• 专利附录
  • 专利说明
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    • 专利摘要:
    A process for the preparation of 1-hydroxyaporphine derivatives of the general formula: <IMAGE> I wherein R1, R3 and R4, which are the same or different, are lower alkyl, aryl or aralkyl radicals or R3 and R4 can together form a lower alkylene bridge member and R2 is a hydrogen atom or a lower alkyl, aralkyl or alkoxycarbonyl radical or an acyl radical derived from an aliphatic, aromatic or araliphatic carboxylic acid.
    公开号:SU878194A3
    申请号:SU782700601
    申请日:1978-12-21
    公开日:1981-10-30
    发明作者:Хартенштайн Иоганнес；Затцингер Герхард
    申请人:Варнер Ламберт Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to an improved method for the preparation of 1-hydroxyaporphin derivatives. general form
    ly 1 B1P - 5 BUT G | G Ί (I) V10r 4 o 0R 3
    where rp
    with a note.
    and R are the same or different methyl or ethyl, or R ^ and R ^ together are 15 methylene, ethylene)
    R ^ is hydrogen or lower alkyl, trifluoroacetylpharmacological active. A method for producing 1-hydroxyaporphin derivatives of the general formula (I) is known, which consists in the fact that tetrahydroisoquinolyl of the general formula 11 (I)
    ("> 878194 (51) M; Cl. 3
    C 07 D 217/04 //
    A 61 K 31/435 (53) UDC 547.94.07 (088.8) is reacted with vanadium fluoride in methylene chloride in the presence of trifluoroacetic acid at a temperature of -1СРС [1].
    The disadvantage of this method is the use of inaccessible vanadium fluoride, as well as the formation of by-products in the process of oxidative cyclization due to the hydroxylation of the starting compound.
    The purpose of the invention is the simplification of the process, the process and the expansion of the range of target products.
    The goal is achieved by the method of obtaining derivatives of 1-hydroxyaporphin of the general formula (I), which consists in the fact that tetrahydroisoquinoline of the general formula II
    (II) where R ^, R 2_> R s and 84 have the above meanings, are reacted with vanadyl chloride at a ratio of 1-3 mol of vanadyl chloride per 1 mol of tetrahydroisoquinoline in dichloroethane, chloroform, carbon tetrachloride in the presence of trifluoroacetic acid at 10 r S.
    Example 1. (+) -1-0xy-2.9,. 10-trimethoxyaporphin ((±) -alicmidine).
    0.9 g (2.63 mol, (+) - 7-hydroxy-b-methoxy-2-methyl-1-veratryl-1,2,3,4-tetrahydroisoquinoline ((+) -codamine) is dissolved in 10 ml of trifluoroacetic acid and cooled to -10 ° C in the absence of moisture.After reaching this temperature in a nitrogen atmosphere, a solution of 0.6 ml (1.1 g, 6.4 mol) of vanadyl trichloride in 5 ml of anhydrous' chloride is added dropwise with stirring. methylene for about 1 minute, the reaction mixture immediately becomes a dark blue color.After the introduction of the reagent, the mixture is stirred at a temperature of -10 ° C for another 10 minutes, followed by trifluoride acetic acid and the solvent are distilled off under vacuum at ambient temperature, the residue is mixed with ice water and extracted with chloroform. After drying the extract with anhydrous sodium sulfate, distilling off the solvent under vacuum and recrystallizing the residue from acetone / ether, 840 mg is obtained (70% of theory) (+) - 1-OXI-2,9,10-trimethoxig aporphine in the form of crystalline red-brown trifluoroacetate, mp. 193-200 ° C.
    Another 100 mg of trifluoroacetate can be isolated from the mother liquor. The total yield of crystalline product: 78.5% of theoretical.
    After treatment with ammonia and recrystallization from ethanol / diethyl ether, (+) - talicmidine is obtained in the form of blackish crystals.
    Mp 183-186 ° C.
    Example 2. (±) -1-Oxy-2, 9, 10-trimethoxy-no-porphine ((±) -Ν-northalicmidine).
    g (3 mmol) of Ш-N-norcodamine is dissolved in 10 ml of trifluoroacetic acid dropwise at a temperature of -10 ° C in an inert gas atmosphere and 0.35 ml (0.57 g, '3.3 mmol) of vanadyl trichloride are added to a solution 5 ml of anhydrous methylene chloride. After this, the reaction mixture was stirred for another 15 minutes at a temperature of -1 ° C, evaporated under vacuum at ambient temperature, the residue was mixed with water and extracted with chloroform. The extract is treated in the usual way and crystallized from acetone to give 730 mg (55% of theory) of (+} - 1-hydroxy-2,9,10-trimethoxy-N-noraporfin as its trifluoroacetate. Mp. 198-209 ° FROM.
    Example 3. (+) - Trifluoroacetyl ~ 1-hydroxy-2,9, 10-trimethoxy-N-noraphorphine.
    g (7.1 mmol) (+) ~! 4 ~ trifluoroacetyl-7-hydroxy-6-methoxy-1-veratril-1, 2,3,4-tetrahydroisoquinoline in 30 ml of trifluoroacetic acid dropwise at a temperature of -10 ° C in an atmosphere of nitrogen is mixed with a solution of 1.65 ml (3.03 g, '17.48 mmol) of vanadium chloride poured into ml of anhydrous 10 methylene chloride for 2 minutes. Analysis by thin-layer chromatography showed that even after 5 minutes the starting compound was almost completely absent in the mixture. Processing by the method described in Example 1 and crystallization from the acetone / diethyl ether system yields 2.64 g (88% of theory) in two doses of crystalline (+) - Ν-trifluoroacetyl-1-hydroxy- ~ 2.9, Yu-trimethoxy-N-noraporfin in the form of dark brown crystals. Mp 210-222 ° C.
    Example 4. (+) - Ν-Trifluoroacetyl-1-hydroxy-2-methoxy-9,10-methi22 len-dioxi-N-noraporfin.
    g (4.9 mmol) (+) - Ν-trifluoroacetyl-7-hydroxy-b-methoxy-1- (3,4-methylenedioxybenzyl) -1,2,3,4-tetrahydroisoquinoline in a mixture with 10 ml of trifluoroacetic acid and 10 ml of anhydrous methylene chloride is added dropwise at a temperature of −10 ° C. to a solution of 0.94 mp (1.73 g; 10 mmol) of vanadyl chloride in 10 ml of anhydrous 0 methylene chloride. According to the analysis performed by thin-layer chromatography, after 5 minutes the starting material was absent in the mixture. The reaction mixture was evaporated in vacuo and recrystallized from methanol-acetone-water, to give (+) - Ν-trifluoroacetyl-1-hydroxy-2-methoxy-9,1O-methylenedioxy-N-norapor'fin. Yield 1.72 g (86.6% of theory).
    T. pl. 282-284 ° C. MS: M + 407. .. Example 5. In a mixture of 10 ml of anhydrous chloroform and 2 ml of trifluoroacetic acid, 0.9 g (2.63 mmol) (±.) ~ 7-hydroxy-b-meto-Xi-2- are dissolved methyl-1-veratryl-1,2,3,4-tetrahydroisoquinoline. To this mixture at a temperature of -10 ° C, excluding moisture, a solution of 0.6 ml (1.1 g, 4 mmol) of vanadyl trichloride in 5 ml of anhydrous chloroform is added over 1 min. Stirring was continued at -10 ° C for another 10 minutes, after which the mixture was worked up as described in Example 1. Crystallization of the crude product from acetone / ether gave 950 ml (79%) (±.) - 1-hydroxy- in two portions. 2, 9,10-trimethoxyaporphine in the form of red-brown trifluoroacetate.
