophosph-ate standard substance；
Fig. 4 shows the HPLC spectrograms of Calcium Dibutyryladenosine Cyclophosph-ate prepared by embodiment 1.
Specific embodiment
The invention discloses a kind of preparation method of Calcium Dibutyryladenosine Cyclophosph-ate, those skilled in the art can use for reference herein
Content, is suitably modified technological parameter realization.Specifically, all similar replacements and change are to people in the art
It is it will be apparent that they are considered as being included in the present invention for member.The method of the present invention and application have passed through preferably real
Apply example to be described, related personnel substantially can be in without departing from present invention, spirit and scope to method described herein
It is modified with application or suitably changes and combine, realizes and apply the technology of the present invention.
In the preparation method of the Calcium Dibutyryladenosine Cyclophosph-ate that the present invention is provided, raw materials used and reagent can be buied by market.
With reference to embodiment, the present invention is expanded on further：
The synthesis of 1 Calcium Dibutyryladenosine Cyclophosph-ate of embodiment
Take 10g adenosine cyclophosphate to be dissolved in the aqueous solution of 80g purified water and 4g triethylamines, stir, concentrated at 50 DEG C
Entirely, residual solid adds 86g pyridine solvents, and after being completely dissolved, concentrating under reduced pressure obtains adenosine cyclophosphate triethylamine salt, 13g into solid.
Take 13g adenosine cyclophosphate triethylamine salts to be placed in 1000ml there-necked flasks, add 600ml tetrahydrofuran stirring and dissolving,
50ml n butanoic anhydrides are added, lucifuge is reacted 36 hours at 30 DEG C, is down to room temperature, add water hydrolysis 1 hour, and 25 DEG C of concentrating under reduced pressure are removed
Tetrahydrofuran is removed, 500ml is added water to, with methyl tertiary butyl ether(MTBE) washings mutually twice, each 100ml, the 60 DEG C of vacuum distillations of water phase,
Remaining water phase 3 times is extracted with dichloromethane again, each 100ml merges organic faciess, dichloromethane is removed under reduced pressure, obtains micro- viscous
Faint yellow dibutyryl adenosine cyclophosphate solid 8g, yield 80%, purity 98.4%.
Take above-mentioned 8g dibutyryl adenosine cyclophosphates to be dissolved in 80ml ethanol；Take 2.4g anhydrous calcium chlorides be dissolved in 10ml butanol with
In the mixed liquor of 2ml water；Two solution are mixed, room temperature reaction 10 minutes, filter, second alcohol and water, plus 80ml ethanol is removed under reduced pressure
Dissolving, 0 DEG C of addition 200ml methyl tertiary butyl ether(MTBE), that is, have white solid to separate out, filter, obtain final product 7.5g white powders, yield
94%, purity 98.2%.
Three step total recoverys 75%.
The mass spectrum of white powder manufactured in the present embodiment as shown in Fig. 2 identified, is Calcium Dibutyryladenosine Cyclophosph-ate.1H-
NMR data is：
1HNMR(400MHZ,D2O) 0.75～0.78 (t, 3H), 1.45～1.50 (m, 2H), 2.32～2.34 (m, 2H),
4.10～4.16 (m, 2H), 4.30～4.38 (dd, 1H), 5.81～5.83 (d, 1H), 5.47～5.48 (d, 1H), 6.08 (s,
1H),8.00(s,1H),8.50(s,1H)。
Mass spectrum diagram data：
m/z:399.1。
The HPLC of white powder manufactured in the present embodiment is as shown in figure 4, the HPLC of standard substance is as shown in Figure 3.
Wherein, the HPLC data of Calcium Dibutyryladenosine Cyclophosph-ate standard substance are：
The HPLC data of white powder manufactured in the present embodiment (Jing Mass Spectrometric Identifications are Calcium Dibutyryladenosine Cyclophosph-ate) are：
The synthesis of 2 Calcium Dibutyryladenosine Cyclophosph-ate of embodiment
Take 10g adenosine cyclophosphate to be dissolved in the aqueous solution of 80g purified water and 4g triethylamines, stir, concentrated at 50 DEG C
Entirely, residual solid adds 86g pyridine solvents, and after being completely dissolved, concentrating under reduced pressure obtains adenosine cyclophosphate triethylamine salt into solid,
12.5g。
The adenosine cyclophosphate triethylamine salt for taking 12.5g is placed in 1000ml there-necked flasks, adds the stirring of 600ml tetrahydrofurans molten
Solution, adds 50ml n butanoic anhydrides, 5ml triethylamines, and at 65 DEG C, lucifuge is reacted 20 hours, is down to room temperature, and add water hydrolysis 3 hours,
35 DEG C of concentrating under reduced pressure remove tetrahydrofuran, add water to 350ml, with methyl tertiary butyl ether(MTBE) washings mutually twice, the 60 DEG C of decompressions of water phase
Distillation, then remaining water phase 3 times is extracted with dichloromethane, each 100ml merges organic faciess, dichloromethane is removed under reduced pressure, obtains micro-
Viscous faint yellow dibutyryl adenosine cyclophosphate solid 8.2g, yield 82%, purity 98.1%.
