JPS601193A - Phosphorylcholine morpholidate metal halide complex and its preparation - Google Patents
Phosphorylcholine morpholidate metal halide complex and its preparationInfo
- Publication number
- JPS601193A JPS601193A JP10879983A JP10879983A JPS601193A JP S601193 A JPS601193 A JP S601193A JP 10879983 A JP10879983 A JP 10879983A JP 10879983 A JP10879983 A JP 10879983A JP S601193 A JPS601193 A JP S601193A
- Authority
- JP
- Japan
- Prior art keywords
- phosphorylcholine
- metal halide
- complex
- morphoresort
- morpholidate
- 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.)
- Granted
Links
- 229950004354 phosphorylcholine Drugs 0.000 title claims abstract description 30
- 229910001507 metal halide Inorganic materials 0.000 title claims abstract description 17
- 150000005309 metal halides Chemical class 0.000 title claims abstract description 16
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 title claims abstract 5
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 abstract description 22
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 abstract description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 5
- 235000005074 zinc chloride Nutrition 0.000 abstract description 5
- 239000011592 zinc chloride Substances 0.000 abstract description 5
- 229960001284 citicoline Drugs 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- RZZPDXZPRHQOCG-OJAKKHQRSA-M CDP-choline(1-) Chemical compound O[C@@H]1[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-M 0.000 abstract 1
- 230000002490 cerebral effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- GWLJTAJEHRYMCA-UHFFFAOYSA-N phospholane Chemical compound C1CCPC1 GWLJTAJEHRYMCA-UHFFFAOYSA-N 0.000 abstract 1
- PYJNAPOPMIJKJZ-UHFFFAOYSA-N phosphorylcholine chloride Chemical compound [Cl-].C[N+](C)(C)CCOP(O)(O)=O PYJNAPOPMIJKJZ-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- RZZPDXZPRHQOCG-OJAKKHQRSA-O CDP-choline(1+) Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-O 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 5
- 229960001231 choline Drugs 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- -1 Phosphorylcholine amides Chemical class 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000004437 phosphorous atom Chemical group 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- ZWIADYZPOWUWEW-XVFCMESISA-N CDP Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(O)=O)O1 ZWIADYZPOWUWEW-XVFCMESISA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- GHDBLWVVUWTQCG-UHFFFAOYSA-N acetonitrile;n,n-dimethylmethanamine Chemical compound CC#N.CN(C)C GHDBLWVVUWTQCG-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- IERHLVCPSMICTF-XVFCMESISA-N cytidine 5'-monophosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(O)=O)O1 IERHLVCPSMICTF-XVFCMESISA-N 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- OMUIQYYMRCBHMU-UHFFFAOYSA-N morpholin-4-yl dihydrogen phosphate Chemical class OP(O)(=O)ON1CCOCC1 OMUIQYYMRCBHMU-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000004816 paper chromatography Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- KYWVDGFGRYJLPE-UHFFFAOYSA-N trimethylazanium;acetate Chemical compound CN(C)C.CC(O)=O KYWVDGFGRYJLPE-UHFFFAOYSA-N 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
属ハライド錯体とそれを工業的に製造する方法に関する
。DETAILED DESCRIPTION OF THE INVENTION This invention relates to genus halide complexes and methods for their industrial production.
ホスホリルコリンアミド類、なかんずくホスホリルコリ
ンモ／ｌ／小すデートは脳外瘍時の意識障害治療薬など
に用いられているシチジン−５′−ジホス７二一トフリ
ン（ ＯＤＰ−コリン＞ ヲ合ａする際の中間物質であ
ることは知られている。Phosphorylcholine amides, especially phosphorylcholine mo/l/sudate, are cytidine-5'-diphos-72-tofurin (ODP-choline> It is known that it is an intermediate substance.
