JPS59155400A - Improved preparation of c-amp acyl derivative - Google Patents

Improved preparation of c-amp acyl derivative

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Publication number
JPS59155400A
JPS59155400A JP2736383A JP2736383A JPS59155400A JP S59155400 A JPS59155400 A JP S59155400A JP 2736383 A JP2736383 A JP 2736383A JP 2736383 A JP2736383 A JP 2736383A JP S59155400 A JPS59155400 A JP S59155400A
Authority
JP
Japan
Prior art keywords
salt
phosphoric acid
cyclic
dbc
tertiary amine
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.)
Pending
Application number
JP2736383A
Other languages
Japanese (ja)
Inventor
Atsushi Nakagawa
淳 中川
Susumu Suzuki
進 鈴木
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SEISHIN SEIYAKU KK
Daiichi Pharmaceutical Co Ltd
Original Assignee
SEISHIN SEIYAKU KK
Daiichi Pharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by SEISHIN SEIYAKU KK, Daiichi Pharmaceutical Co Ltd filed Critical SEISHIN SEIYAKU KK
Priority to JP2736383A priority Critical patent/JPS59155400A/en
Publication of JPS59155400A publication Critical patent/JPS59155400A/en
Pending legal-status Critical Current

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Abstract

PURPOSE:To obtain an N<6>,2'-O-diacyladenosine-3',5'-cyclic phosphate useful as a drug and a reagent advantageously, by reacting adenosine-3',5'-cyclic phosphoric acid with a carboxylic acid anhydride in the presence of a tertiary amine under heating, treating the resultant product with a salt exchanging agent. CONSTITUTION:Adenosine-3',5'-cyclic phosphoric acid is reacted with preferably 3-6 times the molar quantity of carboxylic acid anhydride(e.g., acetic anhydride, etc.) in the presence of preferably 1-3 times the molar quantity of a tertiary amine under heating to form N<6>,2'-O-diacyladenosine-3'5'-cyclic phosphoric acid (DBc-AMP for short), which is treated with a salt exchanging agent (e.g., NaH CO3, etc.), to give an alkali metal salt of DBc-AMP. EFFECT:The desired compound can be prepared efficiently, economically and in high yield.

Description

【発明の詳細な説明】 本発明は氾2’−0−ジアシルアデノシン−s: 51
− 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砥2′−〇−ジ
ブチリルア゛デノシン−31,57−環状燐酸ナトリウ
ム塩の工業的に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 2'-0-diacyladenosine-s: 51
- This invention relates to an improved method for producing alkali metal cyclic phosphates, and provides an industrially advantageous method for producing 2'-〇-dibutyryladenosine-31,57-cyclic sodium phosphate salts, which are particularly useful as medicines and reagents. The purpose is to

以下に、ジブチリル体のナトリウム塩の製造を例として
説明するが9次の略号を使用する。
In the following, the production of the sodium salt of dibutyryl compound will be explained as an example, and the following abbreviations will be used.

c−AMP : アデノシン−3’、5’−環状燐酸D
Bc−AMP: N’、2’−0−ジブチリルアデノシ
ン−8′、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: 〜6−モツブーf−リル7デノシ>
−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。
c-AMP: Adenosine-3',5'-cyclic phosphoric acid D
Bc-AMP: N',2'-0-dibutyryladenosine-8',5'-cyclic phosphoric acid OMc-AMP: 2'-0-monobutyryladenosine-3',5'-cyclic phosphoric acid NMC-AMP: ~6-Motsubu f-Lil 7denoshi>
-3',5'-Cyclic phosphoric acid Conventionally, the following production method is known for DBc-AMP sodium salt. Namely.

a)c−AMPを三級アミンと脱i剤の存在下無水酪酸
と加熱せしめる(特開昭52−89699)。
a) Heating c-AMP with butyric anhydride in the presence of a tertiary amine and a dehydrating agent (JP-A-52-89699).

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、 Bio
−phys、  Acta、  148  9 9〜1
 0 5  (1967ン ) 。
b) Reacting c-AMP triethylamine salt with butyric anhydride in the presence of a deoxidizing agent (Biochim, Bio
-phys, Acta, 148 9 9-1
05 (1967).

c)c−AMP・ナトリウム塩を70°C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. 57-18698)
).

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、先ず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
1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 first 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 one reaction mixture to dryness under reduced pressure, adding anhydrous pyridine to this and drying again. The operation becomes complicated because the operation must be repeated to obtain an anhydride.

