JPS5838282A - Manufacture of ergoline derivative - Google Patents
Manufacture of ergoline derivativeInfo
- Publication number
- JPS5838282A JPS5838282A JP13745982A JP13745982A JPS5838282A JP S5838282 A JPS5838282 A JP S5838282A JP 13745982 A JP13745982 A JP 13745982A JP 13745982 A JP13745982 A JP 13745982A JP S5838282 A JPS5838282 A JP S5838282A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- hydrogen atom
- carbon atoms
- allyl
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
- C07D457/06—Lysergic acid amides
Abstract
(57)【要約】本公報は電子出願前の出願データであるた
め要約のデータは記録されません。(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】
本発明は一般式夏：
〔式中Ｒ１は水素原子又はメチル基を表わし、Ｒ２は、
水素原子、ハロゲン原子又はメチル基を表わし、Ｒ８は
水素原子又はメトキシ基を表わしル基又は式： （ＣＨ
，）ｎＮ（Ｃ４Ｈ６）、 （こと−ｔ’ｎは整数ｔある
）のジメチルアミノアルキル基をｉゎし、Ｒ，はＲ６が
表わすものの任意の基又は水素原子又はピリジル、ピリ
ミジル、ピラジニル、ピリダジニル、チアゾリル又はチ
アジアゾリル基を表わす〕のエルゴリン誘導体のレジオ
特異的な製法に関し、その方法は、次の一般式層のエル
ＪリンアミＰと一般式層のインシアネートとを反応させ
ることよりなる：
〔式中Ｒ□、 Ｒ，、Ｒ，、Ｒ，、Ｒ，及びＲ６は前記
のものを表わす〕。この反応は、７０〜１２０℃の温度
〒、ジオキサン、（ンぜン、トルエン、シクロヘキサン
等の適当な溶剤中で、２４〜７２時間にわたり実施する
のが有利１ある。反応の終りに、生成物は慣用の方法例
えばクロマトグラフィ及び／又は結晶化及び造塩にょ９
単離しかつ精製することができる。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula: [wherein R1 represents a hydrogen atom or a methyl group, and R2 is
represents a hydrogen atom, a halogen atom or a methyl group, and R8 represents a hydrogen atom or a methoxy group; or a formula: (CH
,)nN(C4H6), (where -t'n is an integer t) is a dimethylaminoalkyl group, and R is any group or hydrogen atom represented by R6, or pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl or thiadiazolyl group], the method consists of reacting ergoline derivatives of the following general formula layer with incyanate of the general formula layer: R□, R, , R, , R, , R, and R6 represent the above]. This reaction is advantageously carried out for 24 to 72 hours at a temperature of 70 to 120° C. in a suitable solvent such as dioxane, toluene, cyclohexane, etc. At the end of the reaction, the product is carried out using conventional methods such as chromatography and/or crystallization and salt formation.
It can be isolated and purified.
本発明によるこの方法！使用される出発物質は公知化合
物であるか又は公知化合物から出発一般式鳳のいくつか
の化合物及びその製法は、英国特許出頭第８１０９９４
９号明細書及び相応するベルギー特許第８８８２４３号
、西Ｐイッ特許出ｍ第３１１２８６１号及び特願昭４６
−４８４９１号８ＡＩ！ａ書中に記載されている。This method according to the invention! The starting materials used are known compounds or starting from known compounds Some compounds of the general formula Otori and their preparation are described in British Patent Application No. 810994.
Specification No. 9 and corresponding Belgian Patent No. 888243, Nishi P. Patent No. 3112861 and Japanese Patent Application No. 1973
-48491 No. 8AI! It is described in book a.
ここに記載の方法で（・Ｊｌ一般式Ｉの対称的誘導体を
良好な収率マ製造することが１きるが、その実際的な重
゛要性は、基Ｒ５及びＲ６は異なるものを表わす一般式
層の化合物の製造に使用される際に低下している。この
場合に、相互のレジオ異性体が得られ、単離の困峻性の
結果として、屡々、単離された生成物の収率は低い。本
発明の方法は、それがレジオ特異性であり、前記の困峻
を除きかつ所望のカル−ジイミドの不安定性に基づき、
従来の英１特許第８１０９９４９号明細書に記載の方法
で得ることは１きなかったある種の生物学的に活性の化
合物の製造を可能とするので、最も実際的であることが
立証された。Although the method described here allows the symmetrical derivatives of the general formula I to be prepared in good yields, its practical importance lies in the generality that the groups R5 and R6 represent different In this case, mutual regioisomers are obtained and, as a result of the difficulty of isolation, the yield of the isolated product is often reduced. The method of the present invention is characterized by the fact that it is regiospecific, eliminates the above-mentioned difficulties, and is based on the instability of the desired cal-diimide.
