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    • 45. 发明申请
    • NOVEL PROCESS FOR PRODUCTION OF CABERGOLINE
    • 生产咖啡因的新工艺
    • WO2005085243A2
    • 2005-09-15
    • PCT/HU2005000022
    • 2005-03-02
    • RICHTER GEDEON VEGYESZETGALAMBOS JANOSCZIBULA LASZLOSEBOK FERENCBALINT SANDORNEKASSAI FERENCNEIGNACZNE SZENDREI GYOERGYIDEMETER ADAM
    • GALAMBOS JANOSCZIBULA LASZLOSEBOK FERENCBALINT SANDORNEKASSAI FERENCNEIGNACZNE SZENDREI GYOERGYIDEMETER ADAM
    • C07D457/06C07D457/00
    • C07D457/06
    • A process for preparing cabergoline (I) from ergoline-8beta-carboxylic acid ester (XIII) comprising the following steps. (a) reacting an ergoline-8beta-carboxylic acid ester of formula (XIII), wherein R1 represents a C1-4 alkyl group, in the presence of a catalyst (i) with a compound of formula (XIV), X-COOR2 (XIV) wherein R2 is an optionally substituted straight or branched C1-6 alkyl group, X represents a bromine or chlorine atom, or (ii) with a compound of formula (XV), O(COOR2)2 (XV) wherein R2 is a group as defined above; (b) reacting the obtained carbamate derivative of formula (XVI) with 3-(dimethylamino)-propylamine (DMAPA) in the presence of a catalyst; (c) reacting the obtained ergoline-8beta-carboxamide derivative of formula (XVII) with ethyl isocyanate (EtNCO) in the presence of ligand(s) and Ib and IIb metal group salt catalysts; (d) reacting the obtained protected N-acylurea derivative of formula (XVIII) with a strong aqueous inorganic acid (aq./acid); (e) reacting the obtained secondary amine (XIX) with an electrophyl allyl alcohol derivative in the presence of a palladium or nickel containing catalyst and optionally in the presence of ligand(s) to form cabergoline (I). The intermediates of (XVI), (XVII), (XVIII) and (XIX) are novel. The polymorphic amorphous form of Cabergoline (I) and the production thereof.
    • 一种从麦角灵八羧酸酯(XIII)制备卡麦角林(I)的方法,包括以下步骤。 (ⅰ)在催化剂(ⅰ)与式(ⅩⅣ)的化合物,X-COOR2(ⅩⅣ)的存在下,使式(ⅩⅩⅢ)的麦角灵-8-羧酸酯,其中R 1表示C 1-4烷基, XIV)其中R2是任选取代的直链或支链C 1-6烷基,X代表溴或氯原子,或(ii)与式(ⅩⅤ)化合物,O(COOR 2)2(ⅩⅤ)化合物,其中R 2是 组如上所述; (b)在催化剂存在下使所得得到的式(ⅩⅥ)的氨基甲酸酯衍生物与3-(二甲氨基) - 丙胺(DMAPA)反应; (c)在配体和Ib和IIb金属盐盐催化剂存在下,使得到的式(XVII)的麦角灵八乙酰胺衍生物与异氰酸乙酯(EtNCO)反应; (d)使得到的式(XVIII)的保护的N-酰基脲衍生物与强无机酸水溶液(水溶液)反应; (e)在含钯或镍的催化剂存在下,任选地在配体存在下,使得到的仲胺(XIX)与电子烯丙基醇衍生物反应形成卡麦角林(I)。 (XVI),(XVII),(XVIII)和(XIX)的中间体是新的。 卡麦角林(I)的多晶型无定形形式及其生产。