またC−人MP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9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す) IJ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、不安定なりBc−AMP・す) 
IJウム塩は濃縮中に分解してOMc−AMP−ナトリ
ウム塩または:J M c 、−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-MP or C-AMP triethylamine salt as a starting material, the reaction product is DBc-AMP.
- It 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 to IJium salt, but since the ion exchange resin treatment solution is a dilute solution, a concentration operation is required and it becomes unstable. Bc-AMP・su)
The IJum salt decomposes during concentration to produce OMc-AMP-sodium salt or:JMc,-AMP sodium salt, resulting in a decrease in the purity of the target product.

このように公知方法は、いずれもH全工程が煩雑であり
2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った。
As described above, all of the known methods have disadvantages such as the complicated H process and the decomposition of DBc-AMP/sodium salt during the post-treatment of the two reactions, resulting in a decrease in purity. It wasn't necessarily satisfying.

そこで本発明者は鋭意研究の結果、c−AMPと酸無水
物の反応では、■c−AMPは一旦塩の型にして用いる
必要はないこと、■三級アミンの存在が必要であること
、および■塩交換剤をアシル化反応液に加えることによ
り容易にアルカリ金属塩の型で目的物を得ることができ
ること、を見出し1本発明を完成した。
Therefore, as a result of intensive research, the present inventor found that in the reaction between c-AMP and acid anhydride, (1) it is not necessary to use c-AMP in the form of a salt, and (2) the presence of a tertiary amine is necessary. and (2) The inventors completed the present invention by discovering that the desired product can be easily obtained in the form of an alkali metal salt by adding a salt exchanger to the acylation reaction solution.

すなわち2本発明は、アデノシン−3′、5′−環状燐
酸を、三級アミンの存在下、カルボン酸無水物と加熱し
てN6,2’−0−ジアシルアゾ/シン−3’、5’ 
−環状燐酸を生成させ2次いでこのものを塩交換剤と反
応させることにより鴎2’−0−ジアシルアデノシン−
3′、5/ −9状燐酸アルカリ金属塩を製造する方法
である。
That is, in the present invention, adenosine-3',5'-cyclic phosphoric acid is heated with a carboxylic acid anhydride in the presence of a tertiary amine to form N6,2'-0-diacylazo/syn-3',5'.
-By producing cyclic phosphoric acid and then reacting this with a salt exchanger, 2'-0-diacyladenosine-
This is a method for producing a 3', 5/-9 alkali metal phosphate.

本発明を更に詳細に述べるならば、e−AMPを無溶媒
でまたは溶媒中で1〜3倍モルの三級アミン17)存在
下2〜6倍モルのカルボン酸無水物9例えば無水酪酸と
加熱すればジアシル化体が生成する。このことは、経時
的に反応液中に存在する物質を高速液体クロマトグラフ
ィーで分析することにより確認される。−例として。
To describe the present invention in more detail, e-AMP is heated with 2 to 6 times the mole of carboxylic acid anhydride 9, for example, butyric anhydride, in the presence of 1 to 3 times the mole of a tertiary amine 17) without a solvent or in a solvent. This will produce a diacylated product. This is confirmed by analyzing the substances present in the reaction solution over time using high performance liquid chromatography. -As an example.

c−AMP  1.659+無水ルー酪酸3.17シお
よびトリエチルアミン1.02を140°Cに加熱攪拌
した際の15分後と30分後の高速液体クロマトグラフ
ィーのチャートを図面のA トB ニ示す。図面中aは
c  A M P + bはOMc−AMP、sは内部
標準物質(β−ナフタレンスルホン酸)である。この図
面から、15分後に存在した原料のc−AMPと中間生
成物のOM c −A M Pは、30分後には消失し
Charts of high performance liquid chromatography after 15 minutes and 30 minutes when c-AMP 1.659 + 3.17 g of rubutyric anhydride and 1.02 g of triethylamine were heated and stirred at 140°C are shown in A and B of the drawing. . In the drawing, a represents c A M P + b OMc-AMP, and s represents an internal standard substance (β-naphthalenesulfonic acid). From this drawing, it can be seen that the raw material c-AMP and the intermediate product OM c -A MP that were present after 15 minutes disappeared after 30 minutes.

OB c −A 、M Pが高率に生成していることが
認められる。
It is recognized that OB c -A and MP are produced at a high rate.

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。
This reaction proceeds without solvent, but ethyl butyrate and
It is also possible to use aliphatic esters such as isopropyl acetate, butyl acetate.

三級アミンとしては1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, picoline, etc. can also be used.

