CN1076196A - 麦角灵衍生物的制备方法 - Google Patents
麦角灵衍生物的制备方法 Download PDFInfo
- Publication number
- CN1076196A CN1076196A CN93102663A CN93102663A CN1076196A CN 1076196 A CN1076196 A CN 1076196A CN 93102663 A CN93102663 A CN 93102663A CN 93102663 A CN93102663 A CN 93102663A CN 1076196 A CN1076196 A CN 1076196A
- Authority
- CN
- China
- Prior art keywords
- formula
- ergoline
- alkyl
- group
- dimethylamino
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
- A61P5/08—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Psychology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Control Of Electric Motors In General (AREA)
- Emergency Protection Circuit Devices (AREA)
Abstract
本发明提供了一种制备式I的麦角灵衍生物的
方法,该方法是在金属催化剂和磷化合物存在下使式
II的麦角灵酰胺与式III的异氰酸酯反应,式I的化合
物是有用的抗促乳素和抗帕金森氏病的药物。
Description
本发明涉及麦角灵衍生物的制备方法。
本发明提供了一种制备式Ⅰ的麦角灵衍生物的方法
其中R1代表具有1-4个碳原子的烷基,环己基或苯基或二甲氨基烷基(CH2)nN(CH3)2,其中n是整数,R2是R1所表示的任一个基团,或氢原子或吡啶基、嘧啶基、哌嗪基、哒嗪基、噻唑基或噻二唑基,R3代表具有1-4个碳原子的烃基,R4代表氢或卤原子或甲硫基或苯硫基,R5代表氢原子或甲基,该方法是在金属催化剂和磷化合物存在下使式Ⅱ的麦角灵酰胺与式Ⅲ的异氰酸酯反应。
其中R1、R2、R3、R4和R5具有上面所给的意义。该反应一般在适宜的溶剂中,于0°-80℃下进行。
式Ⅰ的化合物如在我们的英国专利说明书2074566和2103603中所描述的和所要求的那样,是有用的抗催乳素和抗帕金森氏病的药物,在该专利说明书中也揭示了两种制备式Ⅰ化合物的方法,一种是使8-羧基麦角灵与碳化二亚胺反应,另一种的特征在于使麦角灵酰胺与非常过量的异氰酸酯(多达36当量)反应,反应温度为70°-120℃。
后一种方法需要非常过量的式Ⅲ化合物才能获得良好的转化(见Eur.J.Med.Chem.24,(1989),421-426)。
由于异氰酸酯危险的特性和毒性(N.Irving Sax Dangerousproperties of industrial materials,1968,Ed.VanNostrand Reinhold;Schueler,D.Farbe Lack 1987,93,19-21,C.A.;106:72102q;Mowe,G.Contact dermatitis,1980,6,44-45,C.A.93:31108r;Davis,D.S.;DeWolf,G.B.;Nash,R.A.;Stelling,J.S.Report,1989,DCN-87-203-068-05-05,EPA/600/8-87/034M,C.A.113:11426w),在工业化生产过程中须避免大量使用这样的反应物。
再者,令人惊奇的是使用磷化合物可调控异氰酸酯的金属活化,从而避免其加到式Ⅱ化合物的吲哚氮上(当R5为氢原子时)。
本发明的方法比前述的安全得多,其反应条件也比以前所用的条件温和,可避免大量使用异氰酸酯;而且可以较高的选择性获得式Ⅰ的产物。
适宜的金属催化剂包括Ⅰb和Ⅱb族的金属盐(例如ZnI或Ag盐),优选CuI和CuII盐。最优选的是CuCl,CuCl2,CuBr和CuI。适宜的磷化合物包括C1-C4烷基,和任选取代的C6-C10芳基,如苯基或萘基膦,其通式为PR6R7R8,其中R6、R7和R8可独自代表烷基或芳基,这些基团可被1个或多个选自Cl、F、甲基、甲氧基的取代基所取代;适宜的磷化合物也可以是亚磷酸烷基酯;优选的磷化合物是三芳基膦,更优选的是三苯基膦和三对甲苯基膦。适宜的溶剂为二氯甲烷、1,1-二氯乙烷、氯仿、甲苯、乙腈和二甲基甲酰胺;优选的溶剂为甲苯、氯仿、二氯甲烷和1,1-二氯乙烷;最优选的溶剂为二氯甲烷和二氯乙烷。
反应最好在35°-60℃下进行。
式Ⅲ化合物的用量为1-4当量,优选2-3当量。
R4可代表的卤原子最好是氯或溴原子,不过,它也可以是氟原子。R3可代表的烃基可以是烷基或环烷基或烯属或炔属不饱和基团。其实例包括甲基、乙基、正丙基、异丙基、丁基、叔丁基、异丁基、环丙基、甲基环丙基、乙烯基、烯丙基和炔丙基。
优选的是R1为具有1-4个碳原子的烷基或环己基,最优选的是R1为具有1-4个碳原子的直链烷基;R2最好是二甲氨基甲基(CH2)nN(CH3)2,其中n=1,2,3或4;R3最好是烯丙基,R4和R5为氢原子。在本发明方法中所用的起始原料可通过已建立的方法从已知的化合物开始制备,而且某些式Ⅱ化合物在以下文献中有述:欧洲专利说明书No.70562,比利时专利No.888243,德国专利申请No.3112861和日本专利申请No.81/48491。
可按照常规的方法,例如层析法和/或结晶法和盐形成法分离和纯化反应产物。
可将式(Ⅰ)的麦角灵衍生物转变为药物上可接受的盐。随后可将式(Ⅰ)的麦角灵衍生物或其药物上可接受的盐与药物上可接受的载体或稀释剂一起配制成药物组合物。
下列实施例用来说明本发明。
实施例1
