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    • 专利摘要:
    The invention relates to the field of prostaglandias, in particular to the preparation of carbacyclin derivatives of the formula 1 "p :; CH-CH2-0-CH2.-COOH. A-W-D-E-PI where R is methyl; R hydroxy group; A - CH CH group; W is a hydroxymethylene group; D - СНВ-СН -group; B - lower apkyl, E - SnS-group, possessing hypotensive, as well as inhibitory platelet aggregation activity. The goal is to develop a method for obtaining new more active compounds. Obtaining the desired products is carried out by esterification of a compound of formula I, where instead of the group, -CHj-0-CHg-COOH is present, and RI, A, W, D, and E have the indicated values, and the free hydroxy groups are protected as tetrahydropyrannloxy groups. The process is carried out in the presence of a base with a chloroacetic acid derivative of the formula Cl-CH -COORj, where Rj is an alkali metal cation, followed by conversion of the protected OH groups to free and isolation of the desired products. i 0 05
    公开号:SU1367856A3
    申请号:SU813363101
    申请日:1981-12-10
    公开日:1988-01-15
    发明作者:Скубалла Вернер；Радюхель Бернд；Шварц Норберт；Форбрюгген Хельмут；Казальс-Штенцель Хорхе；Шиллингер Эккехард；Гарольд Таун Михаель
    申请人:Шеринг Аг (Фирма)；
    IPC主号:
    专利说明:

    sd
    O5
    one
    This invention relates to the preparation of novel carbatiklin derivatives of the general formula
    SN - Soon
    I.
    about
    I SNO
    1 day
    l
    WITH-.
    R.
    A-W-D-E-PI
    one
    where r r
    A w d
    methyl group;
    hydroxy group;
     - rpjmna;
    hydroxymethylene group;
    CHB — CHj — group, where B is lower alkyl; E - -C C-group,
    possessing improved pharmacological and antihypertensive properties as well as inhibiting platelet aggregation in comparison with natural ones. prostaglandins r da E.
    The purpose of the invention is to obtain new prostaglandin derivatives that have pharmacologically superior advantages over natural prostaglandins.
    678562
    in a vacuum. After chromatography of the obtained residue on silica gel, the eluting agent is a mixture of ethyl alcohol.
    g of ester of acetic acid and isopropyl alcohol 8: 2).
    290 mg of 11.15 bis-tetra- are obtained. (5E) - (16RS) - 16-methyl-3-oxa-18,18,19,1 9-tetra 10 hydro-6a-carbaprostaglandin-12. For cleavage of the protecting groups, 290 mg of bis-tetrahydropyranyl ether are stirred for 16 hours at room temperature with 28 ml of the mixture, made from α-acetic acid, water and tetrahydrofuran (65:35:10), and immediately thereafter the mixture is evaporated in a vacuo I, The residue is chromatographed on silica gel (eluent: 99: 1 mixture of ethyl ester of acetic acid and acetic acid). 105 mg of the title compound are obtained as a colorless oily substance.
    The starting material used in dp synthesis of the target compound for Example 1 was prepared as follows.
    1a 2-f (E) - (lS, 5S, 6R, 7R) -7- (TeT30 rahydropyran-2-yloxy) -6- (E) - (3S, 4RS) -4-methyl-3- (tetrahydropyran-2 - yloxy) -oct-1-en-6-ynyl-bicyclo (3.3.0) octane-3-Iliden-ethanol-1. To solution 4, and g of triethyl ether 20
    25
    AND
    RiMer 1. (5E) - (16RS) of PA of phosphonooacetic acid in 80 ml
    Tyl-3-oxa-18,18,19,1 9-tetradehyde-6a-carbaprostaglandin-12.
    To a solution of 530 mg of 2- f (E) - (lS, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- I (E) - (3S, 4RS) -4-methyl- H- (tetrahydropyran-2-yloxy) -oct-1-an-6-ynyl-bicyclo (3.3.0) octan-3-ylidene-ethanol- in 3 ml of tetrahydrofuran is added, at 10 ° С 0.77 ml of a 1.52 M solution of butyl lithium in hexane, the mixture is stirred for 5 minutes, then mixed with 3 liters of dimethylformamide and 4 ml of dimethyl sulfoxide, after which 225 mg of lithium salt of acetic acid is added to the mixture. The reaction mixture is stirred for 24 hours at room temperature, poured over ice-water, acidified with I0% citric acid solution, extracted with diethyl ether, the organic solution is washed once with saturated sodium chloride solution, and dried. over magnesium sulphate and evaporated
    1.73 g of potassium t-butoxide was added to the tetrahydrofuran; the mixture was stirred in a. within 10 minutes, mixed with a solution of 4.45 g (1R, 5S, 6R,
    40 7K) -7- (tetrahydropyran-2-yloxy) -6- (E) - (3S, 4RS) -4-methyl-3- (tetrahydro pyran-2-yloxy) -oct-1-en-b-ynyl } -bi cyclo (Z.Z.O.) octanone-Z in 45 ml of luol and then the mixture is stirred in
    45 for 20 h at room temperature. Immediately thereafter, the mixture is diluted with 600 ml of diethyl ether, extracted once with water and once with 20%
    50 with sodium hydroxide solution, the organic solution is washed with water until neutral reaction with industrial water, dried over magnesium sulphate and evaporated in vacuo. The remainder solution u
    55 in a mixture of hexane and diethyl ether (3: 2) and the solution is filtered through a force. kagel. The result is 3.7 g. unsaturated; ester as a colorless oily substance
    1.73 g of potassium t-butoxide was added to the tetrahydrofuran; the mixture was stirred in. within 10 minutes, mixed with a solution of 4.45 g (1R, 5S, 6R,
    40 7K) -7- (tetrahydropyran-2-yloxy) -6- (E) - (3S, 4RS) -4-methyl-3- (tetrahydropyran-2-yloxy) -oct-1-en-b- ynil} bicyclic (Z.Z.O) octanone-Z in 45 ml of toluene and then the mixture is stirred in
    45 for 20 h at room temperature. Immediately thereafter, the mixture is diluted with 600 ml of diethyl ether, extracted once with water and once with 20%
    50 with sodium hydroxide solution; organic solution is washed with water until neutral reaction with industrial water, dried over magnesium sulphate and evaporated in vacuo. The residue is dissolved
    55 in a mixture of hexane and diethyl ether (3: 2) and the solution is filtered through a silica gel. The result is 3.7 g., 1) ester ester as a colorless oily substance.
