JPH0340040B2 - - Google Patents
Info
- Publication number
- JPH0340040B2 JPH0340040B2 JP57078023A JP7802382A JPH0340040B2 JP H0340040 B2 JPH0340040 B2 JP H0340040B2 JP 57078023 A JP57078023 A JP 57078023A JP 7802382 A JP7802382 A JP 7802382A JP H0340040 B2 JPH0340040 B2 JP H0340040B2
- Authority
- JP
- Japan
- Prior art keywords
- sodium salt
- salt
- sodium
- reaction
- dbc
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000004519 manufacturing process Methods 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 150000003512 tertiary amines Chemical class 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 229910000318 alkali metal phosphate Inorganic materials 0.000 claims description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 8
- 159000000000 sodium salts Chemical class 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 2
- -1 alkali metal salt Chemical class 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
- 238000010514 butyrylation reaction Methods 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- FYWLYWMEGHCZAX-MCDZGGTQSA-M sodium [(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl hydrogen phosphate Chemical compound [Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)([O-])=O)[C@@H](O)[C@H]1O FYWLYWMEGHCZAX-MCDZGGTQSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BXJBFCKTIWRKMQ-MCDZGGTQSA-M sodium;(4ar,6r,7r,7as)-6-(6-aminopurin-9-yl)-2-oxido-2-oxo-4a,6,7,7a-tetrahydro-4h-furo[3,2-d][1,3,2]dioxaphosphinin-7-ol Chemical compound [Na+].C([C@H]1O2)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 BXJBFCKTIWRKMQ-MCDZGGTQSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Description
【発明の詳細な説明】
本発明はN6，2′−０−ジアシルアデノシン−
3′，5′−環状燐酸アルカリ金属塩の改良製法に関
するものであり、特に医薬および試薬として有用
なN6，2′−０−ジブチリルアデノシン−3′，5′−
環状燐酸ナトリウム塩の工業的有利な製法を提供
することを目的とするものである。DETAILED DESCRIPTION OF THE INVENTION The present invention provides N 6 ,2'-0-diacyladenosine-
This article relates to an improved method for producing 3',5'-cyclic alkali metal phosphates, particularly N6,2' -0-dibutyryladenosine-3',5'- useful as medicines and reagents.
The object of the present invention is to provide an industrially advantageous method for producing a cyclic sodium phosphate salt.
以下に、ジブチリル体のナトリウム塩を例とし
て説明するが、次の略号を使用する。 The sodium salt of dibutyryl compound will be explained below as an example, and the following abbreviations will be used.
ｃ−AMP：アデノシン−3′，5′−環状燐酸
DBc−AMP：N6，2′−０−ジブチリルアデノシ
ン−3′，5′−環状燐酸
OMc−AMP：2′−０−モノブチリルアデノシン
−3′，5′−環状燐酸
NMc−AMP：N6−モノブチリルアデノシン−
3′，5′−環状燐酸
従来、DBc−AMP・ナトリウム塩については
次の如き製造方法が知られている。すなわち、
ａ） ｃ−AMPを三級アミンと脱酸剤の存在下
無水酪酸と加熱せしめる。（特開昭52−39699）
ｂ） ｃ−AMP・トリエチルアミン塩を脱酸剤
の存在下無水酪酸と反応せしめる（Biochim.
Biophys.Acta，14899〜105（1967））。c-AMP: Adenosine-3′,5′-cyclic phosphate DBc-AMP: N 6 ,2′-0-dibutyryladenosine-3′,5′-cyclic phosphate OMc-AMP: 2′-0-monobutyryl Adenosine-3',5'-cyclic phosphate NMc-AMP: N6 -monobutyryl adenosine-
3',5'-Cyclic phosphoric acid Conventionally, the following production method has been known for DBc-AMP sodium salt. Namely, a) c-AMP is heated with butyric anhydride in the presence of a tertiary amine and a deoxidizing agent. (JP 52-39699) b) React c-AMP triethylamine salt with butyric anhydride in the presence of a deoxidizing agent (Biochim.