6-烯丙基-8β-〔1-乙基-3-(3-二甲氨基丙基)-脲基羰基〕-麦角灵(I:R1=C2H5,R2=(CH2)3N(CH3)2,R3=CH2CHCH2)
在氩气环境下,将5g6-烯丙基-8β-(3-二甲氨基丙基氨基甲酰基)-麦角灵和3.1ml异氰酸乙酯相继加入到0.13gCuCl和0.34gPPh3于200mlCH2Cl2的溶液中,于35℃搅拌15小时。然后从反应混合物中除去溶剂并将剩余物加到装有50g硅胶(0.05-0.2mm)的层析柱中,用丙酮洗脱。减压蒸发含有产物的洗脱物,然后经结晶进行纯化,得到3.95g标题化合物。
实施例2
6-烯丙基-8β-〔1-乙基-3-(3-二甲氨基丙基)-脲基羰基〕-麦角灵(I:R1=C2H5,R2=(CH2)3N(CH3)2,R3=CH2CHCH2)
方法同实施例1,但使用0.17gCuCl2作为催化剂,并于35℃下反应24小时,得到3.67g标题化合物。
实施例3
6-烯丙基-8β-〔1-乙基-3-(3-二甲氨基丙基)-脲基羰基〕-麦角灵(I:R1=C2H5,R2=(CH2)3N(CH3)2,R3=CH2CHCH2)
方法同实施例1,但使用200mlC2H4Cl2作为溶剂,并于40℃下加热反应12小时,得到4.32g标题化合物。
实施例4
6-烯丙基-8β-〔1-乙基-3-(3-二甲氨基丙基)-脲基羰基〕-麦角灵(I:R1=C2H5,R2=(CH2)3N(CH3)2,R3=CH2CHCH2)
方法同实施例1,但使用200ml甲苯作为溶剂,并于60℃下加热反应24小时,得到3.62g标题化合物。
Claims (10)
2、根据权利要求1的方法,其特征是,反应是在适宜的溶剂中,于0℃-80℃下进行的,金属催化剂选自Ⅰb和Ⅱb族的金属盐。
3、根据权利要求2的方法,其特征是,Ⅰb和Ⅱb族的金属盐是CuCl,CuCl2,CuBr或CuI。
4、根据权利要求1-3任一项的方法,其特征是,磷化合物是式PR6R7R8的膦,其中R6、R7和R8独自代表烷基或芳基,这些基团可被1个或多个选自Cl、F、甲基和甲氧基的取代基所取代,或是亚磷酸烷基酯。
5、根据权利要求1-4任一项的方法,其特征是,化合物是三苯基膦或三对甲苯基膦。
6、根据权利要求2-5任一项的方法,其特征是,溶剂为二氯甲烷、1,1-二氯乙烷、氯仿、甲苯、乙腈或二甲基甲酰胺,反应是在35℃-60℃下进行的。
7、根据权利要求1-6任一项的方法,其特征是,R1是乙基,R2是二甲氨基丙基,R3是烯丙基,R4和R5是氢原子。
8、根据前述权利要求任一项的方法,该方法还包括将式(Ⅰ)的麦角灵衍生物转变为其药物上可接受的盐。
9、根据前述权利要求任一项的方法,该方法还包括将式(Ⅰ)的麦角灵衍生物与药物上可接受的载体或稀释剂一起配制成药剂。
10、一种药物组合物,该组合物包含用如前述权利要求任一项所要求的方法制得的6-烯丙基-8β〔1-乙基-3(3-二甲氨基丙基)-脲基羰基〕麦角灵和药物上可接受的载体或稀释剂。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB929205439A GB9205439D0 (en) | 1992-03-12 | 1992-03-12 | Process for the synthesis of ergoline derivatives |
GB9205439.4 | 1992-03-12 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1076196A true CN1076196A (zh) | 1993-09-15 |
CN1038510C CN1038510C (zh) | 1998-05-27 |
Family
ID=10712024
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN93102663A Expired - Fee Related CN1038510C (zh) | 1992-03-12 | 1993-03-09 | 麦角灵衍生物的制备方法 |
Country Status (25)
Country | Link |
---|---|
US (1) | US5382669A (zh) |
EP (1) | EP0593692B1 (zh) |
JP (1) | JP3339858B2 (zh) |
KR (1) | KR100274102B1 (zh) |
CN (1) | CN1038510C (zh) |
AT (1) | ATE180783T1 (zh) |
AU (1) | AU653099B2 (zh) |
CA (1) | CA2106371C (zh) |
CZ (1) | CZ281708B6 (zh) |
DE (1) | DE69325138D1 (zh) |
FI (1) | FI113473B (zh) |
GB (1) | GB9205439D0 (zh) |
HU (1) | HU210407B (zh) |
IL (1) | IL104973A (zh) |
MX (1) | MX9301297A (zh) |
MY (1) | MY109152A (zh) |
NO (1) | NO302754B1 (zh) |
NZ (1) | NZ249115A (zh) |
PH (1) | PH30138A (zh) |
RU (1) | RU2118323C1 (zh) |
SK (1) | SK279039B6 (zh) |
TW (1) | TW215089B (zh) |
UA (1) | UA26400C2 (zh) |
WO (1) | WO1993018034A1 (zh) |