It has proven to be the most practical as it allows the production of certain biologically active compounds which could not be obtained by the conventional method described in British Patent No. 8,109,949. .
次の例は本発明を説明するもの１あって、本発明はこれ
らのみに限定されるもの１はない。The following examples are illustrative of the present invention and are not intended to limit the invention to these.
例１
６−アリル−８β−〔ｌ−エチル−３−（３−ジメチル
アミノプロピル）−ウレイＰカル？ニル〕−二ル！リン
１ ： Ｒ１−Ｒ，”−Ｒ−Ｈ，Ｒ４−アリル、トル
エンｔ ｏ ｏ ｏ ｗａｘ中の６−アリル−８β−（
３−’）Ｉｆルアンノプロｆルーカルノ饗モモイル−エ
ルゴリン（融点１９５１〜２００ｔｌ）２０ｊｌ及びエ
チルイソシアネー） １５０ ｍｊの混合物を７２時間
還流させる。生じる溶液を７０〜８゜ｔ） 及０３０
Ｃ１ｗｈｌＩＦの圧力で蒸溜させ、残分をシリｔＪｌ’
ｋ（０，σ５〜０．２ ａｍ） ６０１の充填されたク
ロマトグラフィカラムに施こし、アセトンで溶離させる
。生成物を含有していることを示している溶離液７ラク
シヨンを集め減圧下に溶剤をこれから除去すると、フオ
ームとしての表題化合物２０ｇが得られ、２燐酸塩とし
てのその融点は１５２〜１５４℃であった。Example 1 6-allyl-8β-[l-ethyl-3-(3-dimethylaminopropyl)-ureiP Cal? Niru] - Niru! Phosphorus 1: R1-R,''-R-H, R4-allyl, 6-allyl-8β-( in toluene too wax
3-') A mixture of 20 jl of Ifruannoproflucarnocarnomoyl-ergoline (melting point 1951-200 tl) and 150 mj of ethyl isocyanate is refluxed for 72 hours. The resulting solution was heated to 70~8°t) and 030
Distill at a pressure of C1whlIF and distill the residue
Applied to a chromatography column packed with k(0,σ5-0.2 am) 601 and eluted with acetone. The eluent 7 lactate, which was shown to contain the product, was collected and the solvent was removed from it under reduced pressure to give 20 g of the title compound as a form, whose melting point as the diphosphate was 152-154°C. there were.
例２
６−アリル−８β−（ｌ−エチルウレイＰカルｉニル）
−エルザリン
１ ： Ｒ，−Ｒ，−１−Ｒ，−Ｒ，−Ｈ、Ｒ４−アリ
ル、６−アリル−８β−（３−ジメチルアミノ！ロピル
ーカルＡモイル）−エルゴリン（７）代５４：６−７９
ｋ −８β−カルノ々モイルーエルゴリン（融点１９
０−１９３℃）を用いて、例１に記載と同様に操作する
と、表題化合物（融点２１０〜２１２℃）が９０−の収
率で得られた。Example 2 6-allyl-8β-(l-ethylurei Pcarinyl)
-Erzarin 1: R, -R, -1-R, -R, -H, R4-allyl, 6-allyl-8β-(3-dimethylamino!ropyrucal A moyl) -ergoline (7) 54:6- 79
k-8β-carnomoyl ergoline (melting point 19
Working as described in Example 1 using 0-193°C), the title compound (mp 210-212°C) was obtained in 90-yield.
例３
６−アリル−８β−（１，３−ジメチルウレイＰカルー
ニル）−エルゴリン
１ ： Ｒ１−Ｒ，−Ｒ，−Ｈ，Ｒ４−アリル、Ｒ，−
Ｒ，ｍ ＣＨ。Example 3 6-allyl-8β-(1,3-dimethylureiP carunyl)-ergoline 1: R1-R,-R,-H,R4-allyl,R,-
R,m CH.