Biophys. Acta, 148 99-105 (1967)).
ｃ） ｃ−AMP・ナトリウム塩を70℃以上の温
度で無水酪酸と加熱反応せしめる（特開昭57−
18698）。c) Heat reaction of c-AMP/sodium salt with butyric anhydride at a temperature of 70°C or higher (Japanese Patent Application Laid-Open No. 1983-1999)
18698).
これ等公知方法のうち、ｃ−AMP・トリエチ
ルアミン塩またはｃ−AMP・ナトリウム塩を出
発原料とする方法は、ｃ−AMPから無水のトリ
エチルアミン塩またはナトリウム塩を製造するこ
とが必要である。例えば、ｃ−AMP・トリエチ
ルアミン塩は、ｃ−AMPをトリエチルアミン水
溶液に溶解し、室温で反応させたのち、反応混合
物を減圧下濃縮乾固し、これに無水ピリジンを加
えて再び乾固し、この操作を繰返して無水物とし
なければならないので、操作が煩雑となる。 Among these known methods, the method using c-AMP triethylamine salt or c-AMP sodium salt as a starting material requires producing anhydrous triethylamine salt or sodium salt from c-AMP. For example, c-AMP/triethylamine salt can be prepared by dissolving c-AMP in an aqueous triethylamine solution, reacting at room temperature, concentrating the reaction mixture to dryness under reduced pressure, adding anhydrous pyridine to it, and drying it again. The operation becomes complicated because the operation must be repeated to obtain an anhydride.
またｃ−AMPまたはｃ−AMP・トリエチルア
ミン塩を出発原料とする方法は、反応生成物は
DBc−AMP・トリエチルアミン塩の型でありこ
れを有用なナトリウム塩に変換するための塩交換
操作が必須である。例えば、DBc−AMP・トリ
エチルアミン塩をナトリウム型陽イオン交換樹脂
で処理してナトリウム塩に変換させるが、イオン
交換樹脂処理液は希薄溶液のため、濃縮操作が必
要であり、不安定なDBc−AMP・ナトリウム塩
は濃縮中に分解してOMc−AMP・ナトリウム塩
またはNMc−AMP・ナトリウム塩が生成し、目
的物の純度が低下する。 In addition, in the method using c-AMP or c-AMP/triethylamine salt as a starting material, the reaction product is
DBc-AMP is a triethylamine salt type, and a salt exchange operation is essential to convert it into a useful sodium salt. For example, DBc-AMP/triethylamine salt is treated with a sodium-type cation exchange resin to convert it into sodium salt, but since the ion exchange resin treatment solution is a dilute solution, a concentration operation is required, and DBc-AMP is unstable. - Sodium salt decomposes during concentration to generate OMc-AMP sodium salt or NMc-AMP sodium salt, reducing the purity of the target product.
このように公知方法は、いずれも製造工程が煩
雑であり、反応の後処理中、DBc−AMP・ナト
リウム塩が分解して純度が低下する等の不利があ
り、工業的な製造法としては必ずしも満足すべき
ものではなかつた。 As described above, all of the known methods have disadvantages such as complicated manufacturing steps and decomposition of DBc-AMP/sodium salt during post-treatment of the reaction, resulting in a decrease in purity. It was not something to be satisfied with.
そこで本発明者等はDBc−AMP・ナトリウム
塩の改良製造法について鋭意研究を重ねた結果、
三級アミンおよび塩交換剤の存在下ｃ−AMPを
無水酪酸と60℃以上の温度で加熱撹拌させると、
驚くべきことにブチリル化反応と同時に塩交換反
応までが進行し、目的とするDBc−AMP・ナト
リウム塩が有利に得られることを見出し、これら
の知見に基づいて本発明を完成した。 Therefore, the present inventors conducted extensive research on an improved manufacturing method for DBc-AMP/sodium salt, and as a result,
When c-AMP is heated and stirred with butyric anhydride at a temperature of 60°C or higher in the presence of a tertiary amine and a salt exchanger,
Surprisingly, it was found that the salt exchange reaction proceeded simultaneously with the butyrylation reaction, and the desired DBc-AMP sodium salt was advantageously obtained, and the present invention was completed based on these findings.