従来ホスホリルコリンアミド類の製造法に関しては種々
知られており、たとえばホスホリルコリンクロリドとモ
ルホリンとをジシクロへキシルカルボジイミド存在下に
反応する方法（特公昭４５−４７４７号、同４５ −
２７５６１号、コリンリン酸モ／りｐリトヘ〜をアンモ
ニアまたはアミンと反応する方法（特開昭４７ − ３
８９２９号）などがあげられる。しかしながら、これら
の方法においては、高価な試薬を大量に使用すること、
吸湿性が高く不安定なりＨ ＩＪド〜〜を原料として用
いることなどから、操作が煩雑でありまた目的物の収率
も低くなる欠点を有している。一方モルホリノリン酸誘
導体から製造する方法として、２−モルホリノー２−オ
キソー１．３．２−ジオキサホスホランをトリメチルア
ミンと反応させる方法（特開昭４９ − ９４６５０号
）などが知られており、前記欠点は若干改良されてはい
るものの封管中高温で長時間の反応が必要であり、工業
的に有利な方法とは言い難い。Various methods for producing phosphorylcholineamides have been known in the past, including a method in which phosphorylcholine chloride and morpholine are reacted in the presence of dicyclohexylcarbodiimide (Japanese Patent Publication No. 45-4747, No. 45-45).
No. 27561, Method of Reacting Choline Phosphate with Ammonia or Amine (JP-A-47-3
No. 8929). However, these methods require the use of large amounts of expensive reagents;
Since HIJ is used as a raw material because it is highly hygroscopic and unstable, it has the drawbacks that the operation is complicated and the yield of the target product is low. On the other hand, as a method for producing from morpholinophosphoric acid derivatives, a method is known in which 2-morpholino-2-oxo-1,3,2-dioxaphosphorane is reacted with trimethylamine (Japanese Unexamined Patent Publication No. 49-94650). Although the drawbacks have been somewhat improved, it requires a long reaction time at high temperature in a sealed tube, so it cannot be said to be an industrially advantageous method.
本発明者らは工業的に有利なシチジンジホスフェートコ
リンの新製法を開発すべく鋭意研究中、２−モルホリノ
−２−オキソ−１，３，２−ジオキサホスホランとトリ
メチルアミンとを金属ハライドの存在下に反応させるこ
とによって室温短時間で極めて円滑に反応が進行し、シ
チジンジホスフェートコリンを合成する際の新規中間体
であるホスホリルコリンモルホリゾート金属ハライド錯
体をほぼ定量的に高収率で取得しうろことを見出し、本
発明を完成するに至った。該錯体はホスホリルコリンモ
ルホリゾートとは分析値はもとより物性の面でも異なる
全く別種の化合物でアリ、ホスホリルコリンモルホリゾ
ートと金属ハライドとの単なる混合物ないしはホスホリ
ルコリンモルホリゾートの金属ハライド塩とも異なるも
のである。このことはたとえば、ホスホリルコリンモル
ホリゾート金属ハライド錯体そのものや該錯体をシチジ
ン−５′−モノリン酸との反応条件溶媒中に数時間保持
後のものを、それぞれ同条件下のホスホリルコリンモル
ホリゾート、ホスホリルコリンモルホリゾートと金属ハ
ライドとの混合物と薄層クロッＦ分析でそのＲｆ値を比
較したところ、金属ノ）ライド錯体とその他のものの値
が異なることからも明らかである。The present inventors are conducting intensive research to develop an industrially advantageous new method for producing cytidine diphosphate choline. By reacting in the presence of cytidine diphosphate, the reaction proceeds extremely smoothly at room temperature in a short time, and phosphorylcholine morphoresort metal halide complex, which is a new intermediate for synthesizing cytidine diphosphatecholine, is obtained almost quantitatively in high yield. The inventors discovered that this was the case, and completed the present invention. The complex is a completely different type of compound that differs from phosphorylcholine morphoresort not only in analytical values but also in terms of physical properties, and is also different from a mere mixture of phosphorylcholine morphoresort and a metal halide or a metal halide salt of phosphorylcholine morphoresort. . This means, for example, that the phosphorylcholine morphoresort metal halide complex itself or the complex after being kept in a solvent for several hours under reaction conditions with cytidine-5'-monophosphoric acid, phosphorylcholine morphoresort, phosphorylcholine When comparing the Rf value of a mixture of morphoresort and metal halide by thin-layer Crop F analysis, it is clear that the values of the metal halide complex and others are different.