反応条件は、溶媒を使用するか否か、三級アミンと酸無
水物9例えば無水酪酸、のモル数によって異なるが、6
0〜150°Cで005〜20時間、好ましくは90〜
120°Cで1〜5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 the tertiary amine and acid anhydride, such as butyric anhydride.
0-20 hours at 0-150°C, preferably 90-20 hours
It is preferable to carry out the reaction at 120°C for about 1 to 5 hours until OMc-AMP disappears.

この反応混合物に塩交換剤を加えて反応させることによ
り、N6,2’−〇−ジアシルc−AMPは所望の塩と
して得ることができる。反応は。
By adding a salt exchanger to this reaction mixture and causing the reaction, N6,2'-〇-diacyl c-AMP can be obtained as a desired salt. What is the reaction?

塩交換剤が溶解するまで加熱して行なうのが適当であり
1通常1〜2時間で充分である。
It is appropriate to carry out heating until the salt exchanger is dissolved, and usually 1 to 2 hours is sufficient.

9 塩交換剤としては1通常炭酸水素す) IJ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てきる。
9 As a salt exchange agent, 1) usually hydrogen carbonate, IJium is preferred, but sodium iodide, sodium carbonate, sodium methylate, sodium butyrate, sodium acetate, etc. may also be used.

生成したジアシルc −A M Pのアルカリ金属塩は
9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 alkali metal salt of diacyl c-A MP produced can be isolated and purified by appropriately treating the reaction mixture.

すなわち、DBc−AMPナトリウム塩の場合は反応混
合物にインプロビールアルコールドイソプロビルエーテ
ルの混合溶媒または含水テトラヒドロフランの適当量を
加えると粗結晶が析出する。この粗品を少量の水(lり
当り3顎以下)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
ランか優れており。
That is, in the case of DBc-AMP sodium salt, crude crystals are precipitated by adding an appropriate amount of a mixed solvent of Improvyl alcohol doisoprobyl ether or aqueous tetrahydrofuran to the reaction mixture. Dissolve this crude product in a small amount of water (less than 3 cups per liter), add 1.2 g of tetrahydrofuran,
It is appropriate to add an appropriate amount of = dimethoxyethane, 1,3-dioxolane, acetonitrile or propionitrile for recrystallization. Among them, tetrahydrofuran, 1,2-dimethoxyethane or 1,3-dioxolane are excellent.

また、これらとメチルエチルケトンの混合溶媒も工業的
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またはテトラヒドロフラン
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。
Further, a mixed solvent of these and methyl ethyl ketone is also industrially excellent, and the most preferred is a combination of tetrahydrofuran and methyl ethyl ketone or tetrahydrofuran, which makes it possible to obtain sufficiently purified DBc-AMP sodium salt.

本発明は、従来操作が煩雑で工業的(q実施する(こけ
不満足であったDBc−AMP・ナトリウム塩の製造を
、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。
The present invention has made it possible to produce DBc-AMP sodium salt efficiently and with high yield, whereas conventional operations were complicated and unsatisfactory. ,Economic.

工業的に優れた方法を提供するものである。This provides an industrially superior method.

実施例1 C’−A1.(Pa。29りに無水酪酸6.83!7お
よびトリエチルアミン2.027を加え、油浴中110
〜120°Cで2時間攪拌する。次いで。
Example 1 C'-A1. (Pa. 29, add 6.83!7 of butyric anhydride and 2.027 of triethylamine,
Stir at ~120°C for 2 hours. Next.

反応液に炭酸水素ナトリウム0.849を加え同温で1
時間攪拌する。反応液を冷却し、1゜5%含水テトラヒ
ドロフラン130tnlを加えると結晶が析出する。こ
の結晶を濾取し、さらに1.5%含水テトラヒト20フ
ラン150−より再結晶し、油取、乾燥するとDBc−
AMP・ナトリウム塩3.539(収率□71ノ9%)
が得られる。
Add 0.849% sodium hydrogen carbonate to the reaction solution and add 1% at the same temperature.
Stir for an hour. When the reaction solution is cooled and 130 tnl of 1.5% aqueous tetrahydrofuran is added, crystals are precipitated. The crystals were collected by filtration, recrystallized from 1.5% hydrated tetrahydrofuran, 150% of 20-furan, removed from oil, and dried.
AMP sodium salt 3.539 (yield □71 no 9%)
is obtained.

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
ィーによる分析値は、純度99.1%で不純物はOMc
−AMP・ナトリウム塩0.25%、NMC=A1.l
P・ナトリウム塩0゜21%である。
The IR of this product completely matches that of the standard sample of DBc-AMP sodium salt synthesized separately, and the analysis value by high performance liquid chromatography shows that the purity is 99.1% and impurities are OMc.
-AMP/sodium salt 0.25%, NMC=A1. l
P. Sodium salt is 0°21%.