すなわち、本発明は、アデノシン−3′，5′−環
状燐酸を、三級アミンおよび塩交換剤の存在下、
カルボン酸無水物と加熱することによりN6，
2′−０−ジアシルアデノシン−3′，5′−環状燐酸
アルカリ金属塩を製造する方法である。 That is, the present invention provides a method for treating adenosine-3',5'-cyclic phosphoric acid in the presence of a tertiary amine and a salt exchanger.
N 6 by heating with carboxylic anhydride,
This is a method for producing an alkali metal salt of 2'-0-diacyladenosine-3',5'-cyclic phosphoric acid.
本発明を更に詳細に述べるならば、DBc−
AMP・ナトリウム塩の製造においては、ｃ−
AMPを無溶媒または溶媒中１〜３倍モルの三級
アミンと等モルの塩交換剤の存在下３〜６倍モル
の無水酪酸と加熱反応せしめることによつて達成
される。 To describe the present invention in more detail, DBc-
In the production of AMP sodium salt, c-
This is achieved by heat-reacting AMP with 1 to 3 times the mole of tertiary amine and 3 to 6 times the mole of butyric anhydride in the presence of an equimolar amount of a salt exchanger, either without a solvent or in a solvent.
本反応は無溶媒で進行するが、溶媒として酪酸
エチル、酢酸イソプロピル、酢酸ブチル等の脂肪
族エステル類を使用することも可能である。 Although this reaction proceeds without a solvent, it is also possible to use aliphatic esters such as ethyl butyrate, isopropyl acetate, butyl acetate, etc. as a solvent.
三級アミンとしては、通常トリエチルアミンが
好適であるが、他にトリメチルアミン、トリプロ
ピルアミン、トリブチルアミン等またはピリジ
ン、ピコリン等の環状三級アミンを用いることも
できる。 As the tertiary amine, triethylamine is usually preferred, but trimethylamine, tripropylamine, tributylamine, etc., or cyclic tertiary amines such as pyridine and picoline can also be used.
塩交換剤としては、通常炭酸水素ナトリウムが
好適であるが、他にヨウ化ナトリウム、炭酸ナト
リウム、ナトリウムメチラート、酪酸ナトリウ
ム、酢酸ナトリウム等を用いることもできる。 As the salt exchange agent, sodium hydrogen carbonate is usually preferred, but sodium iodide, sodium carbonate, sodium methylate, sodium butyrate, sodium acetate, etc. can also be used.
反応条件は、溶媒を使用するか否か、三級アミ
ン、無水酪酸のモル数によつて異なるが、60〜
130℃で１〜20時間、好ましくは90〜120℃で２〜
５時間程度であり、OMc−AMPが消失するまで
反応を行なうのが望ましい。 The reaction conditions vary depending on whether or not a solvent is used and the number of moles of tertiary amine and butyric anhydride;
1-20 hours at 130℃, preferably 2-20 hours at 90-120℃
The reaction time is approximately 5 hours, and it is desirable to carry out the reaction until OMc-AMP disappears.
生成したDBc−AMP・ナトリウム塩は、反応
混合物に適当な処理を行なうことにより単離精製
することができる。 The produced DBc-AMP sodium salt can be isolated and purified by appropriately treating the reaction mixture.