また本発明のホスホリルコリンモルホリゾートの塩化ア
ルミニウム錯体の赤外ｉｅ収スベクトルとホスホリルコ
リンモルホリプ−トドの赤外線吸収スペクトルとを比較
したところ、ホスホリルコリンモルホリゾートに顕著に
みられるＰ＝０ノ吸収がホスホリルコリンモルホリゾー
ト塩化アルミニウム錯体には全くみられないことから、
本発明の錯体においては金属が結合してリン酸部のリン
原子と酸素原子の二重結合部が大きく変化したことが示
される０
本発明の方法でえられるホスホリルコリンモルホリゾー
ト金属ハライド錯体は単離精製後または精製することな
く反応液より生成物を戸数したままでもシチジン−５′
−モノリン酸との反応に供しえ、シチジン−５′−ジホ
スフェートコリンを高収率で生成しうろことを見出した
。Furthermore, when the infrared ie absorption vector of the aluminum chloride complex of the phosphorylcholine morphoresort of the present invention was compared with the infrared absorption spectrum of the phosphorylcholine morphoresort, it was found that the P = 0 absorption was observed in the phosphorylcholine morphoresort. is not observed at all in the phosphorylcholine morphoresort aluminum chloride complex.
In the complex of the present invention, it is shown that the double bond between the phosphorus atom and the oxygen atom in the phosphoric acid moiety has changed significantly due to the binding of the metal. After separation and purification, or even if the product is removed from the reaction solution without purification, cytidine-5'
- It has been found that cytidine-5'-diphosphatecholine can be reacted with monophosphoric acid to produce cytidine-5'-diphosphatecholine in high yield.
本発明に用いられる出発物質である２−モルホリノ−２
−オキソ−ｉ、３．．２−ジオキサホスホランは製造法
公知の化合物である（たとえば、ｚｈ。2-morpholino-2, the starting material used in the present invention
-oxo-i, 3. ．． 2-Dioxaphosphorane is a compound whose production method is known (for example, zh.
０ｂｓｈｃｈ、 Ｋｈｉｍ、 ３６．９２３ （１９６
６） ） ｏ使用される金属ハライドとしては塩化アル
ミニウム、塩化第二鉄、塩化チタニウム、塩化第二スズ
、塩化亜鉛などフリーデルクラフト型触媒として知られ
る金属ハライドがあげられ、有利には塩化アルミニウム
、塩化亜鉛が好ましい。かかる金属ハライドは出発原料
のホスホランに対し、等モルから若干過剰モル（１，２
倍モル程度）必要であり、使用量が少ないと目的物の収
率の低下をきたす。反応は溶媒の存在下に実施され、好
適な例としてアセトン、アセトニトリル、エーテルなど
があげられる。反応温度は０〜５０ｏＯ程度、反応時間
は１〜６時間で充分である。目的物のホスホリルコリン
モルホリゾート金属ハライド錯体は、反応終了後析出し
た沈殿物をｐ取し、適当な溶媒、たとえばメタノールー
エーテｙなどから結晶化することによって反応混合物か
ら単離できる。本発明における錯体は成分としてホスホ
リルコリンモルホリゾートと金属ハライドのモル比がほ
ぼ１：１のものに相当する〇つぎに実施例および参考例
をあげて本発明をさらに詳しく説明するが、本発明はか
かる実施例のみに限定されるものではない。0bshch, Khim, 36.923 (196
6) ) o The metal halides used include metal halides known as Friedel-Crafts type catalysts such as aluminum chloride, ferric chloride, titanium chloride, stannic chloride, and zinc chloride; aluminum chloride, Zinc chloride is preferred. Such metal halide is used in an equimolar to slight molar excess (1,2 molar amount) relative to the starting material phosphorane.
If the amount used is too small, the yield of the target product will decrease. The reaction is carried out in the presence of a solvent, and suitable examples include acetone, acetonitrile, ether and the like. A reaction temperature of about 0 to 50 oO and a reaction time of 1 to 6 hours are sufficient. The target phosphorylcholine morphoresolved metal halide complex can be isolated from the reaction mixture by removing the precipitate that precipitates after the completion of the reaction and crystallizing it from a suitable solvent such as methanol. The complex in the present invention corresponds to one in which the molar ratio of phosphorylcholine morphoresort and metal halide as components is approximately 1:1.Next, the present invention will be explained in more detail by giving examples and reference examples. The present invention is not limited to these examples.
実施例１
３０重ｆｆ１％トリメチルアミンアセトニトリル溶液２
５ｍ／に２−モルホリノ−２−オキソ−１，３，２−ジ
オキサホスホラン６ｇを溶解し、ついで塩化アルミニウ
ム４．２ｇを加えて室温で２時間攪拌した。Example 1 30 heavy ff 1% trimethylamine acetonitrile solution 2
6 g of 2-morpholino-2-oxo-1,3,2-dioxaphosphorane was dissolved in 5 m/ml, and then 4.2 g of aluminum chloride was added and stirred at room temperature for 2 hours.
反応終了後少量のエーテルを加えて沈殿物をｐ ・取し
、これをクロ！ホルム、エーテルの順で洗浄した。つい
でメタノール−エーテルから結晶化することによってホ
スホリルコリンモルホリゾート塩化アルミニウム錯体１
１．１りをえた。After the reaction is complete, add a small amount of ether, remove the precipitate, and chlorinate it! It was washed with form and ether in that order. The phosphorylcholine morphoresolved aluminum chloride complex 1 was then prepared by crystallization from methanol-ether.
I got 1.1 points.
つぎにえられた錯体の特性値を示す。Next, the characteristic values of the obtained complex are shown.
融点２８０〜以上（約１９８％から徐々に着色）ペーパ
ークロマトグラフィー（展ＮＷ＆、エタノール：ｏ、ｓ
Ｍ酢酸アンモニウム＝１０：１ 、Ｈ工試薬で検／ｉｉ
） Ｓ Ｒｆ値０．２８ （モノスポット）（比較：
特開昭４９−９４６５０号の方法で製造したホスホリル
コリンモルホリゾートは融点２５０°Ｃ１前記と同様な
条件でのペーパークロ本実施例でえられたホスホリルコ
リンモルホリゾート塩化アルミニウム錯体の赤外線吸収
スペクトルを第１図に、また比較のための特開［４９−
９４６５０号の方法で製造したホスホリルコリンモルホ
リゾートの赤外線吸収スペクトルを第２図にそれぞれ示
す。Melting point 280~ or higher (gradually colored from about 198%) Paper chromatography (exhibition NW&, ethanol: o, s
M ammonium acetate = 10:1, tested with H engineering reagent/ii
) S Rf value 0.28 (mono spot) (comparison:
The phosphorylcholine morphoresort produced by the method of JP-A-49-94650 has a melting point of 250°C. Figure 1 also shows JP-A [49-
The infrared absorption spectra of phosphorylcholine morphoresort produced by the method of No. 94650 are shown in FIG.