実施例2 cmAMP8.009に無水酪酸5゜77シおよびトリ
エチルアミン2.309−を加え、iσ1浴中110〜
120°Cで2時rt 4M拌する。Vくいで反応液に
酪酸す) IJウム1.ox9を加え同温で1時間攪拌
する。反応混合物にイソプロピルアルコール8mJ、次
いで・イソプロピルエーテル6゜−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2frLtに溶
解し、テトラヒドロフラン130−より再結晶し、濾取
、°乾燥するとDBc−AMP−ナトリウム塩s、so
g(収率73.7%)が得られる。本品の高速液体クロ
マトグラフィーによる分析値は、−純度98.5%で。
Example 2 To cmAMP8.009, 5.77 cm of butyric anhydride and 2.309 cm of triethylamine were added and
Stir 4M at 120°C for 2 hours at rt. Add butyric acid to the reaction solution using a V-shaped tube.1. Add ox9 and stir at the same temperature for 1 hour. 8 mJ of isopropyl alcohol and then 6° of isopropyl ether are added to the reaction mixture. The precipitated crystals were collected by filtration, dried in a desiccator, dissolved in 2frLt of water, recrystallized from 130% tetrahydrofuran, collected by filtration, and dried to give DBc-AMP-sodium salt s,so
g (yield 73.7%) is obtained. The analysis value of this product by high performance liquid chromatography is - purity 98.5%.

不純物はOMc−AMP・ナトリウム塩o、16%、N
Mc−AMP−ナトリウム塩0.06%である。
Impurities are OMc-AMP sodium salt o, 16%, N
Mc-AMP-sodium salt 0.06%.

【図面の簡単な説明】[Brief explanation of the drawing]

図面はfi1m液体クロマトグラフィーのチャートであ
る。
The drawing is a chart of fi1m liquid chromatography.

Claims (1)

【特許請求の範囲】[Claims] アゾ/シン−3: 51− m状燐酸を、三級アミンの
存在下、カルボン酸無水物と加熱して祇2′−〇−ジア
シルアデノシン−sr、 5/ −環状燐酸を生成させ
1次いでこのものを塩交換剤と反応させることを特徴゛
とする〜6,2’ −’ 0−ジアシルアデノシン−s
′、r、!−環状燐酸アルカリ金属塩の製造法
Azo/Syn-3: 51- M-phosphoric acid is heated with carboxylic acid anhydride in the presence of a tertiary amine to produce 2'-〇-diacyladenosine-sr, 5/-cyclic phosphoric acid. ~6,2'-'0-diacyladenosine-s characterized by reacting the compound with a salt exchanger.
',r,! -Production method of cyclic alkali metal phosphate
JP2736383A 1983-02-21 1983-02-21 Improved preparation of c-amp acyl derivative Pending JPS59155400A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2736383A JPS59155400A (en) 1983-02-21 1983-02-21 Improved preparation of c-amp acyl derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2736383A JPS59155400A (en) 1983-02-21 1983-02-21 Improved preparation of c-amp acyl derivative

Publications (1)

Publication Number Publication Date
JPS59155400A true JPS59155400A (en) 1984-09-04

Family

ID=12218963

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2736383A Pending JPS59155400A (en) 1983-02-21 1983-02-21 Improved preparation of c-amp acyl derivative

Country Status (1)

Country Link
JP (1) JPS59155400A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02169597A (en) * 1988-12-21 1990-06-29 Kikkoman Corp Production of sodium adenosine-3',5'-cyclic phosphate
WO2004085453A1 (en) * 2003-03-20 2004-10-07 Pharmacore, Inc. Synthesis and method of purification of cyclic nucleotide derivatives
CN104017040A (en) * 2014-06-27 2014-09-03 上海第一生化药业有限公司 Preparation method and application of monobutyryl adenosine cyclophosphate or salt thereof

Citations (2)

* Cited by examiner, † Cited by third party
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
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

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02169597A (en) * 1988-12-21 1990-06-29 Kikkoman Corp Production of sodium adenosine-3',5'-cyclic phosphate
WO2004085453A1 (en) * 2003-03-20 2004-10-07 Pharmacore, Inc. Synthesis and method of purification of cyclic nucleotide derivatives
CN104017040A (en) * 2014-06-27 2014-09-03 上海第一生化药业有限公司 Preparation method and application of monobutyryl adenosine cyclophosphate or salt thereof

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