すなわち、反応混合物にイソプロピールアルコ
ールおよび／またはイソプロピルエーテルの適当
量を加えると粗結晶が析出する。この粗晶を少量
の水（1g当り３ml以下）に溶かし、テトラヒド
ロフラン、１，２−ジメトキシエタン、１，３−
ジオキソラン、アセトニトリルまたはプロピオニ
トリルの適当量を加えて再結晶化させるのが適当
である。なかでも、テトラヒドロフラン、１，２
−ジメトキシエタンまたは１，３−ジオキソラン
が優れており、特にこれらとメチルエチルケトン
の混合溶媒が工業的に優れており、最も好ましい
のはテトラヒドロフランとメチルエチルケトンの
組合せであり、充分に精製されたDBc−AMP・
ナトリウム塩を取得することができる。 That is, when an appropriate amount of isopropyl alcohol and/or isopropyl ether is added to the reaction mixture, crude crystals are precipitated. Dissolve this crude crystal in a small amount of water (3 ml or less per 1 g), add tetrahydrofuran, 1,2-dimethoxyethane, 1,3-
Suitably, recrystallization is carried out by adding an appropriate amount of dioxolane, acetonitrile or propionitrile. Among them, tetrahydrofuran, 1,2
-dimethoxyethane or 1,3-dioxolane are excellent, especially a mixed solvent of these and methyl ethyl ketone is industrially excellent, and the most preferred is a combination of tetrahydrofuran and methyl ethyl ketone.
Sodium salt can be obtained.
本発明は、従来操作が煩雑で工業的に実施する
には不満足であつたDBc−AMP・ナトリウム塩
の製造を、三級アミンおよび塩交換剤の存在下、
ｃ−AMPを無水酪酸と混合し、加熱反応せしめ
ることにより、効率的にかつ高収率に製造するこ
とを可能ならしめたものであり、経済的、工業的
に優れた方法を提供するものである。 The present invention enables the production of DBc-AMP sodium salt, which has conventionally been complicated and unsatisfactory to be carried out industrially, in the presence of a tertiary amine and a salt exchanger.
By mixing c-AMP with butyric anhydride and subjecting it to a heating reaction, it has been made possible to produce it efficiently and with high yield, providing an economically and industrially superior method. be.
実施例 １
ｃ−AMP3.29gに無水酪酸7.91g、酪酸ナトリ
ウム1.10gおよびトリエチルアミン2.02gを加え、
油浴中110〜120℃で４時間撹拌する。反応後、反
応液にイソプロピルアルコール５ml、次いでイソ
プロピルエーテル50mlを加えると結晶が析出す
る。この結晶を濾取し、デシケータ中で乾燥後、
水５mlに溶解し、テトラヒドロフラン70mlおよび
メチルエチルケトン150mlより再結晶し、濾取、
乾燥するとDBc−AMP・ナトリウム塩3.72g（収
率75.8％）が得られる。このものは別途合成した
DBc−AMP・ナトリウム塩の標品とIRが完全に
一致し、高速液体クロマトグラフイーによる分析
値は、純度99.3％で不純物はOMc−AMP・ナト
リウム塩0.32％、NMc−AMP・ナトリウム塩
0.11％である。Example 1 7.91 g of butyric anhydride, 1.10 g of sodium butyrate and 2.02 g of triethylamine were added to 3.29 g of c-AMP,
Stir for 4 hours at 110-120°C in an oil bath. After the reaction, 5 ml of isopropyl alcohol and then 50 ml of isopropyl ether are added to the reaction solution to precipitate crystals. After filtering the crystals and drying them in a desiccator,
Dissolved in 5 ml of water, recrystallized from 70 ml of tetrahydrofuran and 150 ml of methyl ethyl ketone, collected by filtration,
After drying, 3.72 g (yield 75.8%) of DBc-AMP sodium salt is obtained. This was synthesized separately
The IR completely matches the standard sample of DBc-AMP, sodium salt, and the analysis value by high performance liquid chromatography shows that the purity is 99.3%, and the impurities are OMc-AMP, sodium salt, 0.32%, and NMc-AMP, sodium salt.
It is 0.11%.