    Example 6. 0.9 g (2.63 mmol) of (+) - 7-hydroxy-b-methocry-2 ~ methyl-1 $ 5-veratryl-1,2,3,4-tetrahydroioiohi 5 nolin is dissolved in 10 ml of trifluoroacetic acid cooled to -10 ° C, excluding moisture. To this mixture, a solution of 0.6 ml (1.1 g; 6.4 mmol) of vanadyl trichloride in 10 ml of anhydrous carbon tetrachloride is added dropwise with stirring. Stirring was continued at -10 ° C for another 10 minutes, after which the mixture was treated according to the procedure of Example 1. Yield 925 mg (77%) of (+) - 1-hydroxy-1,9,10-trimethoxyaporphine.
    where Rj, R ^ and R | are the same or different methyl or ethyl, or Rj and 1 ^ together are methylene or ethylene;
    R is hydrogen or lower alkyl, trifluoroacetyl by the interaction of tetrahydroisoquinoline of the general formula I I
    Example Pro. K 200 mg ¢), 47 mmol) (±) -I-trifluoroacetyl-7-hydroxy-6-methoxy-1-veratryl-1,2,3,4tetrahydroisoquinoline in 10 mp anhydrous 1,2-dichloroethane at -10 ° С under a nitrogen atmosphere, a solution of 0.12 ml (0.22 g / 1.27 mmol) of vanadyl chloride in 5 ml of anhydrous 1,2-dichloroethane is added. The mixture was stirred for 2 hours at 0 ° C and then treated by separation between ice water and 1,2-dichloroethane. After drying and evaporation of the organic layer by crystallization from acetone / ether, 160 ml (80% of theory 25) of (+) - M-trifluoroacetyl-1-hydroxy-2,9, 10-trimethoxy-N-noraporphine are obtained.
    权利要求:
    Claims (1)
    [1]
    (54) METHOD FOR OBTAINING DERIVATIVES OF 1-OXIAPORPHINE. This invention relates to an improved process for the preparation of 1-hydroxy-porphin derivatives. The generic form is “IB 5 R, j and R are the same or different from methyl or ethyl, and R together is methylene, ethylene; hydrogen I. OR lower apical, trifluoroacetylase possessing pharmacological activity. 20 A method of obtaining 1-hydroxy-porphine derivatives of general formula (1) is known, which consists in that tetrahydroisoquinolyl of general formula II BP. (I) 30 is reacted with G by vanadium fluoride in methylene chloride in the presence of trifluoroacetic acid at a temperature of -1 (Yas l. The disadvantage of this method is the use of inaccessible fyristy vanadium, as well as the formation of by-products in the process of oxidative cyclization by hydroxy. The purpose of the invention is to simplify the process, process and expand the range of target products. The goal is achieved by the method of obtaining 1-hydroxyhalphine derivatives of general formula (I), that tetrahydroisoquinoline of general formula C and R have higher R values, These values are reacted with vanadyl chloride at a ratio of 1-3 mol of vanadyl chloride per 1 mol of tetrahydroisoquinoline in dichloroethane, chloroform, carbon tetrachloride in the presence of trifluoroacetic acid at that The treatment is -10 ° C. Example 1. (+) - 1-Oxy-2.9, 10-trimethoxy-aporphine ((±) -t shtsmidine 0.9 g (2.63 mol (+) - 7-oxy-b- methoxy 2-methyl-1-veratryl-1, 2,3,4-tetrahydroisoquinoline ((±) -codamin) is dissolved in 10 ml of trifluoroacetic acid and cooled to no moisture. Upon reaching this temperature in a nitrogen atmosphere, a solution of 0.6 ml (1.1 g, 6.4 mol; trichloric vanadyl in 5 ml of anhydrous methylene chloride) is added in approximately 1 minute with stirring in about 1 minute. The reaction mixture It immediately becomes dark blue and after the introduction of the reagent, the mixture is stirred at a temperature of another 10 minutes, after which the trifluoroacetic acid and solvent are distilled off under vacuum at ambient temperature. The residue is mixed with ice water and extracted with chloroform. anhydrous sodium sulfate extract distilling off the solvent under vacuum and