ZA (1) | ZA931720B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105189492A (zh) * | 2012-11-19 | 2015-12-23 | 萨克·W·金 | 麦角灵衍生物作为多巴胺受体调节剂 |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0007308D0 (en) | 2000-03-24 | 2000-05-17 | Pharmacia & Upjohn Spa | Process for preparing crystalline form | of cabergoline |
US6696568B2 (en) | 2001-04-16 | 2004-02-24 | Finetech Ltd. | Process and intermediates for production of cabergoline and related compounds |
IL155545A (en) * | 2003-04-21 | 2009-12-24 | Finetech Pharmaceutical Ltd | Solvate form of cabergoline |
HUP0400517A3 (en) * | 2004-03-04 | 2006-05-29 | Richter Gedeon Vegyeszet | Process for producing cabergoline |
GB0409785D0 (en) * | 2004-04-30 | 2004-06-09 | Resolution Chemicals Ltd | Preparation of cabergoline |
FR2877945A1 (fr) * | 2004-11-18 | 2006-05-19 | Archemis Sa | Procede de la preparation de la cabergoline |
WO2006097345A1 (en) | 2005-03-17 | 2006-09-21 | Synthon Argentina S.A. | Improved process for making cabergoline |
GB0505965D0 (en) * | 2005-03-23 | 2005-04-27 | Resolution Chemicals Ltd | Preparation of cabergoline |
EP1925616A1 (en) * | 2006-10-26 | 2008-05-28 | LEK Pharmaceuticals D.D. | Process for the preparation of crystal forms of cabergoline via stable solvates of cabergoline |
US7939665B2 (en) * | 2007-05-04 | 2011-05-10 | Apotex Pharmachem Inc. | Efficient process for the preparation of cabergoline and its intermediates |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2103603B (en) * | 1981-08-11 | 1985-04-11 | Erba Farmitalia | Ergoline derivatives |
-
1992
- 1992-03-12 GB GB929205439A patent/GB9205439D0/en active Pending
-
1993
- 1993-02-15 AT AT93903972T patent/ATE180783T1/de active
- 1993-02-15 UA UA93003963A patent/UA26400C2/uk unknown
- 1993-02-15 AU AU34974/93A patent/AU653099B2/en not_active Ceased
- 1993-02-15 NZ NZ249115A patent/NZ249115A/en not_active IP Right Cessation
- 1993-02-15 KR KR1019930703386A patent/KR100274102B1/ko not_active IP Right Cessation
- 1993-02-15 CZ CZ932715A patent/CZ281708B6/cs not_active IP Right Cessation
- 1993-02-15 RU RU93058546A patent/RU2118323C1/ru not_active IP Right Cessation
- 1993-02-15 HU HU9303541A patent/HU210407B/hu unknown
- 1993-02-15 WO PCT/EP1993/000360 patent/WO1993018034A1/en active IP Right Grant
- 1993-02-15 SK SK1401-93A patent/SK279039B6/sk unknown
- 1993-02-15 JP JP51527993A patent/JP3339858B2/ja not_active Expired - Fee Related
- 1993-02-15 EP EP93903972A patent/EP0593692B1/en not_active Expired - Lifetime
- 1993-02-15 CA CA002106371A patent/CA2106371C/en not_active Expired - Fee Related
- 1993-02-15 DE DE69325138T patent/DE69325138D1/de not_active Expired - Lifetime