実施例 ２
ｃ−AMP2.00gに無水酪酸3.84g、炭酸水素ナ
トリウム0.52gおよびトリエチルアミン1.20gを加
え、油浴中110〜120℃で2.5時間撹拌する。反応
後、反応液にイソプロピルアルコール２ml、次い
でイソプロピルエーテル40mlを加える。析出した
結晶を濾取しデシケータ中で乾燥後、水３mlに溶
解し、テトラヒドロフラン140mlより再結晶し、
濾取、乾燥するとDBc−AMP・ナトリウム塩
2.05g（収率68.8％）が得られる。本品の高速液体
クロマトグラフイーによる分析値は、純度99.6％
で、不純物はOMc−AMP・ナトリウム塩0.36
％、NMc−AMP・ナトリウム塩0.28％である。Example 2 3.84 g of butyric anhydride, 0.52 g of sodium bicarbonate and 1.20 g of triethylamine are added to 2.00 g of c-AMP, and the mixture is stirred in an oil bath at 110-120°C for 2.5 hours. After the reaction, add 2 ml of isopropyl alcohol and then 40 ml of isopropyl ether to the reaction solution. The precipitated crystals were collected by filtration, dried in a desiccator, dissolved in 3 ml of water, and recrystallized from 140 ml of tetrahydrofuran.
When filtered and dried, DBc-AMP/sodium salt
2.05g (yield 68.8%) is obtained. The purity of this product is 99.6% as analyzed by high performance liquid chromatography.
So, the impurity is OMc-AMP sodium salt 0.36
%, NMc-AMP sodium salt 0.28%.
実施例 ３
ｃ−AMP3.29gに無水酪酸6.33g、炭酸水素ナ
トリウム0.84gおよびトリブチルアミン2.78gを加
え、油浴中95〜105℃で４時間撹拌する。反応後、
イソプロピルアルコール５ml、次いでイソプロピ
ルエーテル60mlを加える。析出晶を濾取、乾燥
後、水５mlおよび１，２−ジメトキシエタン350
mlより再結晶し精製するとDBc−AMP・ナトリ
ウム塩3.96g（収率80.7％）が得られる。本品の高
速液体クロマトグラフイーによる分析値は、純度
99.90％で不純物はOMc−AMP・ナトリウム塩
0.20％、NMc−AMP・ナトリウム塩0.14％であ
る。Example 3 6.33 g of butyric anhydride, 0.84 g of sodium bicarbonate and 2.78 g of tributylamine are added to 3.29 g of c-AMP, and the mixture is stirred in an oil bath at 95-105°C for 4 hours. After the reaction,
Add 5 ml of isopropyl alcohol and then 60 ml of isopropyl ether. After filtering the precipitated crystals and drying, add 5 ml of water and 350 mL of 1,2-dimethoxyethane.
After recrystallization and purification from ml, 3.96 g (yield 80.7%) of DBc-AMP sodium salt is obtained. The analysis value of this product by high performance liquid chromatography indicates that the purity is
99.90% impurity is OMc-AMP/sodium salt
0.20%, NMc-AMP sodium salt 0.14%.
実施例 ４
ｃ−AMP2.00gに無水酪酸3.84g、ヨウ化ナト
リウム0.91gおよびトリエチルアミン0.92gを加え
油浴中100〜110℃で４時間撹拌する。反応後、イ
ソプロピルアルコール３ml、次いでイソプロピル
エーテル40mlを加える。析出晶を濾取、乾燥後、
水３mlおよび１，３−ジオキソラン200mlより再
結晶し精製するとDBc−AMP・ナトリウム塩
2.44g（収率81.9％）が得られる。本品の高速液体
クロマトグラフイーによる分析値は、純度98.90
％で不純物はOMc−AMP・ナトリウム塩0.31
％、NMc−AMP・ナトリウム塩0.11％である。Example 4 3.84 g of butyric anhydride, 0.91 g of sodium iodide and 0.92 g of triethylamine were added to 2.00 g of c-AMP, and the mixture was stirred in an oil bath at 100 to 110°C for 4 hours. After the reaction, add 3 ml of isopropyl alcohol and then 40 ml of isopropyl ether. After filtering and drying the precipitated crystals,
When purified by recrystallization from 3 ml of water and 200 ml of 1,3-dioxolane, DBc-AMP sodium salt was obtained.
2.44 g (yield 81.9%) is obtained. The analysis value of this product by high performance liquid chromatography is 98.90 purity.
% impurity is OMc-AMP sodium salt 0.31
%, NMc-AMP sodium salt 0.11%.
実施例 ５
ｃ−AMP2.00g、無水酪酸4.80g、ナトリウム
メチラート0.33gおよびトリエチルアミン1.23gを
酢酸ブチル10mlに加え、油浴中105〜115℃で３時
間撹拌する。反応後、イソプロピルエーテル40ml
を加える。析出晶を濾取、乾燥後水３ml、テトラ
ヒドロフラン90mlおよびメチルエチルケトン40ml
より再結晶し精製するとDBc−AMP・ナトリウ
ム塩2.31g（収率77.5％）が得られる。本品の高速
液体クロマトグラフイーによる分析値は純度98.6
％で不純物はOMc−AMP・ナトリウム塩0.32
％、NMc−AMP・ナトリウム塩0.38％である。Example 5 2.00 g of c-AMP, 4.80 g of butyric anhydride, 0.33 g of sodium methylate and 1.23 g of triethylamine are added to 10 ml of butyl acetate and stirred at 105-115°C in an oil bath for 3 hours. After reaction, add 40ml of isopropyl ether
Add. Collect the precipitated crystals by filtration, and after drying, add 3 ml of water, 90 ml of tetrahydrofuran, and 40 ml of methyl ethyl ketone.
After further recrystallization and purification, 2.31 g (yield 77.5%) of DBc-AMP sodium salt is obtained. The purity of this product determined by high performance liquid chromatography is 98.6.
% impurity is OMc-AMP/sodium salt 0.32
%, NMc-AMP sodium salt 0.38%.
Claims (1)
ンおよび塩交換剤の存在下、カルボン酸無水物と
加熱することを特徴とするN6，2′−０−ジアシ
ルアデノシン−3′，5′−環状燐酸アルカリ金属塩
の製造法。1 N 6 ,2′-0-diacyladenosine-3′, characterized by heating adenosine-3′,5′-cyclic phosphoric acid with a carboxylic acid anhydride in the presence of a tertiary amine and a salt exchanger. Method for producing 5'-cyclic alkali metal phosphate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7802382A JPS58194895A (en) | 1982-05-10 | 1982-05-10 | Improved method for preparing na salt of dbc-amp (n6,2'-o-dibutyryladenosine-3,5'-cyclic phosphate) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7802382A JPS58194895A (en) | 1982-05-10 | 1982-05-10 | Improved method for preparing na salt of dbc-amp (n6,2'-o-dibutyryladenosine-3,5'-cyclic phosphate) |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58194895A JPS58194895A (en) | 1983-11-12 |
| JPH0340040B2 true JPH0340040B2 (en) | 1991-06-17 |
Family
ID=13650205
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7802382A Granted JPS58194895A (en) | 1982-05-10 | 1982-05-10 | Improved method for preparing na salt of dbc-amp (n6,2'-o-dibutyryladenosine-3,5'-cyclic phosphate) |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58194895A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100457770C (en) * | 2006-12-06 | 2009-02-04 | 杭州美亚药业有限公司 | Process of refining calcium dibutyryl adenosine cyclophosphate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51108090A (en) * | 1975-03-20 | 1976-09-25 | Daiichi Seiyaku Co | Adenoshinjudotaino natoriumuennoseiho |
| JPS5239699A (en) * | 1975-09-26 | 1977-03-28 | Dai Ichi Seiyaku Co Ltd | Improved methods of producing adenosine derivatives |
-
1982
- 1982-05-10 JP JP7802382A patent/JPS58194895A/en active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS51108090A (en) * | 1975-03-20 | 1976-09-25 | Daiichi Seiyaku Co | Adenoshinjudotaino natoriumuennoseiho |
| JPS5239699A (en) * | 1975-09-26 | 1977-03-28 | Dai Ichi Seiyaku Co Ltd | Improved methods of producing adenosine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58194895A (en) | 1983-11-12 |
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