Method of obtaining carbacycline derivatives or their physiologically acceptable salts

专利摘要:
The method of obtaining carbacyclin derivatives of the general formula (1) C, where one of R and RJ is independently from each other hydrogen or methyl; (L C EZ - C-Cd-alkyl; X is COOH or COOU-group, where Y is the cation of an organic base, or their physiologically acceptable salts, characterized in that the compound of the general formula (II) H / CH HCl-CH -C-CH2-C C-gEZ SL - 1 - o.gp OH where R ,, Rj and RJ have the indicated values, TGP is tetrahydropyranyl: the residue is reacted with a Wittyg reagent of formula (III) .0 s: ( CfH5) cP-CH- (Sig) cO 9 RI R2 and the obtained products are separated and isolated as epimers, the protective groups are cleaved and, if necessary, the dividing product, where X - COOH is converted into salt by the interaction Equip with a physiologically acceptable base.
公开号:SU1145926A3
申请号:SU833534779
申请日:1983-01-17
公开日:1985-03-15
发明作者:Скубалла Вернер；Радюхель Бернд；Форбрюгген Хельмут；Казальс-Стенцель Хорхе；Маннесманн Герда；Гарольд Таун Майкл
申请人:Шеринг Аг (Фирма)；
IPC主号:

专利说明:

The invention relates to the method of obtaining new prostaglandin-class derivatives, namely, carbacyclin arginate, general form (I) C W C – CH 2 –C From where R and RJ are independently hydrogen or methyl R, Cy – Cj alkyl, X COOH or COOU group, where Y is a cation of an organic base with valuable pharmacological properties. Known carbaccle derivatives of the general formula COOR (CH2) are known.
X
A-W-D-E-E.
R
en
svg-en-s-
where R jRj and Rj have the indicated values,
THREE tetrahydropyranyl residue j is reacted with a Wittig reagent of formula
.0
(SbN5) zr Sh - (CH2) 5-С

about 6
The goal is achieved according to method j based on the known Bittig C2 reactivity, and the fact that the compound of the general formula
R R, release
and the resulting products are separated and isolated as epimers, split off
protective groups and, if necessary, the target product, where X is COOH, are salified by reacting with a physiologically acceptable base,
The reaction of a compound of general formula (II) with a Wittig reagent of formula (ill) 5 which is obtained from the corresponding phosphonium salt with a mega R is hydrogen, alkyl, cycloalkyl, aryl or a heterocyclic residue, A is the CH —CH — trans-CH — CH group, W— a free or functionally modified hydroxymethyl group, or a free or functionally modified-C ;; Vpynna, the OH group is in the "i - position, D and E-together represent a straight or branched saturated or unsaturated alkylene group with 1-10 carbon atoms, optionally substituted by a fluorine atom, E-oxygen atom or -C Link or direct bond, R-alkyl, dicloalkyl or, if appropriate, substituted aryl or heterocyclic residue, R-free or functionally modified hydroxyl group, with properties to reduce peripheral arterial and coronary pressure, inhibition of thrombosis to reduce systemic blood pressure til the purpose of the invention is to obtain new carbacyclin derivatives that have advantages in properties over their closest structural analogues.
3
tansulfinylmethyl sodium or methanesulfinylmethyl potassium or potassium t-butyl in dimethyl sulfoxide or a mixture of dimethyl sulfoxide and tetrahydrofuran, carried out at a temperature from 0 to, preferably from 20 to. 60 C, in an aprotic solvent or in a mixture of solvents, preferably dimethyl sulfoxide, dimethylformamide or tetrahydrofuran. The separation of the Z and E-configured olefins thus obtained is carried out in the usual manner, for example by columnar or thin layer chromatography. In the case of Wittig olefination, the formation of a 13,14-acetylene bond occurs simultaneously with the cleavage of hydrogen bromide.
The cleavage of the protective group is carried out in an aqueous solution of an organic acid, for example hydrochloric acid. In order to improve the solubility, it is advisable to add an inert organic solvent that mixes it into one. Suitable organic solvents are, for example, alcohols, such as methanol or ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. It is preferable to use tetrahydrofuran. Cleavage is advantageously carried out with temperature from 20 to.
I
Example 1. (5E) - (16RS) -139-Didehydro-16-methyl-18, 18,19,19 tetradehydro-6a-carba-prostaglandin-Ij.
To a solution of 9.4 g of 4-carboxybutyltriphenylphosphonibromide in 20 ml of dimethyl sulfoxide and 7.8 ml of tetrahydrofuran, 4.75 g of potassium t-butylate are added over 45 minutes and stirred for 45 minutes at 5 ° C. A solution of 1.83 g of (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- (3S 4R) -2-bromo-4-methyl-3- ( tetrahydropyran-2-sh1oxy) -rkt-1-en-6-ynyl-bicyclo (3.3.0) octan-3-one in 3 ml of tetrahydrofuran and transfer 4 hours. at. The reaction mixture was poured into ice-water, acidified with 35% citric acid solution to pH 4-5 and extracted three times with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. Remainder
5926. 4.
purified by chromatography over silica gel with eluting liquid hexane: ethyl acetate (3: 2). First get 180 mg of 5-configured. j. olefin, and also as a polar component 680 mg of 11,15-bis- (tetrahydro-pyranyl ether) (5E) -316RS-13,14-didehydro-1b-methyl-18, 18,19,19-tetradehydro-6a -carba0-Andin 1 prostag as a colorless oil.
IR (CHCIj): 3500 (wide), 2940, 2860, 2225, 1710, 1440 cm.
For cleavage of a protecting group of 5,680 mg of the product obtained above
The olefins are transferred from 25 ml of the mixture, acetic acid-water-tetrahydrofuran (65/35/10) for 20 hours at 25 s. Immediately after 0, it is evaporated in vacuo and the residue is chromatographed on silica gel. Using ethyl acetate / acetic acid (99.9: 0.1) as an eluent, 345 mg of the title compound are obtained as a colorless oil.
IR: 3600, 3400 (wide), 2930, 2225, 1710, 1630, 1020 cm
The starting compound for the title compound is 0 as follows.
a) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6- (4Ya8) -2-bromo-4-methyl-3-oxo-oct-1-ene-6-one-JJ bicyclo (3.3.0) octane.
To a suspension of 1.81 g of sodium hydride in 180 ml of dimethoxyethane is added dropwise with a solution of 10.5 g of 3-methyl-2-oxo-0-heppt-5-in-phosphonic acid dimethyl ester in
70 ml of dimethoxyethane, mix
1 h at 0®C and then 7.4 g of finely ground N-bromosucdinimide are added. The mixture is stirred for 30 min1 at 0 ° C, mixed
5 wate with a solution of 11.4 g (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyl-ox1-6-formyl-bicyclo (3.3.0) octane in 90 ml of dimethoxyethane and mix
2h at The reaction mixture is poured into a saturated chloride solution.
ammonium and extracted with ether. The organic extract is washed with water until neutral, dried over magnesium sulphate and evaporated under 5 vacuum. After chromatography of the stack on silica gel with a mixture of hexane / ether (3: 2), the unsaturated ketone is obtained as a colorless oil. IR: 2LAT, 2880, 1712/1688, 1602 1595, 1450, 1275, 945. b) (1R, 5S, 6R, 7U-7-Hydroxy-6- (3Z, 4E) -2-bromo-6-hydroxy-4-methyl-oct-1-en 6-ynyl-bicyclo (3 3,0) -octane- D-on. To a solution of 5.9 g of the ketone prepared in Example 1a in 140 ml of methanol is added with portions of sodium borohydride and stirred for 30 minutes at -40 ° C. Then it is directly diluted with ether and washed with water neutrality is dried over magnesium sulphate and evaporated in a vacuum. product (a mixture of 15-epimers is dissolved in 200 ml of methanol, 2.5 g of Kapak carbonate is added and stirred for 17 h. after this is evaporate the mixture and vacuum dilute with ether and produce salt & solution until neutral. Drain over magnesium sulfate and evaporate on saicy avie. Residue after evaporation mix with 16 h rk at a temperature 300 ml of a mixture consisting of acetic acid and hydrochlorofluoride from: on (65/35/10) to immediately after this is evaporated in vacuum. As a result, the chromatography on the forces of -1kagel ether / g- mixture. here; cl; first from is6 g of 5tL alcohol configurator, and also as a polar component 2.1 g of the target compound (YUPAC 15 nomenclature — g1-shrox) in the form of a colorless oil IR | 3600, 3430 (wide) 5 2960, 2920; 2870/1738, 1600 1400 cm. c) (IR, 5S, 6R, 7K) -7 (Tetrahydropyran-2-yloxy) 6- (ZZ, 4K) 2-bro-4 methyl 3- (tetrahydropyran-2 - ylox-oct 1-en-6- inil-bicyclo (3 s 3 j 0) octan-3-one, a solution of 1.6 g of the 16 o alcohol obtained by measure; 16 mg of p-toluene acid and g of dihydropyran in 50 ml-methnpenchloride is stirred for 35 minutes at. After that, it is diluted with ether, shaken with a dilute solution of sodium bicarbonate, washed with neutral water, dried over magnesium sulphate and evaporated in vacuo. After chromatography of the residue through silica gel, eluting with hexane / e. Fir (7: 3) gives 2.17 g of the title compound as a colorless oil. IR: 2940, 2870, 1735, 1450, 1120, 1018, 965 cm Example 2 (5E) 416RS) -13,14-Didehydro-16 , 20-dimethyl-18,18,19,19 tetrahydro-6a-carba-prostaglandin-o. Example 1 is prepared from 1.6 g (1R, 5S, 6R, 7K) -7- (tetrahydropyran-2-yloxy) - 6 - ((33, 4RS) -2-bromo-4-metsh-3- (tetrahydropyran-2-yloxy) ion-1-en-6-ynyl-3-bicyclo () octan-3-one 630 mg 11.15 bis ( tetrahydro-pyranyl ether) (5E) - (16RS) -13,14-didehydro-16,20-dimethyl-18, 18,19,19-tetrahydro-6a-carba-prostaglandin- in the form of a colorless oil. IR: 3500 (p1) 2942, 2860, 2224, 1710. After the ratio of protecting groups according to Example 1, 0.3 g of the title compound is obtained as a colorless oil. IR: 3600, 3350 (broad), 2932, 2224, 1710, 1602 cm. The starting material for the title compound is prepared as follows; a) (1R, 5S, 6R, 7E) -3,3-Etsh1endioxy-7-benzoshloxy-6- (4R, S) -2 bromo-4-methyl-3-oxy-on-1-en-6 ish- shj-bicyclo (3.3.0) octane. . Analogously to Example 1a, from 6 g of 3-methyl-2-OXO-OCT-5-INIL-Phosphonic acid dimethyl ester 3.7 g of K-bromosuccinimide and 5.6 g (tR, 5S, 6R, 7R) -3.3 -ethylenedioxy-7-benzoyloxy-b-formyl-bicyclo (3,3,0) -octane 4.0 g of non-valuable non-valuable ketone as a colorless oil. IR: 2935, 2883, 1713, 1687, 1602, 1596, 1275, 947 cm b) (1R, 5S, 6R, 7R) -7-Hydroxy-6- (35, 4RS) -2-bromo-3-hydroxy 4-methyl-non-1-en-6-ins 1 D-bicyclo (3.3.0) octan-3-one. Analogously to example 16, 3 g of atan obtained according to example 2a are obtained after reduction of 1.3 g of sodium orhydride, saponification of 1.2 g of potassium arbonate and direct splitting of ketal with 150 ml of a mixture of: acetic acid / water / tetrahydrouran 1.2 g of the target compound
(15c-hydroxy) as a colorless asla.
IR: 3610, 3400 (wide), 2960, 870, 1739, 1600 cm
c) (1R, 5S, 6R, 7U-7- (Tetragid-5 opiran-2-yloxy) -6- (35, 4RS) -2-bromo-4-mvtil-3- (tetrahydropyran-2-yloxy) - non-1-en-6-ynyl-bicyclo (3.3.0) octan-3-one.
Analogously to Example 1c, from 1.18 g of the diol prepared according to Example 26 and 0.7 g of dihydropyran, 1.1 g of the title compound are obtained as a colorless oil.
IR: 2940, 2872, 1736, 1450, 1120, "5 965 cm-.
Example 3. (5E) - (16RS) -20-Ethyl-13, 14-didehydro-16-methyl-18, 18,19,19-tetrahydro-6a-carba-prostaglandin-Ij, .20
Analogously to example 1 is obtained from. 2 g {1R, 5S, 6R, 7R) -7- (tetragone pyran-2-yloxy) -6- (3, 4P) -2-bromo-4-methyl-3- (tetrahydropyran-2-yloxy) -dec -1-en-6; -inyl) -bicyclo (3.3.0) - 25-octan-3-one 900 mg of 11.15-bis- (tetrahydropyranyl ether) (5E) - (16RS) -20-ethyl -13,14-didehydro-16-methyl-18, 18,19,19-tetradehydro-ba-carba-prostaglandin- in the form of 30 colorless oil.
W: 3500 (wide), 2948, 2862, 2220, 1708 cm
After cleavage of the protecting groups according to Example 1, 35 420 mg of the title compound are obtained as a colorless oil.
IR: 3600, 3360 (wide), 2930, 2858, 2220, 1708, 1601 cm
The starting compound for the title compound thereof is obtained in the following way.
a) (tR, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6-) (4RS) -2-bromo-4-methyl-4-oxo-dec-1-ene-6- 45 (ynyl) bicyclo (3.3.0) octane.
As in Example 1a, from 6.23 g of 3-methyl-2-oxo-n6n-5-ynyl-phosphonic acid dimethyl ester, 3.7 g of N-bromosuccinomide and 5.6 g (IR, 50 5S, 6R, 7R) - 3,3-ethylatedIdioxy-7-benzoyl-oxy-6-formyl-bicyclo (3.3.0) octane A gives 4.5 g of an unsaturated ketone as a colorless oil.
IR: 2940, 2880, 1712, 1688, 1601.55 1592, 1275, 949.
b) (tR, 5S, 6R, 7R) -7-rHApOKCH6- (3S, 4R) -2-6poM-3-rHApOKCH-4-Methyl-dec-1-en-b-ynyl) -bicyclo (3.3 , 0) octane-3-one.
Analogously to Example 16, 4 g of the saped as Example Ketone, after reduction with sodium borohydride, saponification with potassium carbonate and subsequent cleavage of the ketal with acetic acid / water / tetrahydrofuran (65/35/10), give 1.5 g of the desired (15-hydroxy) compound in as colorless oil.
IR: 3610, 3400 (wide) 2955, 2868, 1738, 1601 cm
c) (1R, 5S, 6R, 7R) -7- (TeTparHAropyran-2-yloxy-6-) (3S, 4RS) -2-6po-4-methyl-3- (tetrahydropyran-2yloxy-dec-1-ene -6-ynyl) -bicyclo (3.3.0) octane-3-one.
Analogously to Example 1b, 1.81 g of the title compound is obtained as a colorless oil from 1.2 g of the diol prepared in Example 3b.
IR: 2942, 2868, 1738, 1450, 1125, 960 cm
d) 3-Methyl-2-oxo-non-5-ynyl-phosphonic acid dimethyl ester.
To a solution of 15.8 g of sodium in 340 ml of ethyl alcohol, 120 g of methylmalonic acid diethyl ester is added dropwise at 20 ° C. After 30 minutes, 135 g of 1-bromo-2-hexin (obtained hex--2-yn-1-ol with phosphorus bromide in pyridine) are added dropwise and heated for: 16 hours at reflux temperature. Immediately after this, the solution is filtered, the residue is washed with methylene chloride and evaporated in vacuo. The residue is dissolved in 500 ml of methylene chloride, shaken twice with water in 30 ml portions, dried over magnesium sulfate and evaporated in vacuo. The residue is distilled under vacuum at 14 mm Hg. and temperature | 48-152 ° C. Alkyl methyl amino acid is obtained in the form of a distillate, which is heated in 1200 ml of dimethyl sulfoxide and 12 ml of water with 52 g of lithium chloride for .4.5 hours
boiling reflux baths. Immediately after this, the reactive mixture is poured into 5 ml of ice-water, extracted with ether, shaken the extract with water, dried over magnesium sulfate and evaporated in vacuo. Distillation of the residue was carried out 9 at 94-96 ° and 14 mm Hg, thus obtaining 95 g of this 2-methyl oct-4-inic acid ester as a colorless liquid. To a solution of 176 g of dimethyl methanephosphonic acid in 2 m of tetrahydrofuran, 640 ml of IjSM solution of butyl lithium in hexane at. After 15 minutes, a solution of 90 g of ethyl ether 2 methyl-oct-4-inic acid in 300 ml of tetrahydrofurano is slowly added. The reaction mixture is stirred for 4 hours at, neutralized with acetic acid and evaporated in vacuo. The residue is mixed with 20 ml of water. Trgocd5 is extracted with methylene chloride in portions of 500 ML; Shake the extract with water (100 ml), dry over magnesium sulfate and evaporate in vacuo. Distillation of the residue at O535 IM of mercury and 126-128 ° C gives 80 g of the title compound as a colorless plastic. Example 4 (5E) - 13,14-Didegvdro-1 516-dimetsh1-1 8 „18,1 9,1 9- -tetrahydro 6a-carba-prostaglan Dean - 1”. Analogously to example 1 is obtained from 1.5 g (1B ,, 5S, 6R, 7K) -7- (tetrahydropyran 2-yloxy) 6- (35) - 2 - bromine -4,4 - dimethyl 33-- tetrahydropyran-2-yloxy (oct-1-en ™ 6-ynyl) -bicyclo (3,3,0) -octane - 3-pna 610 ml of 11,15-bis- (tetrahydropyran 2-yl ether) (5E) -13., 14-didehydr-16,16-dimethyl-18; , 18,19,19-tetrahydro-6a carba-prostaglaidin-in the form of a colorless caslao IR: 3500 (wide), 2944, 2862, 2222, 1708 cmH After the removal of the protective groups according to Example 1, 290 mg of the title compound are obtained as colorless oils. IR: 3600, 3400 (wide), 2930, 2862, 1708, 1600 cmH a) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzysuksi-6- (2 brom-4,4 Dimethyl- 3-oco oct-1 en-6-ynyl) bicyclo (3.3 5 0) -octane. By analogy, the Pry-Yurom 1a from 6,36 dimethyl ester 3,3-dimethyl-2 Oxo hept-5-in phosphonic acid 3.7 g N-bromosuccinimide and 5.6 g (1R, 5S, 6R, 7R) -3 , 3-ethylenedioxy-benzoyloxy-6 forms; w-bicyclo (3.3, 610 octane, 4.7 g of unsaturated ketone are obtained as a colorless oil. RJ: 2940, 2878, 1710, 1688, 1602, 1594, 1448, 1270, 944. B) (1R, 5S, 6R, 7K) -7-Hydroxy-6) (35) -2-bromo-4,4-dimethyl-3-hydroxy-oct-1-ene-6-ynyl) -bicyclo (3.3.0) lctan-3-one. Analogously to example 16, from 4 g of the ketone obtained in example 4a, after reduction with sodium borohydride, saponification with potassium carbonate and subsequent cleavage of the ketal, 1, 40 g of the title compound (15 ° C-hydroxy) is obtained as a colorless oil. IR: 3600, 3410 (wide) 2958, 2865, 1738, 1600 cm c) (1R, 5S, 6R, 7a) -7- (Tetrahydropyran-2-yloxy) -6- (3S) -2-bromo-4, 4 dimethyl-3-tetrahydropyran-2-yloxy (-oct-1-en-6-ynyl) -bicyclo (353.0) octan-3-one. Analogously to example 1b, from 1.2 g of the diol with dihydropyran prepared according to example 46, 1.6 g of the desired compound are obtained in the form of an oil. IR: 2942, 2870, 1738, 1450, 1132, 960 cm Example 5. (5Е) -13,14-Didehydro-, 18518,19,19- tetradehydro-16, 16 5 20-trimethyl-6a-carba-prostaglandin - ... Analogously to example 1 of 1 g of vIR, 5S, 6R, 7E) -7- (tetrahydropyran-2-yloxy) -6- (3S) -2-6pOM-4,4-dimethyl-3-tetrahydropyran-2 -yloxy (-non-1-en-b-ynyl) bicyclo (3.3.0) -octan-3-one gives 400 mg 11, (tetrahydropyranyl ether) (5E) -13,14-didehydro-18,18 , 19-, 19 tetradehyde-16, 16,20-trimethyl-6 carcass-prostaglandin-Ij in the form of a colorless oil. IR: 3510 (wide), 2940, 2858, 2220, 1708 cm-P (L; after cleavage of the protective groups according to Example 1, 410 mg I .. of the title compound is obtained as a colorless oil. IR: 3600, 3340 (wide) 2940 , 2S32, 2220, 1708, 1600 cmH. The starting compound for the title target compound is prepared as follows: a) (1R, 5S, 6R, 7R) -3.3-Ethylenedioxy-7-benzoyloxy-6- (2-bromo-4,4- dimethyl-3-oxo-non-1-en-6-ynyl) -bicyclo (3.3.0) octane.
P1
As in Example 1a, from 12.6 g of 3,3-dimethyl-2-oxo-oct-5-ynyl-phosphonic acid dimethyl ester, 7.4 g of N-bromo-succinimide and 11.2 g (1R, 5S, 6R, 7U-3,3-ethylenedioxy-7-benzoyloxy-6-formcle-bicyclo (3.3.0) -octane gives 8.7 g of non-saturated acetone as a colorless oil.
IR: 2946, 2880, 1712, 1687, 1601 1594, 1272, 948 cm-.
b) (1R, 5S, 6R, 7R) -7-Hydroxy-6- (38) -2 bromo-4,4-dimethyl-3-hydroxy-non-1-en-b-ynyl-bicyclo (3.3 , 0) octan-4-one.
Analogously to Example 16, from 5 g of the ketone prepared in accordance with 5a, after reduction with sodium borohydride, washing with potassium carbonate and subsequent decomposition of the ketal, 1.80 g of the title compound (15cA-hydroxy) is obtained as a colorless oil.
IR: 3600, 3404 (wide) 2958, 2864, 1738, 1601 cm
c) (1R, 5S, 6R, 7R) -7-3-Tetrahydropyran-2-yloxy-6- ((38) -2-bromo-4, 4-dimethyl-3-tetrahydropyran-2-yloxy (-non- 2-en-6-ynyl) -bicyclo (3.3.0) octan-3-one,
Analogously to Example 1b, from 1.5 g of the diol prepared according to Example 55, 2.20 g of the title compound are obtained as a colorless oil.
IR: 2942, 2878, 1738, 1125, 968 cm
Example 6. (5E) -13,14-Didegidro-18, 18,19,19-tetradehydro-ba carba-prostaglandin-12.
Analogously to example 1 of 400 mg (1R, 5S, 6R, 7R) -2- (tetrahydropyrane -2-yloxy) -6- (38) -2-bromo-3-tetrahydropyran-2-yloxy (oct-1-e- 6-ynyl) bicyclo (3.3.0) octan-3-one gives 130 mg of 11,15-bis- (tetrahydropyranyl ether) {5E) -13,14-didehydro-18, 18,19,19-tetradehydro 6a-carba- “rostaglandin- in the form of a colorless oil.
IK1 3500 (wide), 2948, 2862, 2226, 1708 cm
After cleavage of the protecting groups according to Example 1,
62 mg of the title compound as a colorless oil.
IR: 3610, 3350 (wide), 2930, 2862, 2226, 1709, 1600 cm
The starting compound for the title compound is prepared as follows:
59262
a) (1R, 5S, 6R, 7R) - 3.3-3TmieHdioxy-7-benzoyloxy-6- (2-bromo-3-oxo-oct-1-en-6-ynyl) -bicyclo (3.3 , 0) octane,
5 Analogously to Example 1a, from 5.8 g of 2-oxo-hept-5-ynyl-phosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide and 5.7 g (1R, 5S, 6R, 7R) -353-ethylenedioxy- 7-benzoyl oxy-6-formylbicyclo- (3.3.0) octane gives 4.7 g of unsaturated ketone as a colorless oil.
W: 2932, 2880, 1712, 1688, 1592, 1272 5,948 cmL
5 b) (1R, 5S, 6R, 7R) -7-Hydroxy-6- (38) -2-bromo-3-hydroxy-oct-1-en 6-ynyl j-bicyclo (3.3.0) octane -3-he.
Analogously to example 16 of 4 g of the ketone obtained according to example 6a after
 reduction with sodium borohydride, saponification with potassium carbonate and subsequent cleavage of ketal yields 1.35 g of the title compound as a colorless oil.
IR: 3600, 3410 (wide), 2962, 2866, 1740, 1601 cm.
c) (1R, 5S, 6R, 7R) -2- (Tetrahydropyran-2-yloxy) -6- (35) -2-bromo-3J | etrahydropyran-2-yloxy (-oct-10-ene-6-insh1 ) -bicyclo (3.3.0) octan-3-one.
Analogously to Example 1b, 1.61 g of the title compound is obtained as a colorless from 1.20 g of the diol with dihydropyran prepared in Example 6b.
5 oils.
IR: 2-945, 2882, 1739, 1125, 968 cm.
Example 7. Tris- (hydroxymethyl) -aminomethane salt (5E) p (16RS) 13,14-didehydro-16-methyl-18, 18,19,19-tetradehydro-6a-carba-prostaglandin-.
To a solution of 353 mg (5E) - (16RS) -13, 14-didehydro-16-metsh18-18,18,19,
5 19-tetrade hydro-ba-carba-prostaglandin-60 MJ acetonitrile is added at 65 ° C with a solution of 121 mg tris - (hydroxymethyl) aminomethane in 0.4 ml of water. With stirring the reaction
0 the mixture is cooled, after 16 h the decanter is coziness from the solvent and the residue is dried at 25 ° C at 0.1 mmHg. 310 mg of the title compound are obtained. waxy mass.
The compounds according to the invention act as blood pressure lowering and bronchial dilating compounds. In addition, they

权利要求:
Claims (1)
[1]
A method for producing carbocycline derivatives of the general formula (1)
Rj Rj —CH ^ C — CHg — CrC0H where one of R and bC are independently hydrogen or methyl;
Ex - C ₅ -C ₃ -alkyl;
X is a COOH or COOU group, where Y is an organic base cation, or. their physiologically acceptable salts, ¹ characterized in that the compound of General formula (II)
Hi rd
CH = CBg-CH-C-CH ₂ -C = s-R s
I, 1 otgp
U9) SU article 1145926 where R _% jRj. and R ₃ have the indicated meaning. values, THP - tetrahydropyranyl residue is reacted with the Wittig reagent of formula (III). 0 '(C ₆ H ₅ ) ₃ P = CH- (CH _g ) s- < _p and the products obtained are separated and isolated in the form of epimers, protecting groups are cleaved and if necessary "spruce product, where X - COOH is converted into salt by reaction with a physiologically acceptable base.
The invention relates to a method for producing new derivatives of the class of prostaglandins-1 ₂ , namely, carbocycline derivatives of the general formula (I)

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SU1384196A3|1988-03-23|Method of producing derivatives of |-13,14,18,19,19-hexadehydro-3-oxa-6a-carboprostaglandin-1 sub two or salts thereof

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SU1145926A3|1985-03-15|Method of obtaining carbacycline derivatives or their physiologically acceptable salts

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SU1316555A3|1987-06-07|Method for producing derivatives of carbacyclines or their additive-basic salts of tris-|-aminomethan

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EP0159784A1|1985-10-30|Carbacyclin analogues

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CA1037483A|1978-08-29|Oxabicyclooctanes and process for their manufacture

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US4095036A|1978-06-13|8β,12α,15β-PGF2 β Compounds

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EP0159528A1|1985-10-30|Tetrahydrofuranyl substituted prostaglandin analogs

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CA1076569A|1980-04-29|Prostaglandin analogues

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KR20190084065A|2019-07-15|Method for producing eribulin and its intermediates

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US4170709A|1979-10-09|16-Keto PGE2 methyl esters

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US5097049A|1992-03-17|Process and intermediates for chiral epoxides

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CA1173051A|1984-08-21|Total synthesis of 1rs,4r,5rs-4-|-4-methyl-3,8-dioxabicyclo¬3.2.1| octane-1-acetic acid

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SU1380608A3|1988-03-07|Method of producing carbocycline derivatives or physiologically acceptable salts thereof

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US4201865A|1980-05-06|Novel prostaglandin analogues

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US4110532A|1978-08-29|5-Hydroxy-PGI1 compounds

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同族专利:

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公开号 | 公开日

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IL67839D0|1983-06-15|

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DE3368609D1|1987-02-05|

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AU1118083A|1983-08-18|

---

AT24487T|1987-01-15|

---

EP0086404B1|1986-12-30|

---

DD207901A5|1984-03-21|

---

IE830246L|1983-08-08|

---

FI78064C|1989-06-12|

---

NZ203115A|1986-03-14|

---

AU567867B2|1987-12-10|

---

IE54554B1|1989-11-22|

---

DK52383D0|1983-02-08|

---

FI78064B|1989-02-28|

---

NO830399L|1983-08-09|

---

ES519627A0|1983-11-16|

---

NO155729C|1987-05-20|

---

JPH0611728B2|1994-02-16|

---

JPS58146531A|1983-09-01|

---

EP0086404A1|1983-08-24|

---

DK156563C|1990-01-29|

---

ZA83851B|1983-10-26|

---

DE3204443A1|1983-08-18|

---

GR77967B|1984-09-25|

---

HU191197B|1987-01-28|

---

CS235307B2|1985-05-15|

---

ES8400384A1|1983-11-16|

---

NO155729B|1987-02-09|

---

DK156563B|1989-09-11|

---

DK52383A|1983-08-09|

---

CA1215362A|1986-12-16|

---

FI830414A0|1983-02-07|

---

FI830414L|1983-08-09|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

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DE2845770A1|1978-10-19|1980-04-30|Schering Ag|NEW PROSTACYCLINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF|

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CA1201712A|1980-02-28|1986-03-11|Paul A. Aristoff|Carbacyclin analogs|

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DE3104044A1|1981-02-02|1982-08-26|Schering Ag, 1000 Berlin Und 4619 Bergkamen|NEW PROSTACYCLIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|DE3225287A1|1982-07-02|1984-01-05|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW CARBACYCLINAMIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|

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DE3408699A1|1984-03-08|1985-09-12|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|

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US4927963A|1989-04-28|1990-05-22|SyntexInc.|Novel processes for the synthesis of certain bicyclooctane derivatives with valuable therapeutic properties|

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DE4135193C1|1991-10-22|1993-03-11|Schering Ag Berlin Und Bergkamen, 1000 Berlin, De|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE19823204443|DE3204443A1|1982-02-08|1982-02-08|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|

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