第１図および第２図を比較すると、２９００ｃｍ付近の
モルホリンのＱ−Ｈの吸収、１１０３ｃｍ−１１
付近のＰ−０の吸収、１４８０ｃｍ 、 １６４０〜１
６５００ｍ−１のコリンによる吸収は共通であるが、第
２図に顕著にみられる１２０５ａｍ のＰ＝０の吸収が
第１図には全くみられない。これはアルミニウムが結合
してリン酸部のリン原子と酸素原子間の二重結合部が大
きく変化したことを示すものである。Comparing Figures 1 and 2, we find that the Q-H absorption of morpholine near 2900 cm, the P-0 absorption near 1103 cm-11, 1480 cm, and 1640-1
Absorption by choline at 6500 m-1 is common, but absorption at P=0 at 1205 am, which is conspicuous in Fig. 2, is not seen at all in Fig. 1. This indicates that the double bond between the phosphorus atom and the oxygen atom in the phosphoric acid moiety has changed significantly due to the bonding of aluminum.
元素分析値
実測値し）： ｏ ２７．６８ Ｈ６，５８Ｎ ７．０
６ ｈｔ ７．９２Ｆ７．９００１１２．２８
実施例２
６０重量％トリメチルアミンアセ（ニトリル溶液１２．
５ｍｊに２−モルホリ／−２−オキソ−１，３，２−ジ
オキサホスホラン６ｇを溶解し、ついで塩化亜鉛２．１
９を加えて室温で２時間攪拌した。以下実施例１と同様
にしてホスホリルコリンモルホリゾート塩化亜鉛錯体ろ
、９ｇをえた。Actual elemental analysis value): o 27.68 H6,58N 7.0
6 ht 7.92F7.900112.28 Example 2 60% by weight trimethylamine acetate (nitrile solution 12.
Dissolve 6 g of 2-morpholy/-2-oxo-1,3,2-dioxaphosphorane in 5mj, and then add 2.1 g of zinc chloride.
9 was added and stirred at room temperature for 2 hours. Thereafter, in the same manner as in Example 1, 9 g of phosphorylcholine morphoresort zinc chloride complex was obtained.
参考例
ピリジン４０ ｍｌおよび水５ｍｌの混合溶媒に実施例
１でえられたホスホリルコリンモルホリゾート塩化アル
ミニウム錯体６．９ｇとシチジン−５ｔ−モノリン酸ト
リーｎ−ブチルアミン塩５．１ｇとを加え、１００ ’
Ｏで５時間反応させた。反応終了後、減圧下に濃縮し、
残渣を水に溶解し、アンモニア水でｐＨ９，５に調整し
、ダイアイオン５ＡｉＩＢ（ギ酸型）カラムにかけた。Reference Example 6.9 g of the phosphorylcholine morphoresort aluminum chloride complex obtained in Example 1 and 5.1 g of cytidine-5t-monophosphate tri-n-butylamine salt were added to a mixed solvent of 40 ml of pyridine and 5 ml of water, and the mixture was heated to 100 ml.
The reaction was carried out at O for 5 hours. After the reaction is completed, concentrate under reduced pressure,
The residue was dissolved in water, adjusted to pH 9.5 with aqueous ammonia, and applied to a Diaion 5AiIB (formic acid type) column.
水洗後０．０１Ｍギ酸で溶出すると、はじめに０ＤＰ−
コリンが溶出してくるのでこの分画を集めて濃縮し、残
渣にエタノールを加えることによって０ＤＥ−コリンを
えた。After washing with water and eluting with 0.01M formic acid, initially 0DP-
Since choline was eluted, this fraction was collected and concentrated, and 0DE-choline was obtained by adding ethanol to the residue.
えられた化合物の赤外線吸収スペクトル、核磁気共鳴ス
ペクトルは標品と完全に一致した。The infrared absorption spectrum and nuclear magnetic resonance spectrum of the obtained compound completely matched those of the standard product.
叙上の結果より、本発明の化合物がＣＤＰ−コリンを工
業的に有利に生産するため中間体として有用であること
が明らかである。From the above results, it is clear that the compound of the present invention is useful as an intermediate for industrially advantageous production of CDP-choline.
なお、ホスホリルフリンモルホリデー１化アルミニウム
錯体をピリジン−水（９：１）中で一１００°ｏ、２時
間攪拌抜水を加えて沈殿物を溶解したのち薄層りシマト
ゲラフイー（エタノール：０，５Ｍ酢１％アンモニウム
＝１”１、Ｈ工試薬で検出）で分析した結果、Ｒｆ値０
．０７であった。一方、同じ条件下でのホスホリルコリ
ンモルホリゾートはＲｆ値０．６０であった。このこと
から、ホスホリルコリンモルホリゾート塩化アルミニウ
ム錯体から０ＤＰ−コリンを製造する際、該錯体が溶媒
中で加水分解してホスホリルコリンモルホリゾート経由
で反応するのではないことがわかる。In addition, phosphorylfurin morpholii aluminum monide complex was stirred in pyridine-water (9:1) at -100°C for 2 hours to remove water and dissolve the precipitate. As a result of analysis using vinegar 1% ammonium = 1"1, detected with H engineering reagent), the Rf value was 0.
．． It was 07. On the other hand, phosphorylcholine morphoresort under the same conditions had an Rf value of 0.60. This shows that when ODP-choline is produced from the phosphorylcholine morphoresort aluminum chloride complex, the complex does not hydrolyze in the solvent and react via the phosphorylcholine morphoresort.
第１図はホスホリルコリンモルホリゾート塩化アルミニ
ウム錯体の赤外線吸収スペクトル、第２図はホスホリル
コリンモルホリプ−トドの赤外線吸収スペクトルである
。FIG. 1 shows the infrared absorption spectrum of phosphorylcholine morpholyte aluminum chloride complex, and FIG. 2 shows the infrared absorption spectrum of phosphorylcholine morpholate.
Claims (1)
。 ２２−モルホリノ−２−オキソ−１，６，２−ジオキサ
ホスホランを金属ハライドとトリメチルアミンと反応さ
せることを特徴とするホスホリルコリンモルホリゾート
金属ハライド錯体の製造法。[Claims] 1. Phosphorylcholine morphoresort metal halide complex. A method for producing a phosphorylcholine morphoresort metal halide complex, which comprises reacting 22-morpholino-2-oxo-1,6,2-dioxaphosphorane with a metal halide and trimethylamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10879983A JPS601193A (en) | 1983-06-16 | 1983-06-16 | Phosphorylcholine morpholidate metal halide complex and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10879983A JPS601193A (en) | 1983-06-16 | 1983-06-16 | Phosphorylcholine morpholidate metal halide complex and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS601193A true JPS601193A (en) | 1985-01-07 |
| JPS629598B2 JPS629598B2 (en) | 1987-02-28 |
Family
ID=14493771
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10879983A Granted JPS601193A (en) | 1983-06-16 | 1983-06-16 | Phosphorylcholine morpholidate metal halide complex and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS601193A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61273933A (en) * | 1985-05-30 | 1986-12-04 | Nhk Spring Co Ltd | Preparation of sheet |
| JP2002064898A (en) * | 2000-06-06 | 2002-02-28 | Shingo Minazu | Foamed plastic resonator |
| CN114106043A (en) * | 2021-12-06 | 2022-03-01 | 成都海博为药业有限公司 | Compound, preparation method thereof, method for preparing citicoline by compound and application |
-
1983
- 1983-06-16 JP JP10879983A patent/JPS601193A/en active Granted
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61273933A (en) * | 1985-05-30 | 1986-12-04 | Nhk Spring Co Ltd | Preparation of sheet |
| JP2002064898A (en) * | 2000-06-06 | 2002-02-28 | Shingo Minazu | Foamed plastic resonator |
| CN114106043A (en) * | 2021-12-06 | 2022-03-01 | 成都海博为药业有限公司 | Compound, preparation method thereof, method for preparing citicoline by compound and application |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS629598B2 (en) | 1987-02-28 |
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