recrystallizing the residue from an acetone / ether mixture to obtain 840 mg (70% of theory) (+) - 1-OXY-2,9,10-trimethoxy aporphine in the form of a crystalline trifluoroacetate of red-brown color Mp 193-2000 ° C. Another 100 mg of trifluoroacetate can be isolated from the mother liquor. The total yield of the crystalline prodactus is 78.5% of the theoretical. After treatment with ammonia and recrystallization from ethanol / diethyl ether is obtained ( +) - Talitsmidin in the form of blackish crystals. Mp: 183-186 ° C. Example 2. (±) -1 Oxy-2,9, 10-trimethoxy-N, nopropophen ((±) -N-nortalitsmidin). 1 g (3 mmol) (tJ M of norcodamine is dissolved in 10 ml of trifluoroacetic acid, dropwise at a temperature of -10 ° C. And an inert gas atmosphere is poured into a solution of 0.35 ml (0.57 g of 3.3 mmol) of vadiol trichloride 5 ml of anhydrous methylene chloride.After this, the reaction mixture is stirred for 15 minutes at temperature, evaporated under vacuum at ambient temperature, the residue is mixed with water and extracted with chloroform. The extract is worked up in the usual way and crystallized from acetone, 730m are obtained (55 % of theory) (±) -1-hydroxy-2,9,10-trimethoxy-N -norraporphine in the form of its trifluoroacetate. Tp. 198-209s. Example 3. (+) - Trifluoroacetyl-1-OXY-2, 9, 10-trimetoxy-N-noreporphine. 3 g (7.1 mmol) ( +) - N-trifluoroacetyl-7-hydroxy-6-methoxy-1-veratryl-1, 2,3,4-tetrahydroisoquinoline in 30 ml of trifluoroacetic acid at -10 ° C in a nitrogen atmosphere is mixed with solution 1, 65 ml (3.03 g; 17.48 mmol) of vanadyl chloride in 15 ml of anhydrous methylene chloride for 2 minutes. Analysis by thin layer chromatography showed that after 5 minutes the starting compound is almost completely absent in the mixture. Treatment by the method described in Example 1 and crystallization from the acetone / diethyl ether system yields 2.64 g (88% of theory) in two doses of crystalline (+) - J-trifetropacetyl-1-hydroxy-2, 9, 10 trimethoxy-n-porphine in the form of dark brown crystals. M.p. 210-222 ° C. Example 4. (±) -N-Trifluoroacetyl-1 - hydroxy-2-methoxy-9, 10-methylene-dioxy-N-noraporphine. 2 g (4.9 mmol) (+) - N-trifluoroacetyl-7-hydroxy-6-methoxy-1- (3,4-methylenedioxybenzyl) -1,2,3, 4-tetrahydroisoquinoline mixed with 10 ml of trifluoroacetic acid and 10 ml of anhydrous methylene chloride are added dropwise at -10 ° C to a solution of 0.94 ml (1.73 g; 10 mmol) of vanadyl chloride in 10 ml of anhydrous methylene chloride. According to the analysis carried out by the method of thin layer chromatography, after 5 min, the starting material was absent in the mixture. The reaction mixture is evaporated in vacuo and recrystallized from methanol-acetone-water to give (+) - N-trifluoropetyl-1-oxo-2-methoxy-9, 10-methylenedioxy-M-noraporphine. Output 1.72 g (86.6% of theory) ,. T. pl. 282-284 ° C. MS: M 407. Example 5. In a mixture of 10 ml of anhydrous chloroform and 2 ml of trifluoroacetic acid, 0.9 g (2.63 mmol) of (1.) 7-hydroxy-6-methoxy-2-methyl 1-veratryl are dissolved. -1, 2, 3, 4-tetrahydroisoquinoline. To this mixture at a temperature of -10 ° C / excluding the ingress of moisture, with stirring, a solution of 0.6 ml (1.1 g; b, 4 mmol) of vanadyl trichloride in 5 ml of anhydrous chloroform is added over 1 minute. Stirring is continued at -10 ° C for another 10 minutes, after which the mixture is treated as described in Example 1. The crystallization of the crude product from acetone / ether gives in two portions 950 ml (79%) (t) -1 hydroxy-2, 9, Yu-trimethoxyaporphine in the form of raspberry trifluoroacetate. Example 6. O, 9 g (2.63 mmol) of (+) - 7-hydroxy-6-methokri-2-methyl-1-veratryl-1, 2, 3,4 tbtrahidroioeohygulina is dissolved in 10 ml of trifluoroacetic acid, cooled before, excluding moisture. While stirring, a solution of 0.6 ml (1.1 g, 6.4 mmol) of vanadyl trichloride in 10 ml of anhydrous carbon tetrachloride is added dropwise to this mixture. Stirring is continued for a further 10 minutes, after which the mixture is treated as described in Example 1. Yield 925 mg {77%) (+) - -hydroxy-1, 9,10-trimethoxy-porphine Example For. K 200 mg f), 47 mmol) (±) - | trifluoroacetyl-7-hydroxy-b-methoxy-1-veratryl-1,2,3,4 tetrahydroisoquinoline in 10 ml of anhydrous 1,2-dichloroethane was added a solution of 0.12 ml (0.22 g ; 1.27 mmol) of vanadyl chloride in 5 ml of anhydrous 1,2-dichloroethane. The mixture is stirred for 2 hours at, and then treated by separation between ice water and 1,2-dichloroethane. After drying and evaporation of the organic layer by crystallization from acetone / ether, 160 ml (80% of theoretical) (±) -M-trifluoroacetyl-1-hydrox-2,9,10-trimethoxy-M-noraporphin are obtained. Claims of Invention A method for producing 1-hydroxy-porphin derivatives of general formula I BiO de R., RO and Pd are the same or different methyl or ethyl. or Rj together methylene or ethylene hydrogen or lower alkyl, trifluoroacetyl interaction: Ethhehydroisoquinoline of the general formula II where R, R, R 3. and R have the above values with vanadyl halide in a chlorine-containing organic solvent in the presence of trifluoroacetic acid, with, characterized in that in order to simplify the process and expand the range of target products, vanadyl chloride is used at a ratio of 1-3 mol of vanadyl chloride per 1 mol of tetrahydroisoquinoline and, as, dichloroethane, chloroform, carbon dioxide. Sources of information taken into account in the examination 1. Kupchan S.M., From R. Efficient: 1 ptgamo1 eU1 and g Monophenol Oxidative Coupling. - 1. Org. Chem. 1976, 41.4049.
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    同族专利:
    公开号 | 公开日
    FI68223C|1985-08-12|
    CH637642A5|1983-08-15|
    DE2757281C3|1980-10-23|
    IT7852364D0|1978-12-19|
    JPS54119475A|1979-09-17|
    GB2011393B|1982-05-06|
    FR2412534A1|1979-07-20|
    DD139845A5|1980-01-23|
    US4202980A|1980-05-13|
    FR2412534B1|1983-05-20|
    FI68223B|1985-04-30|
    CS219347B2|1983-03-25|
    DE2757281A1|1979-06-28|
    IT1110876B|1986-01-06|
    HU178804B|1982-06-28|
    GB2011393A|1979-07-11|
    DE2757281B2|1980-02-21|
    BE872842A|1979-04-17|
    NL7812393A|1979-06-26|
    FI783971A|1979-06-23|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3950344A|1973-09-13|1976-04-13|The University Of Virginia|Non-phenol oxidative coupling|
    DE2625116C2|1976-06-04|1984-01-26|Gödecke AG, 1000 Berlin|Process for the preparation of 4-hydroxy-aporphine derivatives|US5109136A|1990-08-09|1992-04-28|Warner-Lambert Company|Tetracyclic amines useful as cerebrovascular agents|
    US6210680B1|1999-06-11|2001-04-03|Univera Pharmaceuticals, Inc.|Method for the prevention and treatment of chronic venous insufficiency|
    TWI225397B|2000-05-04|2004-12-21|Nat Science Council|Uses of thaliporphine or its derivatives in treatment of cardiac diseases and preparation of the same|
    US20030187011A1|2001-12-20|2003-10-02|Lashuel Hilal A.|Apomorphine inhibitors of amyloid-betafibril formation and their use in amyloidosis based disease|
    TWI386396B|2008-06-20|2013-02-21|Standard Chem & Pharm Co Ltd|Pharmaceutically acceptable salts of aporphine compounds and carboxyl group-containing agents and methods for preparing the same|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19772757281|DE2757281C3|1977-12-22|1977-12-22|Process for the preparation of 1-hydroxy-aporphine derivatives|
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