    they are sequentially extracted with a 5% solution of sulfuric acid, water, a 5% solution of sodium hydrogencarbonate, rinsed with water until neutral reaction with industrial water, dried over magnesium sulfate, and evaporated in vacuo. The residue obtained is crystallized from a mixture of hexane and diethyl ether. 80 g of tosylate (m.p.43 ° C) are obtained. To the suspension, 8.7 g of sodium hydride (55% suspension in oil) are added 34 g of methyl ether and the mixture is heated at reflux temperature for A h. After that, directly to the mixture, 35 g of 1-tooyloxy-Zyentin and 130 ml of DME are added to the mixture at room temperature, followed by a 20 ° compound (yield: 5.3 g).
    The mixture is heated at reflux temperature for 8 hours. Then the mixture is neutralized with acetic acid, mixed with 130 ml of water, extracted with diethyl ether, washed three times with organic solution with water, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by distillation in vacuo at 12 mm Hg. At 150-156 ° C, 24 g of alkylated methylmalonic ester is distilled, which is heated in 160 ml of dimethyl sulfoxide and 1.5 ml of water for 6 hours with 7.5 g of lithium chloride at the boiling point of the reaction mixture under reflux. Immediately after this, the reaction mixture is poured into 400 g of water with ice, extracted with diethyl ether, the organic solution is washed twice with water, dried over magnesium sulphate and evaporated in vacuo. After distillation of the residue at 92 ° C and 12 mm Hg. 14 g of ethyl ester of 2-methylheptic acid-5 are obtained as a colorless liquid.
    To a solution of 18.6 dimethyl methanephosphonic acid in 280 ml of tetrahydrofuran is added dropwise at -70 ° C with 73 ml of a 1.7 M solution of butyl lithium in hexane. The mixture is stirred for 15 minutes and then a solution of 10.5 g of 2-methyl-peptonic acid 5-ethyl ester in 48 ml of tetrahydrofuran is slowly added to it. The reaction mass is stirred for 4 h at -7 0 ° C,
    35
    IR spectrum, cm-: 3600, 3410 2940, 1712, 1602, 1588, 1277, 948.
    5c. (1K, 58.6K, 7K) -7- (Tetrag 25 pyran-2-yloxy) -6 t (E) - (3S, 4RS (tetrahydropyran-2-sh1oxy) -4-m non-1-en7-ynil -bicyclo (3.3 tanon-e J.
    By analogy with that described in p. 30 ЗЬ from 5.3 g o / -alcohol obtained according to Example 5b, 5.4 g of bis-tetrahydropyranyl ether in the form of oily ve
    IR spectrum, cm-: 2963, 2866 968.
    5 d. 2- (E) - (lS, 5S, 6R, 7R) -7 rahydropyran-2-yloxy) -6- (E) 4K8) -4-methyl-3- (tetpagidropyr Sh1oxy) -non-1-en-7 α-vinyl bicyc 40 (3.3.0) octan-3-ylidene-ethanol By analogy with example 1a and ketone, obtained in accordance with example 5c, after separating the measures using chromatography, 1.4 g 2 - {( Z) - (IS, 5S, 6R, 7R) -7hydropyran-2-yloxn) -6- (E) - (3 4-methyl-3 - (tetrahydropyran-2-and non-1-en-7-ynyl -bicyclo (3.3 tang-3-ylidene-ethanol-1 and 2.9 left compound as a colorless oily substance.
    IR spectrum, cm-: 2610, 3400 2862, 1600, 970.. ,
    EXAMPLE 6 (5Z) - (16RS) Dimethyl-3-oxa-19, 19,20,20-tet hydro-ba-carbaprostaglandin By analogy with that described in paragraph 1 of 810 mg of allyl alcohol
    45
    50
    55
    -
    13678568 neutralized with acetic acid and evaporated in vacuo. After distillation of the residue in vacuum at 0.6 mm Hg.
    and 130 ° C gives 10.8 g of the title compound as a colorless liquid.
    5 b (1К, 55, бК, 7К) -3,3-Ethylenedioc-1 Si-7-benzoyloxy-6- (E) - (35.4К8) -3-hydroxy-4-methylnon-1-ene-7-ynyl bicyc
    Lo-SZ.3.0) octane.
    By analogy with the example described in Example Of 12.2 g (1К, 5В, бК, 7Ю-3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo (3.3.0) -octane and 11.9 g the phosphonate obtained in accordance with Example 5a gives 14.5 g of an unsaturated ketone, which is converted into target 5 by reduction using 8.2 g of sodium borohydride
    IR spectrum, cm-: 3600, 3410, 2940, 1712, 1602, 1588, 1277, 970, 948.
    5c. (1K, 58.6K, 7K) -7- (Tetrahydro-5 pyran-2-yloxy) -6 t (E) - (3S, 4RS) -3- (tetrahydropyran-2-sh1oxy) -4-methyl-non -1-en7-inyl-bicyclo (3.3.0) octanone-e J.
    By analogy with that described in example 0, Zb from 5.3 g o / -alcohol obtained in accordance with example 5b, 5.4 g of bis-tetrahydropyranyl ether are obtained in the form of an oily substance.
    IR spectrum, cm-: 2963, 2866, 1737, 968.
    5 d. 2- (E) - (lS, 5S, 6R, 7R) -7- (TeT- rahydropyran-2-yloxy) -6- (E) (3S, 4K8) -4-methyl-3- (tetpagidropyran-2- N-1-non-1-en-7-ynyl-bicyclo 0 (3.3.0) octane-3-ylidene-ethanol 1.