- 1993-02-16 TW TW082101067A patent/TW215089B/zh active
- 1993-03-08 IL IL104973A patent/IL104973A/xx not_active IP Right Cessation
- 1993-03-09 CN CN93102663A patent/CN1038510C/zh not_active Expired - Fee Related
- 1993-03-09 MX MX9301297A patent/MX9301297A/es not_active IP Right Cessation
- 1993-03-09 PH PH45839A patent/PH30138A/en unknown
- 1993-03-09 US US08/028,286 patent/US5382669A/en not_active Expired - Lifetime
- 1993-03-10 ZA ZA931720A patent/ZA931720B/xx unknown
- 1993-03-11 MY MYPI93000439A patent/MY109152A/en unknown
- 1993-11-08 FI FI934933A patent/FI113473B/fi active
- 1993-11-11 NO NO934077A patent/NO302754B1/no unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105189492A (zh) * | 2012-11-19 | 2015-12-23 | 萨克·W·金 | 麦角灵衍生物作为多巴胺受体调节剂 |
US9670199B2 (en) | 2012-11-19 | 2017-06-06 | Regents Of The University Of Minnesota | Ergoline derivatives as dopamine receptor modulators |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1038510C (zh) | 麦角灵衍生物的制备方法 | |
JPS61161237A (ja) | 不飽和カルボン酸の線状ジカルボン酸へのハイドロカルボキシル化方法 | |
US4889949A (en) | Catalytic (co)dimerization of alkyl acrylates | |
CN1157284A (zh) | 制备2-氯-5-氯甲基噻唑的方法 | |
US4098763A (en) | Technique for stabilization of vinyl chloride polymers using organic thiols | |
JPS63283756A (ja) | オレフイン複分解用の活性持続改良触媒系 | |
DE10062577B4 (de) | Carben-Dien-Komplexe von Nickel,Palladium und Platin | |
US4485245A (en) | Hydrogenation of carboxylic acid anhydrides to lactones or esters using a ruthenium trichlorostannate catalyst | |
US4855469A (en) | Preparation of cycloorganotrisilazanes | |
US4695635A (en) | Process for the production of 2,3-dihydroergolines | |
Barton et al. | New reactions for use in natural products chemistry | |
Hayashi et al. | Efficient synthesis of unsaturated branched-chain sugars in aqueous media by Heck-type reaction | |
EP0647228B1 (en) | Asymmetric hydrogenation of furoimidazole derivatives | |
JPS5944303B2 (ja) | α−ケトアシド類の製造法 | |
JP2876331B2 (ja) | 付加方法 | |
JPH069499A (ja) | ハロゲノシクロプロパンカルボン酸誘導体の製法 | |
JPH0267264A (ja) | ビス(2,2,6,6−テトラメチル−4−ピペリジノ)セバケートの製造方法 | |
JPH06263763A (ja) | ジヒドロフロイミダゾール誘導体の非対称水素添加 | |
Zamashchikov et al. | Kinetics and mechanism of the decomposition of Cs 2 Pt [CH 3] 2 Cl 4 in aqueous solution with concurrent formation of C 2 H 6, C 2 H 4, and C 2 H 5 Cl | |
JPH05139998A (ja) | ハロゲノシクロプロパンカルボン酸誘導体の製法 | |
CN1420857A (zh) | 通过烯烃羰基化来制备羧酸的方法 | |
JPS62283970A (ja) | 2,3,5−三置換テトラヒドロフランの製造法 | |
JPH01230537A (ja) | 光学活性アルコールの製造法 | |
JPH02129133A (ja) | α,α−ジクロロ−ジフェニルメタン類の製造法 | |
JPH0482145B2 (zh) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |