• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    There are prepared compounds of the formula <IMAGE> (I) where >A-B- has either the structure >C(OH)-CH2- or the structure >C=CH, Alk is a straight or branched chain C1-C5-alkylene group and Y is a C3-C7-cycloalkyl group, a benzyl group, a methylenedioxybenzyl group, a benzyl group having one, two or three C1-C4-alkyl or C1-C4-alkoxy group substituents, a C1-C6-alkyl group, or a C1-C6-alkyl group substituted by an amino group, a di C1-C4-alkylamino group, a mono C1-C4-alkyl-amino group, a morpholino group, a piperazino group or a 4-(C1-C4-alkyl)-piperazino group, or Y is <IMAGE> where R is hydrogen or a C1-C4-alkyl group and T is hydrogen or a C2-C6-alkanoyl group or where -NHY is <IMAGE> where R' is hydrogen, phenyl, phenyl substituted once or twice by C1-C4-alkyl groups, a C1-C4-alkoxy group or by halogen atoms, a C1-C6-alkyl group, a C1-C4-hydroxyalkyl group or a phenalkyl group whose alkyl portion consists of 1-4 carbon atoms or such a phenalkyl group containing 1 to 3 C1-C4-alkoxy group substituents or when Alk has 2 to 5 carbon atoms the group -NHY is a di-C1-C4-alkylamino group or the group -NH-CH(R)-CH(OH)-C6H5 and salts thereof. The compounds are effective in improving peripheral and cerebral circulation. There are also produced intermediate compounds of formula (II) where NHY is replaced by chlorine, bromine or iodine.
    公开号:SU747426A3
    申请号:SU782563907
    申请日:1978-01-11
    公开日:1980-07-23
    发明作者:Клееманн Аксель；Нуберт Ингомар；Штроман Фритц；Тимер Клаус
    申请人:Дегусса (Фирма)；
    IPC主号:
    专利说明:

    one
    This invention relates to a new process for the preparation of dithienylalkylamines of the general formula
    (I)
    B-A1K NHY
    Where A and B together is a group) C (OH) -CH2 or
    unbranched
    A1 k or branched C | -Cj-alkyl;
    unbranched or branched C, -C jj-alkyl
    or a group of the general formula
    , Ori
    (but).
    -CHlRl-CH- (01l) where R is hydrogen or -alkyl;
    RI is hydrogen or C2 -C-acyl, or the group —NHY means a group
    formulas
    / -K N-Rj (5
    where Rn is unsubstituted or etched
    one, two or three methoxy groups, phenyl or benzyl,
    or their salts, which have biological activity and therefore can be used in medicine.
    There is one known method for the preparation of dithienyl derivatives of the general formula
    ABOUT

    10B-CH -y-ClT-Cll-f
    I.I I Rj Kj j
    where both thienyl residues can be substituted by one or more lower alkyls, bridge AB is a group
    ) with (OH) or
    the hydrogen atom of the B or CHg, -group may be replaced by lower alkyl;
    Ry and 2 are hydrogen or lower alkyl ;, 20 is hydrogen or hydroxy;
    R and Rf, are hydrogen, halogen, hydroxy, lower alkyl, lower halogenated alkyl, or lower alkoxy, which is combined with 25 g and g 1 magnesium halide with the corresponding ketone.
    The yield of the target products does not exceed 8% l.
    The disadvantage of this method is the low yield of the target product. In addition, a relatively limited amount of the desired products is obtained by this method. The aim of the invention is to increase the yield and expansion of the range of target products. A method for preparing dithienylalkylamines of formula I or salts is proposed, which consists in reacting thienyl lithium with a compound of general formula C-diig-AlK-jiail {C where Alk has the above values Z - chlorine, bromine, yodo lower alkoxy or thiyl group Na1 is chlorine, bromine or yots, in a mixture of solvents consisting of a saturated ether and a saturated hydrocarbon, and / or mono- or di-C -C4 alkylbenzene, at a temperature of (-50) - (- 80) and the compound of the general formula bN obtained with this formula, where Alk has the above values X - chl p, bromine or iodine are treated with an amine of the general formula (s where Y and the -NHY group have the above meanings, followed by isolation of the target product and, if necessary, dehydration of the latter to the target compound of the general formula T, where together they mean the group isolation of the target product in free form or in the form of a salt, using acids such as salt on maleic, etc. The yield of the target product is 15-90.4%. A distinctive feature of the method: is that the compound of formula M is reacted with thienyl lithium after processing the compound of the formula lT thus obtained (an amine of the formula | y. Example 1. 1,1-Dithienyl (3 -1-hydroxypropyl- (3) -1-hydroxy 1 (p-hydroxyphenyl) propyl- (2) -amine. 25 g (0.15 mol) p-oxy-nor -ephedrine, 22 f 5 ml of triethylamine and 4 5 ,, 5 g (0.15 mol) of 1,1-dithienyl- (3) -3-bromylpropanol- (1) are heated in 80 ml of dioxane with stirring for 8 hours at 100 ° C. The mixture is then evaporated S substantially in a rotary evaporator, the residue is mixed with 150 ml of water and shaken three times each time with 100 ml of diethyl ether.The combined ether extracts are dried with magnesium sulfate. After a few hours, a slightly colored substance catches out. The rest is recrystallized from acetone. 15 g of a colorless crystalline substance are obtained, mp 174-175 C. To obtain the acid maleic acid salt, 5.0 g of the base is stirred up in 30 ml of ethyl acetate. After adding 1.5 g of maleic acid, a clear solution is obtained, which begin to mix with diethyl ether until a clearly discernable beginning opacity. After holding for 12 hours, the crystallized crystal is sucked off, washed with ethyl acetate and dried. Obtain 4.0 g of the acid maleic acid salt, so pl. 198-K) 9 ° C. Preparation of the starting material is 1,1-diethyl- (3) -3-bromopropanol- (1). In a four-necked flask with a volume of 1.5 liters, supplied with a dropping funnel, a drying tube, a stirrer, a thermometer and a tube for supplying nitrogen, it is cooled under a nitrogen atmosphere with 300 ml of absolute diisopropyl ether in a cooling bath using a mixture of methanol and solid carbon dioxide. During cooling, a solution of 335.2 ml of n-butyl lithium in hexane (0.55 mol) is added; at the same time the ether cooled down to -75-С. A solution of 81.5 g of 3-bromothiophene (0.5 mol) in 100 ml of absolute diisopropyl ether is then added dropwise over 90 minutes so that the temperature does not exceed. Thereafter, the reaction mixture was kept for 1 hour at (-70) - (- 75) ° C for further reaction. Next, a solution of 36.2 g of ethyl 6-bromopropionic acid ester (0.2 mol) in 60 ml of absolute diisopropyl ether is added dropwise over 90 minutes so that the temperature does not exceed -70 seconds. After that, the mixture is kept for 4 hours to further proceed the reaction. The cooling bath is then removed and the reaction mixture is dissolved in 160 ml of water. The temperature rises to. It is further stirred for a while until the temperature rises to O-C, after which the organic phase is separated, dried over magnesium sulfate, filtered and all light-boiling substances are distilled off in a vacuum, in a rotary evaporator. In the residue get a light oil. Yield 54 g (96%, calculated as bromopropionic acid ester). 1,1-dithienyl- (3) -4-bromobutanol- (1) and 1,1-dithienyl ... (3) 5-bromopentance) L- (1) are also obtained in the form of a light oil. Example 2, 1,1-Dithienyl- (3) -1-OXY - 4- (4-phenylpiperazino) -butane. A solution of 16.2 g (0.1 mol) of 4-phenylpiperazine, 14 ml of triethylamine and 1.7 ptO, mol) 1,1-dithienyl (3) -1-hydroxy-4-bromobutane in BO ml of diisopropyl ether is left stand for 3 days at room temperature. The crystalline product is sucked off, washed with ether, dried, vzmuchivayut in water, sucked off, washed and dried. Crude yield 24.4 g (61.3%) i.
    8 g (0.02 mol) of the crude base is dissolved in 50 ml of acetone. After adding an acetone solution containing 2.32 g (0.02 mol) of maleic acid, warm and filter the ether until the beginning turbidity is added. After a short time, a substance crystallizes.
    sucked off, washed with a mixture of acetone ester (1: 1) and dried. Yield 8.3 g (81%), m.p. maleate 110-111 s.
    Example 3. 1,1-Dithienyl- (3) -1-OXY-4- 4- (3-methoxyphenyl) -piperazino-butane.
    This compound is prepared analogously to example 2, using 0.1 mol of 4- (3-methoxyphenyl) -piperaein. The melting point of maleate is 149-150 ° C, yield 94%.
    Example 4. Preparation of other 1,1-dithienyl- (3) -1-hydroxypropyl- (3) -amines of the formula T (the values of -NHY are listed in Table 1)
    Table 1
    Also
    Ethanol ether
    140-141
    51.0
    186-187
    45.0 Methanol ether 130-131 39.9
    The compounds listed in Table 1 were prepared according to the following procedure.
    0.1 mol of 1,1-dithienyl- (3) -3-bromopropanol- (1), 0.11 mol of triethylamine and 0.1 mol of the primary or secondary amine (see column 2 of table 1) are heated in 60 ml of diisopropyl ether for about 12-13 hours with stirring and the action of the reverse refrigerator. After cooling, the crystals are filtered off with suction, washed with diisopropyl ether and dried. Then vzmuchivayut in water, sucked off, washed with water, dried, recrystallized and get, as indicated in example 1, in this case, the salt of maleic acid.
    Example 5. 1,1-Dithienyl- (3) -l-propylene- (3) -1-OXY-1- (p-hydroxyphenyl) propyl- (2) -amin.
    23 g (0.15 mol) of p-hydroxy-nor-ephedrine, 22/5 ml of triethylamine and 45.5 g (0.15 mol) of 1,1-dithienyl (3) -3-bromobropanol- (1) are heated in 80 ml of dioxane with stirring for 8 hours at 100 ° C. Then the mixture is largely evaporated in a rotary evaporator and the syrupy residue
    twice treated with portions of 250 ml of diethyl ether. The combined ethereal solutions are acidified with an isopropanol solution of hydrogen chloride and a highly viscous product precipitates out. After draining the solvent, the residue is taken up in 100 ml of standard, heated for 10 minutes at boiling and refluxing, then the solution is concentrated in a rotary evaporator. The residue is dissolved in 100 ml of warm acetone, and after
    CH.2NSE Methanol
    СН 2НСе Same
    CH 2Hse IsopropanolT J
    CH 2NSR Methanol NIL-Cil CH NN NCSO OSS of CHj her N11-He, (CH) 2 her
    OSI:
    (CH ,,) 2CE Methanol-ether 212-213
    (CHj) j 2NSE Methanol
    CH ::
    I / g-
    CH-CH-f V
    (CH) NSR Same
    - he I /
    he
    cooling is slowly crystallized substance. After recrystallization from isopropanol, the compound is obtained as the hydrochloride salt as colorless crystals.
    Yield 10.2 g; m.p. hydrochloride 138-140 ° C.
    Example 6. Preparation of 1,1-dithienyl- (3) -alkene- (1) -lamines of formula I (for the meaning of -NHY and Alk, see Table 2).
    table 2
    90.4
    244-245
    220 (decomp.) 63.0
    160-161
    65
    -ether
    194-195
    42
    56
    72
    thirty
    216-217
    49 (different)
    68
    210-211 Isopropanol-142-143 ester Methanol ester 137-138 Acetone ester 155-156
    Continuation of table 2
    权利要求:
    Claims (1)
    [1]
    Claim
    A method of producing dithienylalkylamines of the general formula where or where
    A and B 'together are a group; C (OH) -CH „or> C = CH ~;
    - unbranched or branched C ^ -Cg-alkyl, '- unbranched or branched C.J-Cg-alkyl group of the general formula
    - bj (W) (fl) λ
    R is hydrogen or (C-Cd-alkyl;
    R 1 is hydrogen or C2 “C ^ acyl g or the group —NHY means groups of the general formula
    Order 3989/56 where R 2 is phenyl or benzyl or their salts unsubstituted or substituted by one, two or three methoxy groups, characterized in that, in order to increase the yield and expand the range of target products, the corresponding thienyl lithium is reacted with a compound of the general formula
    ABOUT.
    (C) g
    where Aik has the above meanings; Z is chlorine, bromine, iodine, lower alkoxy or thienyl group,
    On the! - chlorine, bromine or iodine, in a mixture of solvents consisting of simple saturated ether and nasy. (valuable hydrocarbon and / or mono- or di-C „-C4 -alkylbenzene, at a temperature of '(-50) - (-80) ° C and the resulting compound of the general formula
    W / Hg-ASK-K where Aik has the above meanings; X is chlorine, bromine or iodine, treated with an amine of the formula
    HNHY ; where Y and the group-NHY have the above meanings, followed by isolation of the target product and, if necessary, dehydration of the latter to the target compound of the general formula Ϊ, where A and B together mean a group> C = CH-, and isolation of the target product in free form or in in the form of salt.
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    引用文献:
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    US3086021A|1957-09-20|1963-04-16|Lakeside Lab Inc|Tertiaryamino butynyl alcohols|
    US3002946A|1957-11-25|1961-10-03|Dow Corning|Coating composition of polysiloxane resin and two polysiloxane fluids|
    FR387M|1960-03-04|Rech S Mauvernay Lab De|New parasympatholytic and antispasmodic drug.|
    DE1219038B|1962-12-08|1966-06-16|Degussa|Process for the preparation of thiophene compounds|
    BE638151A|1963-08-30|
    FR1462206A|1965-06-08|1966-04-15|Innothera Lab Sa|Gem-bithienyl compounds and their preparation|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB1121/77A|GB1597591A|1977-01-12|1977-01-12|Dithienyl alkylamines and alkenylamines and a process for their production|
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