    By analogy with example 1a, from 5.3 g of ketone obtained in accordance with example 5c, after separation of the isomers by chromatography, 1.4 g of 2 - {(Z) - (IS, 5S, 6R, 7R) is obtained as a nonpolar compound ) -7 (TeTpa-hydropyran-2-yloxn) -6- (E) - (3S, 4RS) - 4-methyl-3 - (tetrahydropyran-2-yloxy) - non-1-en-7-ynyl - bicyclo (3.3.0) octan-3-ylidene-ethanol-1 and 2.9 g of the title compound as a colorless oily substance.
    IR spectrum, cm-: 2610, 3400, 2940, 2862, 1600, 970.. ,
    EXAMPLE 6 (5Z) - (16RS) 16,20- Dimethyl-3-oxa-19,19,20,20-tetradehydro-ba-carbaprostaglandin.
    By analogy with that described in example 1 of 810 mg of allyl alcohol, polu5
    0
    five
    In accordance with Example 5d and in its Z-configuration, 180 mg of the title compound are obtained as a colorless oily substance. ,
    IK-SP KTR ,. : 3430 (broad), 2030, 1721, 1600, 1425, 968.
    PRI me R 7. (5E) - (15RS) -15-Methyl 3-oxa-18,18,19,19-tetradehydro-carbaprostaglandin-lj,
     By analogy with that described in example 1 of 0.45 g 2 - {(E) - (lS, 5S, 6R, 7R) -7- (tetrahydrocyran-2-yloxy) -b-f (E) - (ЗК8) - 3-metsh-3- (tetrahydropyran-2-yloxy) -oct-1-ene-6-ynyl-bicyclo- (3.3.0) octan-3-ylidene-ethanol-1 and 210 mg of the lithium salt of chloroacetic acid get 270 mg 11,15-byb-tetrahydropyranyl ether (5E) - (15K5) -15-methyl-3-oxa-18,18-, 19,19-tetradehydro on-ba-carbaprostaglandin-i. After cleavage of the protecting groups, 108 mg of the title compound are obtained as a colorless oily substance.
    IR spectrum, cm-: 3410 (wide), 2945, 1720, 1600, 968.
    The starting material used for the synthesis of the target compound, according to Example 7, is obtained by the following method.
    7a. 2 - (E) - (lS, 5S, 6R, 7R) -7- (TeT- rahydropkran-2-yloxy) -6- (E) - (3RS) - 3-methyl-3- (tetrahydropyran-2- sh1oxy) ect-1-en - 6-inn-bicyclo (3.3,0) octane-3-shn-schen-ethanol-.
    According to the procedure described in Example 1a, from 1.7 g (1R, 5S, 6R, 7R) -7- (TeTPa-hydropyran-2-yloxy) -6- (E) - (3RS) -3- myoyl-3 - (Te trad ideropyran-2-yloxy) - oct-1-en 6-ynyl-benzloss (3.3.0) -ox-tanone-3 after separation of the isomers with the aid of an exciter. chromatography is obtained as a foreign compound 320 mg 2 - {(Z) - (: 1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- (E) - (3RS) -3 -methyl 3- (tetra idropyran-2-yloxy) -oct-1-en-6-ynyl-bicyclo (3.3.0) octane-3-ylidene-ethanol-1 and 950 mg of the target; the compounds are in the form of a colorless oil;
    IR spectrum, cm-: 3600, 3400, 2945 2865, 1600, 970.
    PRI me R 8. (5E) -3-Oxa-18,18, 19,19-tetrahydro-6a-carbaprostaglan-,.
    By analogy with that described in example 1 of 0.92 g 2 - {(E) - (lS, 5S, 6R, 7R) -7
    0
    five
    (tetrahydropyran-2-yloxy) -6-G (E) -3- (tetrahydropyran-2-yloxy) -oct-1-en-6-ynil-1-bicyclo (3.3.0) -octan-3-ylden) - methanol-1 and 430 mg of the lithium chloroacetic acid salt, 51 Omg of 11,15-bis-tetrahydropyranyl ether (5E) -3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandi-: - on -C. As a result of the subsequent cleavage of the protecting groups, 245 mg of the title compound are obtained as a colorless oily substance.
    IR spectrum, CM: 3400 (wide), 5 2225, 1722, 1600, 972.
    The starting material used to synthesize the target compound is prepared by the following method.
    8a. 2 {(F,) - (lS, 5S, 6R, 7R) -7- (TeTpa-hydropyran-2-yloxy) -6- (E) -3- (tetrahydropyran-2-yloxy) -oct-1-en -6- ynyl-bicyclo (Z.Z.O.) -octane-3-ylden} -ethanol-1.
    By analogy with that described in example 1a from 3.35 g of (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-Sh10k si) -6- (E) -3-tetrahydropyran-2-yloxy) - oct-1-ene-6-ynylbicyclo (3.3.0) octanone-3 after separation of the isomers with chromate. 0 graphs are obtained as a non-polar compound 820 mg (Z) - (1 S, 5S, 6R, 7R) -, 7- (tetrahydropyran-2-yloxy) -6- (E) - 3- (tetrahydropyran-2-yloxy) -oct-1-en-6-ynyl-bicyclo- (3.3.0) octane-3-ylidene-ethanol- and 1.9 g of the title compound as a colorless oily substance.
    IR spectrum, cm-: 3600, 3405, 2943, 2865, 1600, 968.
    PRI me R 9. (5E) - (16RS) -16 ..19. Dimethyl-3-oxa-18,19-didehydro-6a carbaprostaglandin-1,
    By analogy with that described in example 1 of 0.97 g of 2-t (E) - (lS, 5S, 6R, 7R) -7-, 5 (tetrahydropyran-2-yloxy) -6- (1E) - (3 S , 4RS) -4,7-dimethyl-3- (tetrahydropyran-2-yloxy) -oct-1, 6-dienyl-bicyclic (3.3.0) octane-3-ylidene-1-ethano-la- and 450 mg of lithium salts to chloroxy hydrochloric acid get 490 mg of 11,15-bis-tetrahydropyranyl zfir (5E) - (16RS) -16,19-dimethyl-3-oxa-18,19-didehydro-6a-carbaprostaglan-. As a result of the subsequent cleavage of the protecting groups, 160 mg of the title compound is obtained as an oily substance.
    IR, 3410 (wide), 2925, 1720, 1600, 965,
    five
    0
    0
    five
    3
    ShS-spectrum, cm-: 2945, 2870, 1700, 1655, 970.
    .1.2 g lithium aluminum hydride is added in portions at 0 ° C to a stirred solution of 3.9 g of the ester obtained as described above in 130 ml of diethyl ether followed by stirring the mixture for 30 minutes at 0 ° s The excess reagent is disrupted by adding dropwise ethyl acetate and then bml of water is added, the mixture is stirred for 2 hours at, filtered and evaporated in vacuo. The residue is chromatographed on silica gel (eluent-mixture of diethyl ether and hexane 3: 2).
    1.05 g of 2-f (Z) - (1S, 5S, 6R, 7R) - 7- (tetrahydropyran-2-yloxy) -6- t (E) is obtained as a non-polar compound; (3S, 4R, S) -4-methyl-3- (tetrahydropyran 2-yloxy) -oct-1-ene-6-ynyl j-bicyclo (3., 3.0) octan-3-ylidene-3-ethanol and 2.2 g of the target compound in the form of a colorless oily substance.
    IR spectrum, cm-: 3605, 3450, 2940 2865, 1600, 970.
    EXAMPLE 2. (5Z) - (16RS) -16-Methyl-3-oxa-18, 1 8,19,19-tetradehydrob-c-arbaprostaglandin-12 ..
    By analogy with the description in Example 1, out of 490 mg of all-alcohol, prepared in accordance with the procedure described in Example 1a and having the g-configuration, 85 mg of the target compound are obtained as a colorless oily substance.
     IR spectrum (СНС1з). : 3340 (broad), 2920, 1722, 1600, 1420, 966.
    P i m i r 3. (5E) - (16RS) -16,20-Dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carbaprostaglandin-1,2.
    By analogy with that described in example I of 0.5 g of 2-i (E) - (lS, 5S, 6R, 7R) -7- (tetrahydropnran-2-yloxy) -6 (E) - (ЗS54RS) -4- Methyl-3- (tetragamide-2-yloxy) -Hen-1-6-ynyl-J-Bits Iklo (3.3.0) octane-3-ylidene-ethanol-1 and 220 mg of lithium chloroacetic acid 260 mg 11, 15-bis-tetrahydropyranyl ether (5E) - (16RS) -16,20 Dimethyl-3-oca-18,18, 19,19-tetrahydro-6a-carbaprostaglandin-lj. After cleavage of the protecting groups, 90 mg of the title compound are obtained as a colorless oily substance.
    67856,
    IR spectrum, cm-: 3400 (wide), 2920, 172, 1600, 1420, 966.
    The starting material used for synthesizing the title compound of Example 3 was prepared as follows; in a way.
    Behind. (1R, 5S, 6R, 7R) -3,3-z tylenediox-7-benzoyloxy-b - f (E) - (3S, 4RS) -3-10 oxy-4-methylene-1-en-6 vinyl bicyclo (3.3.0) octane.
    To a suspension of 1.46 g of sodium hydride (55% in oil) in 130 ml
    15 dimethoxyethane (DME) is added dropwise a solution of 9.02 g of 3-methyl-2-oxo-oct-5-ynylphosphonic acid dimethyl ester in 67 ml of DME, after which the reaction mixture is stirred
    20 sew for 1 h at. Immediately after this, when mixing with a solution of 9.4 g (1R, 5 S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo- (3.3.0) -
    25 octane in 130 ml of DME, the reaction mixture is stirred for 1.5 hours at -20 ° C, after which it is poured into 600 ml of a saturated solution of ammonium chloride and extracted with diethyl ether three times. Or- The solution is washed with water until neutral reaction with industrial water, dried over magnesium sulphate and evaporated in vacuo. After chromatography
    35 fin. Residue on silica gel (eluent: 1: 1 mixture of diethyl ether and hexane) 9.1 g, / 5-unsaturated ketone as an oily substance are obtained.
    40 / V.
    To a solution of 9.1 g of ketone in 300 ml of methyl alcohol at -40 ° C, 5.2 g of sodium borohydride are added in portions, after which the reaction mixture is stirred; stay at 1 hour at. Immediately after this, the mixture is diluted with diethyl ether, washed with water until neutral reaction with washed water, dried with organic matter.
    The 50 solution is over magnesium sulfate and evaporated in vacuo. As a result of chromatography on a column filled with silica gel (eluent is a mixture of diethyl ether and hexane
    55 7; 3) first get 3.9 g of the target compound (PG-nomenclature: 1 5c / -oxy), and also 3.2 g of an isomeric 15 L-hydroxy compound as a polar component.
    IR spectrum, cm; 3600, 3400 (broad), 2942, 1711, 1603, 1588, 127.6. 968, 947.
    Sc (III, 58.6K, (Tetrahydropyran-2-yloxy) -6-G (E) - (3S, 4RS) -3- (tetragi cycran-2-yloxy) -4-methyl non-1-en 6 -bin-bicyclo. (3.3.0) ok-such-3.
    The mixture, consisting of 3.6 g of o1-alcohol prepared as described in Example A and 1.4 g of potassium carbonate in 120 ml of methyl alcohol, is stirred for 16 hours at room temperature under argon atmosphere. Directly thereafter, the mixture is evaporated in vacuo, the residue is diluted with ether, the solution is washed with a saturated solution of sodium chloride. Then the solution of supta over magnesium sulfate and evaporated in vacuo. Semi: after evaporation, the residue is stirred at room temperature for 75 hours with 75 ml of a mixture consisting of - aqueous acetic acid and tetrahydrofuran (65:35:10), and immediately after that, a vacuum is produced. After filtering the residue over silica gel (eluant is a mixture of ethyl acetic acid ester and hexane 7; 3), 2.2 g of ketone are obtained as an oily substance.
    A solution consisting of 2.2 g of ketone, 2.4 ml of dihydropyran, 23 mg of para-toluenesulfonic acid and 75 ml of methylene chloride is stirred for 30 minutes at 0 ° C. Immediately thereafter, the mixture is diluted with diethyl ether, extracted with a dilute sodium carbonate solution, the organic solution is washed with water until neutral wash water, dried over magnesium sulfate and evaporated in vacuo. The result is 3.4 g of bis-tetrahydropyranyl ether, which is used without further purification.
    Zh-spectrum, cm-: 2960, 2865, ELV 970,
    3c. 2- (E) - (lS, 5S, 6R, 7R) -7- (TeT- rahydropi; ran-2-shyoxy) -6- (E) - (3 S, 4К8) -4-methyl-3- ( tetrahydropyran-2-yloxy) -non-1-en-6-ynyl-bicyclo (3.3.0) o: ctan-3-ylidene-ethanol-1.
    By analogy with that described in example 1a of 3.3 g of the ketone obtained in accordance with Example 3 after
    separation of isomers by chromatography is obtained as a non-polar compound 720 mg 2- (Z) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-sh1oxy) -6- G (E) - (3S, 4RS) -4-methyl-3- (tetrahydropyran-2-Sh1Oxy) -non-1-en-6-ynyl-bicyclic (3.3.0) octan-3-ylidene-ethanol and 1.6 g of deluxe compound in
    as a colorless oily substance.
    IR spectrum, 3600, 3430, 2942, 2863, 1600, 972.
    Example 4. (5Z) - (16RS) -I6.20 Dimethyl-3-oxa-18, 18,19,19-tetrade- p-schro-ba-carbaprbstaglandin-,.
    By analogy with that described in example 1 of 0.65 g of allyl alcohol obtained in accordance with example 3c
    With the Z configuration, 120 mg of the title compound is obtained as a colorless oily substance.
    IR spectrum, cm: 3320 (wide), 2925, 1720, 1600, 1420, 968.
    EXAMPLE 5. (5E) - (16RS) -16,20-Dimethyl-3-oca-I 9,19,20,20-tetrahydro-6a-carbaprostaglandin-I.
    By analogy with that described in example 1 of 0., 75 g 2 - {(E) - (lS, 5S, 6R, 7R) -7 (tetrahydropyran-2-yloxy) -6- (E) - (3 S 5 4RS ) -4-methyl-3- (tetrahydropyran-2-yloxy si) -non-1-en-7-ynyl-b icyclic (3.3c 0) octan-3-ylidene 1 -stanol-1 and 330 mg of lithium salt Chloroacetic
    acids receive 420 mg of 11 ,, 1-bis-tetrahydropyranyl ester (5E) - (16RS), 20-dimethyl-3-oxa-19,19, 20,20-tetradehydro-6a-carbaprostaglandin-1. After cleavage of the protecting groups, 180 mg of the title compound are obtained as a colorless oily substance.
    IR spectrum, cm: 3410 (wide), 2925, 1722, 1601, 1420, 965..
    The starting material used to synthesize the title compound of Example 5 is obtained by the following method.
    5a. 3-Methyl-2oxooct-8-ynylphosphoric acid dimethyl ester.
    To a solution of 40 g of 3-pentinol-1 in 240 ml of pyridine I09 g of p-toluenesulfonic acid chloride was added and the reaction mixture was stirred for 48 hours at 0 ° C. Immediately thereafter, 30 ml of water was added to the mixture, the mixture was stirred for 2 hours and then diluted with diethyl ether. After this mixture
    one
    The starting material used to synthesize the title compound of Example 9 is prepared by the following method.
    9a. (1К, 55, бК, 7К) -3,3-Ethylenedioxy-7-benzoyloxy-6- (IE) - (3S, 4Я8) -3-hydroxy-4,7-dimethyl-oct-1,6- dien.yl-bicyclo (3.3.0) octane.
    By analogy with the example described in Example From 6.5 g (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo (3.3.0) octane and 6 g dimethyl ether 2-ox-6-3,6-dimethyl-hept-5-ene-1-phosphonic acid gives 6.3 g of an unsaturated ketone, which is reduced by reduction with 4 g of sodium borohydride to the desired compound (yield 2.7 g).
    IR spectrum, cm-: 3600, 3420, 2945, 1713, 1ba2, 1587, 1278, 972, 948.
    9b. (1R, 5S, 6R, 7R) -7- (Tetragahidropopyran-2-yloxy) -6- (1E) - (3S, 4RS) - -4,7-dimethyl-3- (tetrahydropyran-2-sh1Oxy) oct-1,6-dienyl-bicyclo (3.3.0) octanone-3.
    By analogy with the example described in Example 3b, 2.6 g of the compound obtained in accordance with Example 9a yielded 2.6 g of the title compound as a colorless oily substance.
    IR spectrum, cm-: 2965, 2865, 1738, 965.
     9c. 2 i; (E) - (IS, 5S, 6R, 7R) -7 (TeT-rahydropyran-2-Sh10ksi) -is- (1E) - (3S, 4RS) -4,7-dimethyl-3- (tetrahydropium - ran-2-yloxy) oct-1,6-dienyl-bicyclo (3.3.0) octan-3-ylidene-ethanol-1
    By analogy with that described in example 1a, from 2.6 g of ketone obtained in accordance with example 9b, after separation of the isomers by chromatography, 0.65 g 2 (Z) - (lS, 5S, 6R) is obtained in the form of a non-polar compound, 7R) -7- (tetrahydropyran-2-yloxy) -6- (IE) - (3S, 4RS) -4,7-dimethyl-3- (tetrahydropyran-2-yloxy) -oct-1,6-dienyl bicyclo- (3.3.0) -octane-3-yl-d-ethanol-1 and 1.4 g of the title compound as a colorless oily substance.
    IR spectrum, cm-: 3600, 3400 (shchi), 2945, 2860, 1600, 968.
    Example 10, Methyl ester (5E) - (16RS) -16-methyl-3-oca-18.18, 19 $ 19-tetradehydro-6a-carbaprostaglandin-Ii,
    6785612
    A solution of 150 mg of the acid obtained in accordance with npimepOM I in 10 ml of methylene chloride is mixed dropwise at effluent; with a solution of diazomethane until that time. Until the solution becomes yellow, after the paci is arrested, the thief in vacuo is half aspirated: the filter is filtered through silica gel, using
    10 as a zerous agent, a mixture of methylene chloride and isopropyl alcohol (95: 5), resulting in 120 g of methyl ester as a colorless oily substance.
    Zh-spectrum, cm-: 3600, 3400, 2960, 1740, 1600, 972.
    Example 11. Carboxiamide (5E) - (16RS) -16-MeTmi-3-OKca-18,18,
    20 19,19-tetrahydro-K-methanesulfon-1-6a-carbaprostaglandin-1.
    A solution of 360 MG acid prepared in accordance with the example in 8 ml of dimethylformamide is mixed at
    25 ° C with 160 mg of isobutyl chloroformate and 120 mg of triethylamine. After 30 minutes, 480 mg of sodium methyl-, sulfonamide (prepared from methylsulphonamide and sodium methylate) and 2 ml of phosphoric acid hexamethyltriamide were added to the mixture, after which the reaction mixture was stirred for 3 hours at. Immediately after this reaction
    g mixture is poured into citrate buffer solution (pH 5), extraction is carried out several times with ethyl acetate and acetic acid; the organ is washed in phase with a saturated solution
    40 sodium chloride, dried over magnesium sulphate and ynapiiBawT in vacuum. As a result of chromatography of the residue on silica gel (eluent is a mixture of methylene chloride and isopropyl
    45 alcohol) 160 mg of the title compound are obtained as an oily substance.
    Zh-spectrum: 3600, 3400 (broad), 1730, 1600, 970.
    5Q Example12. (5E) -16,16-Dnmethyl-3-oxa-18,18,195 9-tetradehydro-6a-carbaprostaglandin-1.
    By analogy with example 1, from 800 mg of 2 - {(E) - (lS, 5S, 6R, 7R) -7- (Tegg trahydropyran-2-yloxy) -6- (E) - (3R) - 4.4- dimetsh-3- (tetrahydropyran-2-yl-oxy -) - oct-1-en-6-ynyl-bicyclo (3.3.0) octan-3-ylidene-ethane-ol and 352 mg lithium chloroacetate
    i313678561
    salts 450 mg of (5E) -16,16-dimethyl 3-ok-- and 346 mg of lithium chloroacetic acid get 431 mg (5E -) - 3 Oksa-18, 185195 9 tetradehydro-16,16,20-tris-18, 18 1 9-5 1 9 tetradehydro-6a-carba-. prostaglandin-1 -: 1 1, 15-bis- (tetrahydropyranyl ether). After cleavage of the protecting groups, 185 mg of the basic compound are obtained in the form of a colorless oil.
    Zh-spectrum, cm-: 3410 (wide), 2942, 1720, 1423, 974.Y.
    The starting material for the above basic compound is obtained by the following procedure.
    12a. (No. 58.6K ,, 3-Ethylenedioxy-7-be1Hzoyloxy b- (E) - (3R) -3-OK- .ig c-4,4-dr methyl-oct-1-en-b- inyl-b.i. cyclo (3.3.0) -octane.
    By analogy with the example of 9.4 tons
    methyl ba-carbaprostaglandin-1 „11,15 bis (tetrahydropyranyl ether). After cleavage of the protecting groups, 178 mg of the basic compound are obtained in the form of a colorless oil.
    IR, 3410 (wide), 2936, 1721, 1601, 1432, 1 1 o l, 970,
    For the above basic compound, the starting material is prepared as follows.
     13a. 353-Dimetsh1-2-oxo-oct-5-ynyl-phosphonate dimethyl ether.
    In a suspension of 7.1 g of sodium chloride (50% suspension in oil) in 220 ml of abs. tetrahydrofuran with
    In a suspension of 7.1 g of sodium chloride (50% suspension in oil) in 220 ml of abs. tetrahydrofuran with
    (1RS 5S, 6R 5 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo (Z.Z.O.) -ox- 20 ° C 24 ° C drop in a solution of 31.5 g
    of tan and 9.1 g of 353-dimethyl-2-oxo Oct-3-methyl-2-oxo-butylphosphonic acid
    5-inyl-phosphonate dnmetiether
    9.2 g of unsaturated ketone are obtained.
    When reconstituted with sodium borohydride, 3.7 g of the main compound is obtained.
    compound in the form of a colorless oil.
    Zh-spectrum, cm-: 3600, 3400, 2942, 1712, 1602, 1589, 972, 949.
    12 b. (1К555, бК, 7К) -7 (tetrahydrodimethyl ether in 74 ml abs.tetrahydro-, furan, stirred for 1.5 hours, after
    This is added 111 mg of a 1.6 M butyl-25 lithium solution in hexane at-0 ° C and stirred for 20 minutes. Immediately thereafter, the mixture is dropped in with a solution of 29 g.
    1-bromo-2-pentine in 44 ml of abs.tetra-pyran-2-yloxy) -6- (E) (LC) -4,4-dime-30 hydrofuran, stirred for 3-til (tetrahydropyran- 2-yloxy) -oct- 3 h at the same temperature, neutralized using 3 n. hydrochloric acid and concentrated in vacuo. The mixture is diluted with 50 ml of brine} three times ex-
    1-en-6-ynil-bcyclo (3.3.0) yoktan-3-one.
    By analogy with the example of ZB of 3.7 g
    The o / alcohol prepared according to Example 5 is tragedy with methylene chloride (200 ml each) 12a, to obtain 3.4 g of bis-tetrahydropyranyl ether as a colorless oil.
    Zh-spectrum, 2960, 2865, 1737, 970.
    12c. 2- (E) - (1S, 5S, 6R, 7R) -7- (Tet-rahydropyran-2-yloxy) -6-t (E) (3R) - 4,4-dimethyl-3- (tetrahydropyran-2 - yloxy) oct-1-en-6-ynyl-bi-diclo (3.3.0) octan-3-ylidene-ethan-1-ol.
    By analogy with Example 1a, from 1.1 g of ketone prepared according to Example I2b5, 1.1 g of the basic compound are obtained as a colorless oil.
    Zh-spectrum: 3610, 3440, 2942, 50 2865, 1600, 970.
    Example 13 (5E) -3-Oxa-18.185 19.1 9-tetradehydro-1 6, 16, 20-trimethyl-6a-carbaprostaglandin-1,
    The organic extract is shaken twice with 50 ml of brine (each time), dried with magnesium sulfate and evaporated in vacuo. After distillation of the residue 40 at 0.6 Torr, and 125 ° C, 23 g of the basic compound are obtained as a colorless oil.
    IR spectrum, cm-: ZOOO, 2962, 45 2860, 1720.
    13b. (lR, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoshe1 Oxy-6- (E) - (3R) -3-hydroxy-4,4-Dimethyl-non-1-en-6- ynil1-bicyclo (3.3.0) octane.
    A suspension of 0.7 g of sodium hydride (55% suspension in oil) in 60 ml of dimethoxyethane (, CME) is dropped into a solution of 4.5 g of the phosphonate obtained in Example 13a in 35 ml
    From 800 mg of 2 - {(E) - (lS, 5S, 6R, 7R) -7-55, DMEi is stirred for 1 hour at 0 ° C. The non- (tetrahydropyran-2-yloxy) -6- (E) - immediately after this is diluted with (ZR) 4,4-dimethyl-3- (tetrahydropyran-solution of 4.75 g (1R, 5S, 6R, 7R) - 2-yloxy) -non- -En-6-inyl-cyclic 3,3-ethylenedioxy-7-benzoyloxy-6-form- (3.3.0) octane-3-ylidene-ethane-1-ola mil-bicyclo ( 3.3.0) octane in 60 ml
    methyl ba-carbaprostaglandin-1 „11,15 bis (tetrahydropyranyl ether). After cleavage of the protecting groups, 178 mg of the basic compound are obtained in the form of a colorless oil.
    IR, 3410 (wide), 2936, 1721, 1601, 1432, 1 1 o l, 970,
    For the above basic compound, the starting material is prepared as follows.
     13a. 353-Dimetsh1-2-oxo-oct-5-ynyl-phosphonate dimethyl ether.
    In a suspension of 7.1 g of sodium chloride (50% suspension in oil) in 220 ml of abs. tetrahydrofuran with
    24 ° C drop in a solution of 31.5 g
    dimethylether in 74 ml abs.tetrahydro-, furan, 1.5 h stirred, after,
    This is added 111 mg of a 1.6 M butyl-25 lithium solution in hexane at-0 ° C and stirred for 20 minutes. Immediately thereafter, the mixture is dropped in with a solution of 29 g.
    tragedy methylene chloride (200 ml)
    The organic extract is shaken twice with 50 ml of brine (each time), dried with magnesium sulfate and evaporated in vacuo. After distillation of the residue at 0.6 Torr, and 125 ° C, 23 g of the basic compound are obtained as a colorless oil.
    IR spectrum, cm-: ZOOO, 2962, 2860, 1720.
    13b. (lR, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoshe1 Oxy-6- (E) - (3R) -3-hydroxy-4,4-Dimethyl-non-1-en-6- ynil1-bicyclo (3.3.0) octane.
    A suspension of 0.7 g of sodium hydride (55% suspension in oil) in 60 ml of dimethoxyethane (, CME) is dropped into a solution of 4.5 g of the phosphonate obtained in Example 13a in 35 ml
    15
    DME at -20 ° C, stirred for an hour at the same temperature, poured into a saturated solution of ammonium chloride and extracted with ether. The organic extract is washed with neutral water, dried with magnesium sulfate and evaporated in -vacuum. After chromatography of the residue on silica gel (eluant is a mixture of ether and hexane 6: 4), 4.7 g of unsaturated ketone are obtained in the form of an oil,
    IR spectrum, cm: 2940, 2860, 1715, 1670, 1627, 948.
    In a solution of 4.7 g of ketone in 150 ml of methanol at -40 ° C, 2.6 g of sodium borohydride are introduced in portions and stirred at the same temperature for 1 hour. After that, it is diluted with ether, washed with neutral water, dried with agni sulphate and evaporated into vacuum.
    After chromatography on silica gel columns (eluant: ether: hexane 7: 3), 1.8 g of the basic compound (PS nomenclature: si) are obtained, and the isomer 1 5/5-hydroxy is the compound in the form of 1.6 g of colorless oil.
    IR spectrum, cm-: 3610, 3410, 2943, 1712, 1603, 1588,.
    13c. (1K, 58, BK, 7K) -7- (Tetrahydropyran-2-sh10xy) -6- (E) - (WE) -4,4-diethyl-3- (tetrahydropyran-2-yloxonon -1-en-6-ynyl) -bicyclo (3.3.0) ok tan-3-one.
    A mixture of 1.8 g of the o-alcohol prepared in Example 13 and 0.7 g of potassium carbonate in 60 ml of methanol is stirred for 16 hours at a temperature of argon. Immediately thereafter, the mixture is concentrated in vacuo, diluted with ether and washed with neutral brine. Dry with magnesium sulfate and evaporate in vacuo. The residue from the mixture was stirred for 16 hours at room temperature with 40 ml of a mixture consisting of acetic acid, water and tetrahydrofuran (65:35:10), and then evaporated in vacuo. After filtration of the residue on silica gel in the presence of an acetic acid-hexane mixture (7: 3), 1.15 g of ketone are obtained in the form of an oil.
    A solution of 1.15 g of ketone, 1.2 ml of di-. hydropyran and 1 O mg of p-toluenesulfonic acid in 40 ml of methylene chloride are stirred for 30 minutes at. After that
    67856 °,
    it is diluted with ether, agitated with a dilute solution of sodium carbonate, washed with water, dried over
    from Fato magnesium and evaporated in vacuo, - 1.65 g of bis-tetra are obtained. psiropyranilater, which can be used without any subsequent cleaning.
    Zh-spectrum, cm-: 2962, 2865,
    10 1738, 972.
    13d. 2 {(R) - (lS, 5S, 6R, 7R) -7- (TeT- rahydropyran-2-yloxy) -6- (E) - (3R) - 4,4-dimetsh-3- (tetrahydropyran-2 - yloxy) -ion-1-en-6-ynyl-bicyclo
    15 (3.3.0) octane-3-ylidene-ethane-1-ol.
    To a solution of 2.1 g of phosphonoacetic acid triethylether in 40 ml of tetrahydrofuran is added at 0 ° CO, 9 g of potassium tert-butylate, stirred in
    20 for 10 minutes, dilute with a solution of 2.2 g of ketone, prepared in Example 13c, in 20 ml of toluene and stir for 20 hours at room temperature. Then 200 ml of ether are introduced, twice -; 25 shaken with water, then once with a 20% sodium hydroxide solution, washed with water, dried with magnesium sulfate and evaporated in vacuo. The precipitate is filtered in the presence of a mixture.
    30 hexane - ether (3: 2) through silica gel. In this way, 1.95 g of unsaturated ester is obtained in the form of a colorless oil. Zh-spectrum, cm: 2943., 2865,1700, 1655, 972.
    35 To a stirred solution consisting of 1.95 g of the obtained ether and 60 ml of ether, 0.6 g of lithium aluminum hydride is added in portions at and stirred for 30 minutes at the same temperature.
    40 re. Excess reagents are destroyed when the acetic acid ester is added. Then pour 3 ml of water, stir for 2 hours at, filter and evaporate in vacuo. Sediment pod45. Chromatography on silica gel is carried out; in the presence of an ether-hexane mixture (3: 2). As a result, 0.45 g of 2- (Z) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-250 yloxy) -6- (E) - (RR) -4.4 is obtained in the form of a non-polar compound. -dimethyl-3- (tetrahydropyran-2-shtoksi) -non-I-en-b-inst-bicyclo- (3.3 .0) octan-3-yl-de-d-ethan-1-ol and 0.7 g of the main compounds in the form of a colorless oil.
    55 IR spectrum, cm -: 3600, 3445, 2940, 2865, 1600, 972.
    Pharmacological action of the compound of example 1.
    171367856
    This compound in the inhibition of ag-platelet regga-tions was 5.16 times more effective than PGE. In addition, this compound has a high metabolic stability, 0.52 versus 120 in PGE, (due to prostaglandin and c ogenase).
    The toxicity of the target products is high.
    about with
    formula of invention
    The method of obtaining derivatives of acycline of the general formula
    SNO-COOH

    about
    BUT
    one.
    sn
    L
     /
    VA-W-D-E. 2
    RI
    where R is methyl;
    RJ is a hydroxy group;
    18
    A w d
    -CH CH-group;
    -oxymethylene group;
    -CHB-CH -group, where B is lower alkyl;
    E - uppa, similar to that of the general formula
    sng
    what
    l
    A-W-D-E-P,
    where R ,, R2, A, W, D and E have the indicated meanings, free oxy groups are protected as tetrahydropyranyloxy groups, esterified in the presence of a base with a chloroacetic acid derivative of the general formula
    C1 - CHi - COOR.3
    where RJ is an alkali metal cation, followed by translation protected. hydroxyl groups in the free and in the separation of the target products.
    权利要求:
    Claims (1)
    [1]
    Claim
    A method of obtaining derivatives of car ^ acycline of the general formula sn 2 -soon o
    , I sn 2
    I. th
    CH n
    γ AWDER,. * 2 where R 7 is methyl;
    Rj is an oxy group ;.
    - CH = CH group;
    - oxymethylene
    - START ~ -CH g-r group, shek alkyl;
    - -C = C ~ g r. Uppa, ichichivaya group; where B is a lower compound of the general formula
    CH 2 0H
    CH
    Δ in that “2 where R 7 , R 2 , A, W, D, and E have the indicated meanings
    C1 - CH g - COOR ; E where R 5 is an alkali metal cation, followed by the transfer of protected. hydroxyl groups in the free and isolation of the target products.
    类似技术:
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    同族专利:
    公开号 | 公开日
    ES508124A0|1982-11-01|
    US4708963A|1987-11-24|
    CS232719B2|1985-02-14|
    CS913881A2|1984-06-18|
    NO155537C|1987-04-15|
    EP0055208B1|1985-03-13|
    AT12094T|1985-03-15|
    DK169815B1|1995-03-06|
    GR77633B|1984-09-25|
    US4423067A|1983-12-27|
    FI813967L|1982-06-20|
    NO814357L|1982-06-21|
    DE3048906A1|1982-07-15|
    ES8300090A1|1982-11-01|
    NO155537B|1987-01-05|
    NZ199319A|1985-07-12|
    EP0055208A2|1982-06-30|
    HU187398B|1985-12-28|
    JPS6228937B2|1987-06-23|
    JPS57145833A|1982-09-09|
    AU7867681A|1982-06-24|
    AU548662B2|1986-01-02|
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    PH19419A|1986-04-10|
    YU293081A|1983-10-31|
    ZA818788B|1982-11-24|
    DE3169305D1|1985-04-18|
    FI71122B|1986-08-14|
    CA1223255A|1987-06-23|
    IL64577D0|1982-03-31|
    EP0055208A3|1982-08-25|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19803048906|DE3048906A1|1980-12-19|1980-12-19|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
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