Take above-mentioned 8.2g dibutyryl adenosine cyclophosphates to be dissolved in 80ml ethanol；Take 2.5g anhydrous calcium chlorides be dissolved in 10ml ethanol with
In the mixed liquor of 2ml water；Two solution are mixed, room temperature reaction 10 minutes, filter, second alcohol and water, plus 80ml ethanol is removed under reduced pressure
Dissolving, 0 DEG C of addition 200ml methyl tertiary butyl ether(MTBE), that is, have white solid to separate out, filter, obtain final product 7.4g Calcium Dibutyryladenosine Cyclophosph-ates
White powder, yield 90%, purity 98.5%.
Three total recoverys 74%.
The synthesis of 3 Calcium Dibutyryladenosine Cyclophosph-ate of embodiment
Take 10g adenosine cyclophosphate to be dissolved in the aqueous solution of 80g purified water and 4g triethylamines, stir, concentrated at 50 DEG C
Entirely, residual solid adds 86g pyridine solvents, and after being completely dissolved, concentrating under reduced pressure obtains adenosine cyclophosphate triethylamine salt into solid,
13.2g。
The adenosine cyclophosphate triethylamine salt for taking 10g is placed in 1000ml there-necked flasks, and nitrogen protection is lower to add 600ml pyridines to stir
Dissolving is mixed, 50ml n butanoic anhydrides are added, 5ml triethylamines, at 80 DEG C, lucifuge is reacted 25 hours, is down to room temperature, and the hydrolysis 1 that adds water is little
When, 45 DEG C of concentrating under reduced pressure remove pyridine, add water to 400ml, with methyl tertiary butyl ether(MTBE) washings mutually twice, each 100ml, water phase
60 DEG C of vacuum distillations, then remaining water phase 3 times is extracted with dichloromethane, each 100ml merges organic faciess, dichloromethane is removed under reduced pressure
Alkane, obtains micro- viscous faint yellow dibutyryl adenosine cyclophosphate solid 7.8, yield 78%, purity 97.7%.
Take above-mentioned 7.8g dibutyryl adenosine cyclophosphates to be dissolved in 80ml ethanol；Take 2.4g anhydrous calcium chlorides be dissolved in 10ml ethanol with
In the mixed liquor of 2ml water；Two solution are mixed, room temperature reaction 10 minutes, filter, second alcohol and water, plus 80ml ethanol is removed under reduced pressure
Dissolving, 0 DEG C of addition 200ml methyl tertiary butyl ether(MTBE), that is, have white solid to separate out, filter, obtain final product 7g Calcium Dibutyryladenosine Cyclophosph-ates white
Color powder, yield 90%, purity 98%.
Three step total recoverys 70%.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (8)
1. a kind of preparation method of Calcium Dibutyryladenosine Cyclophosph-ate, it is characterised in that comprise the following steps：
Step 1：Obtain adenosine cyclophosphate triethylamine salt；
Step 2：The adenosine cyclophosphate triethylamine salt is mixed with n butanoic anhydride in aprotic solvent, issued in organic base catalytic
Raw acylation reaction, hydrolysis collect dibutyryl adenosine cyclophosphate；
The acylation reaction is that lucifuge reacts 20～36h at 30 DEG C～80 DEG C；
Step 3：The dibutyryl adenosine cyclophosphate is taken into salt, is obtained final product；
Wherein, in terms of g/mL/mL, adenosine cyclophosphate triethylamine salt described in acylation reaction, the n butanoic anhydride, institute described in step 2
The mass volume ratio for stating aprotic solvent is 1：4～10：50～60, the aprotic solvent is tetrahydrofuran.
2. preparation method according to claim 1, it is characterised in that step 1 is specially：Triethylamine salt is mixed with water
Afterwards, then with adenosine cyclophosphate mix, adenosine cyclophosphate triethylamine salt is obtained.
3. preparation method according to claim 2, it is characterised in that after mixing with adenosine cyclophosphate described in step 1 again
The step of also including the first purification.
4. preparation method according to claim 3, it is characterised in that first purification is specially the vacuum at 50 DEG C and does
Aprotic solvent is dissolved the solid by dry acquisition solid, is concentrated, is dried.
5. preparation method according to claim 1, it is characterised in that described in step 3 into salt be specially by calcium salt and alcohol-
After water mixed solution mixing, mix generation salt-forming reaction with the alcohol of the dibutyryl adenosine cyclophosphate.
6. preparation method according to claim 1, it is characterised in that also include the second purification described in step 3 into after salt
The step of.
7. preparation method according to claim 6, it is characterised in that second purification is specially and takes the salt-forming reaction
Solution filter, collect after filtering residue mix with alcohol, mix with ether, filter in 0 DEG C, collection filtering residue, drying.
8. preparation method according to claim 1, it is characterised in that dibutyryl adenosine cyclophosphate tool is collected described in step 2
Body is plus the water of 30-50 times of volume after 25 DEG C～45 DEG C concentrating under reduced pressure remove solvent, with ether solvents washings phase 2 times, 40 DEG C
～60 DEG C of vacuum distillations, then remaining water phase is extracted with dichloromethane, merging organic faciess, vacuum distillation removes dichloromethane, obtains two
Butyryl adenosine cyclophosphate.
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