６−アリル−８β−（３−ジメチルアミノゾロビルーカ
ルノ々モイル）−エルゴリンの代りに６＝アリル−８β
−メチルカルＡモイルーエル！リンを用い、エチルイソ
シアネートの代９にメチルインシアネートを用いて、例
１に記載と同様に操作すると、表題化合物（融点１０６
〜１０８℃）が８７−の収率で得られた。6-allyl-8β-(3-dimethylaminozoloby-carnomoyl)-ergoline instead of 6=allyl-8β
-Methyl Cal A Moi Ruel! Proceeding as described in Example 1 using phosphorus and replacing ethyl isocyanate with methyl incyanate gives the title compound (melting point 106
~108°C) was obtained in a yield of 87°C.
Claims (1)
素原子、ハロゲン原子又はメチル基を表わし、Ｒ１は水
素原子又はメトキシ基を表わし、Ｒ４は炭素原子数１〜
４を有する炭化水素基を表わし、Ｒ６は炭素原子数１〜
４を有するアルキル基、シクロヘキシル基、置換又は非
置換のフェニル基又は式： （ＯＨ，）ｎＮ（ＯＨ，）
。 （ここでｎは整数である）のジメチルアミノアルキル基
を表わし、Ｒ，はＲ６が表わすものチアジアゾリル基を
表わす〕のエル♂リン誘導体を製造するために、適当な
溶剤中に溶かした一般式厘： 〔式中Ｒ１，Ｒ，、Ｒ，、Ｒ，、Ｒ，及びＲ６は前記の
ものを表わす〕のエル＝ｒ９ンアξドと、式厘： Ｒ，−Ｎ −０−０（１） 〔式中Ｒ６は前記のものを表わす〕のイソシアネートと
を、７０〜１２０℃の温度で２４〜７２時間反応させて
所望の１式のエルｔリン誘導体を形成させ、場合によっ
ては、これを精製しかつ公知方法で単離する仁とを特徴
とするエルゴリン誘導体の製法。[Claims] 1. General formula I: [In the formula, R1 represents a hydrogen atom or a methyl group, R8 represents a hydrogen atom, a halogen atom, or a methyl group, R1 represents a hydrogen atom or a methoxy group, and R4 represents a hydrogen atom or a methoxy group. Number of carbon atoms: 1~
represents a hydrocarbon group having 4 carbon atoms, and R6 has 1 to 1 carbon atoms.
an alkyl group, a cyclohexyl group, a substituted or unsubstituted phenyl group having 4 or the formula: (OH,)nN(OH,)
. (wherein n is an integer) represents a dimethylaminoalkyl group, and R represents a thiadiazolyl group], the general formula is dissolved in a suitable solvent. : [In the formula, R1, R,, R,, R,, R, and R6 represent the above] and the formula: R, -N -0-0 (1) [ isocyanate of formula (R6 represents the above) at a temperature of 70 to 120° C. for 24 to 72 hours to form the desired ertrin derivative of formula 1, which may be purified if necessary. and a ergoline derivative isolated by a known method.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8124549 | 1981-08-11 | ||
| GB8124549 | 1981-08-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5838282A true JPS5838282A (en) | 1983-03-05 |
| JPH0321030B2 JPH0321030B2 (en) | 1991-03-20 |
Family
ID=10523868
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13745982A Granted JPS5838282A (en) | 1981-08-11 | 1982-08-09 | Manufacture of ergoline derivative |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS5838282A (en) |
| BE (1) | BE894060A (en) |
| DE (1) | DE3229665A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007501274A (en) * | 2003-05-08 | 2007-01-25 | イヴァックス ファーマシューティカルズ エス．アール．オー． | Cabergoline polymorph |
-
1982
- 1982-08-09 DE DE19823229665 patent/DE3229665A1/en not_active Ceased
- 1982-08-09 JP JP13745982A patent/JPS5838282A/en active Granted
- 1982-08-09 BE BE0/208772A patent/BE894060A/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007501274A (en) * | 2003-05-08 | 2007-01-25 | イヴァックス ファーマシューティカルズ エス．アール．オー． | Cabergoline polymorph |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0321030B2 (en) | 1991-03-20 |
| DE3229665A1 (en) | 1983-02-24 |
| BE894060A (en) | 1982-12-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |