Process for preparing 9-desoxy-9a-methyleneisosters pgi 2 or their lactones or salts

专利摘要:
9-deoxy-9A-methylene-isosteres of PGI2, including processes for their preparation and pharmaceutical and veterinary compositions containing same, are disclosed. The compounds are useful as therapeutic agents, for example as anti-aggregating agents, disaggregating agents, and as vasodilators.
公开号:SU1053745A3
申请号:SU792719752
申请日:1979-01-25
公开日:1983-11-07
发明作者:Гандольфи Кармело；Пассаротти Карло；Фава Вильям；Фумагалли Анджело；Фаустини Франко；Чесерани Роберто
申请人:Фармиталия Карло Эрба С.П.А. (Фирма)；
IPC主号:

专利说明:

D is methylen, cis - or trans-CH, CHOCORg or oxygen or D, R), AND (CH) g ,, 2 Form a group
-sn- (sn), oh
X, But, Hfg, and mj are given,
subjected to interaction with the compound of the General formula
WB
E- H-C- {CH2) nrf L- (CH2) „In“
20 "6
where Z is hydrogen or halo,
E - () zP or () P (0), gd R C -C-alkyl or phenyl;
n, n, Rj-Ry and X have the indicated values,
to give a compound of the general formula
SH (CH2U, DH (SH2)
(CH2) p (CHg) HV-fil
(2. 5 1СНг) „у- | -Х-1 (Н2)„, - Н7
 About dB where RJ, w, t, d, piq. P | , n, Rj, Z, Rj, R, X And By have the indicated values,
and, if desired, restore to obtain, if desired, after separation of free hydroxy groups from esterified hydroxy groups, which may be present in the compound of the formula, where Y is CHJCH, and R and u together form an oxo group, OR if desired, the compound of the form Jia G, where R and R4 together form oxo-. the group is reacted with a mixed hydride to obtain a compound of formula I, where one of. H and R4 are hydroxy and the other is hydrogen, or is reacted with an organomagnesium compound followed by the preparation of a compound of formula I, where one of Rg and R4 is hydroxy, and the other is dical, alkenyl, alkynyl or phenyl, and if desired, a compound of formula I, where Y is a facet, Z is a halogen, and the presence of oxygrone can be free or esterified, dehydrohalogenated, if desired, after isolating the free hydroxyl groups of the formula, where Y is, or, if desired, compounds of the formula, where one of R and R - oxygr ppa, which can be esterified to obtain a compound of formula I, where one of Rj and R is C (-C-alkoxy, or, if desired, a compound of formula I, where one of and Rj. is hydrogen and the other is hydroxy and / or D-oxymethylene, oxide
to obtain a compound of the formula where R and together form a hydroxy group and / or D - or a compound of formula I, where one of R and R is hydrogen and the other is hydroxy group and / or D is hydroxymethylene, is converted to the methanesulfonic acid ester or I-toluenesulfonic acid and then reduced or, if necessary, a compound of formula I, where R is carboxyl, is esterified, or a compound of formula I, where R is an ester group, is washed, followed by isolation of the target product in free form or in the form of a lactone, or salt .
Priority featured:
i 01/26/78 - the radicals have
all specified values, except those
when one of p and q is O, 2 or 3, and
the other is 0, 1, 2 or 3, with p + q
 1-6;
21.12 „78 - when one of the p and q 0, 2 or 3, and the other - 0,1,2 or 3, and p + q 1-6.
one
The invention relates to methods for preparing the 9-deoxy-9A-methylenisosters PGlj of the general formula T not described in the literature:
H "JH4) m, Dl" Helin "
(ypM
iVgtta)
L 1) 11g | -ac-1 "n,)„, - L7
1C
 s
where R is free or esterified carboxyl, CCORg), where Rg is lower alkyl, where R9 is hydroxy or - alkoxy, formyl or CH (), where X is kis, hydrogen or sulfur, alkyl or two; R Q together form a C -G alkylene,
D is methylene, hydroxymethylene, csn- or trans-CH CH, Cgc, or oxygen; one of R and Rj and independently one of R-j and Ri). - hydrogen, Cf-Cg-alkyl, C2 Sat alkenyl, Cj-Cg-alkynyl or feiyl, and another hydrogen, hydroxy group, C-C-alkoxyl or R and R and independently R and R together form an ox group,
R5- and R.6 are the same or different, hydrogen, C-C -alkx1 or halo-,
Y - СН „СНл,, ЦИС- or Транс
X - - (CH) t - O or 1), Cis- or trans - CH-CH or oxygen
t, t, n and ng - 0.1-12 provided that AND 15J
p and q - O, 1-3, provided that the sum p + q is 1-6 /.
. R is hydrogen / C-Cd-alkyl, C, jC is cycloaliphatic, phenyl, (unsubstituted or substituted C-C5 alkyl, tetrahydrofuryl, or lactones obtained by intermolecular condensation of compounds of the formula I, where R is carboxyl and D ICOHON, or salts of the compound of the form .ly, I, where R is COOH, possessing physiological activity.
A known method for producing a compound of the formula
(H2) in COOCHN l-A ,,
and
the fact that the compound of the formula
-; dsn2) b ooossnz
subjected to interaction with dimethyl-2-oxoheptylphosphonate l. The purpose of the invention is a method for the preparation of new physiologically active 9-deoxy-9A-methylenisosters PGl of the general formula I or their lactones, or their salts.
: The goal is achieved by a method for preparing 9-deoxy-9A-methylenisosteres PG12 of general formula I based on the known reaction that the compound of general formula II:
Cll (CH2lm, D (lH2) ICHsV (JH2) t
SSS
where is carboxyl, free or esterified, or in the form of a salt, or C- (OKD) 3, where Rg has the indicated meanings, a group of the formula -CHj-R / where R (5 is esterified hydroxy or C -Cr-alkoxy, or
CH (, p), where X and have the indicated meanings,
ha ,, t, p, q have the indicated values
one of H and R is hydrogen, C -Cb-alkyl, C -C alkenyl, C -C alkynyl or phenyl, and the other is hydrogen, hydroxy, Cz-Sat-alkoxy or Cj-C acyloxyj
D-methylene, and, isl -trans-CH, CH-CHE-CHOCOR, where R has the indicated values, or oxygen or D, R and -C-CH7) t2 Form the group (CH i) my, where that has the indicated
 OS 0
meanings
subjected to interaction with the compound of the general formulaSh:
B
E-CH-C- (CH2) fj7f- - (3H2) nr "7 Z OKB
where Z is hydrogen or halogen, 25E - (C (, - or {R, 0) 2 P {0)
where R - With | -Sb alkyl or phenyl.
,, n, Rj-, R, R7 IM have
P
specified values
to give a compound of general formula I:
5Н (СН2)) ш2 «И
 (CHj),
35 HV-day
 (f
RS
at; -ZHH-1 5G) n | - j-x-lCHjlnj-R
R.
II
WB
about
0 where R,, m,
D
p.q, Ri I R-, Z,
AND)
n, Ry, Rg, X, nq, and Ry have the indicated meanings,
and, if desired, restore to obtain, if desired, after separation of free hydroxy groups from esterified hydroxy groups, which may be present in the compound of formula I, where Y is CH2CHf, and R q and R4 together form an oxo group or, if desired, a compound of formula I, where R3 and H4 together form an oxo group, reacts with a mixed hydride to produce a compound of formula I, where one of R5 and R4 is hydroxy and the other is hydrogen, or reacts with an organomagnesium compound to form a compound of formula D, g e one of R and R4 is a hydroxy group, and the other is alkyl, alkenyl, alkynyl or phenyl, and if desired, a compound of the formula where Y is a trans, and Z is a halogen, the oxigroups present can be free or esterified by dehydrohalide to produce, if desired, after isolating the free hydroxy groups, a compound of the formula where Y is CgC, or if desired a compound of formula i J where one and RJJ is an hydroxy group that can be esterified to give a compound of formula 1 f where one of R and B4, C - With alkoxyl, or, if desired, a compound of formula 1 g e, one of R and R is hydrogen, and the other hydroxy group and / or D-hydroxymethylene is oxidized to give a compound of formula I, where R (and R2 together form an oxo group and / or D - or a compound of formula I, where one of R, and R, 2 is hydrogen, and the other hydroxy group and / or D is hydroxymethylene, is converted to the methanesulfonic acid ester or P-toluenesulfonic acid ester and then reduced, or, if necessary, a compound of the formula, where R is a carboxyl, is esterified, or a compound of formula I, where R is an ester group, is saponified, followed by isolation of the desired product in its free form, and and a lactone, or salts thereof.
 The reaction of a compound of general formula II with a compound of general formula 1P is carried out in an inert solvent, such as ether, tetrahydrofuran, dioxane, dimethoxyethane, in aliphatic or aromatic hydrocarbons, in halohydrocarbons, such as methylene chloride or carbon tetrachloride. In the case when E in the compound of general formula 1I is the group (), as: solvent, use polar anpoTOHHiae solvents {dimethyl sulfoxide, hexamethylphosphoric triamide
The process is carried out in the presence of an alkali metal hydride in the temperature range of 0-100 ° C, the most preferable is the room temperature,
Example. 1Dg of sodium borohydride (sodium) (0.029 mol) was added with p stirring to a solution of 11.6 g of bicyclo (3.3.0) octane-3,7-dione (8, xU mol) in 100 No. 1 methylene chloride and 100 ml of ethanol. After 45 minutes at room temperature, excess excess reagent is decomposed slowly by adding 20 ml of acetone. The resulting mixture is neutralized with 1.4 ml of acetic acid and evaporated in vacuo to a residue, which is poured into water and methylene chloride. The organic phase is evaporated to dryness and filtered on silica gel {using 70:30 hexane-ethyl ether as eluent). 9, .1 g of 7-hydroxybicyclo (3.3.0) octan-3-one are obtained, IR (film): 3400, 1740.
A solution of this compound (0.065 mol) in 27 ml of anhydrous dimethylformamide is treated with 12.8 g of dimethyl-1ret. -Butyl-silyl chloride and 8.85 g of imidazole. The resulting mixture was heated for 5 hours, cooled, diluted with two volumes of water, and extracted with ether (340 and 220 ml). The combined organic extracts are washed with 5% NaHCO and then with water until neutral and evaporated to dryness. 15.8 g of crude product is obtained (yield 95%). As a result of the purification on silica gel, 2.85 g of 7-exooxybicyclo (3.3.0) octan-3-one-dimethyl-t-tert-butylsilyl ether are obtained, mp 40-42 ° C, and 11.8 g 7-endooxybicyclo (3.3.0) octane-3-one-7-dimethyl-tert.-butylsilyl ether, m.p. 51-520С.
A solution of the latter (11.8 g, 4, bZ10 mol) in 295 ml of methyl carbonate () is stirred with the exception of water in an inert atmosphere and carefully treated with 6.95 g of 80% sodium hydride. When hydrogen evolution ceases, the reaction mixture is heated at 75-80 ° C for 40 minutes. After cooling, the mixture is diluted with two volumes of ether and carefully treated with 13 g of glacial acetic acid. The organic phase is then separated with buffer pH 5.2-5.5 and the aqueous layer is extracted with ether. The combined organic extracts are dried with Na-zSO and evaporated to dryness. 12.72 g of d, l7-endooxybicyclo (3.3.0) octan-3-one 2- (carboxymethyl ester) 7-dimethyl-t-butyl (DMTV) -silyl ether are obtained (85% of the theoretical yield). After purification on silica gel (45 g) (eluent 97: 3 hex-ethyl ester), 10.81 g of pure product, I 01; 254 microns, e 7000.
Beginning with the exo-isomer, according to this procedure, d, 1-7-exoxybicyclo (3.3.0) octane-3on-2- (carboxymethyl ester, 7-dimethyl-triTbutylsilyl ether; “max 254 mmc, E 6500
PRI mme R 2. A solution of 7.5 g d, 1-7-endooxybicyclo (3.3.0) octan-3-2- (carboxymethyl ester) -7- (daTV) -silyl ether in 75 ml of dichloromethane and 75 ml of ethanol is cooled before and treated with stirring 0.9 g of sodium borohydride. After stirring for 15 minutes, the excess reagent is decomposed by adding 12 ml of acetone. The temperature of the mixture is made up, 20 ml are added, the solvent is evaporated in I vacuum, and the residue is extracted several times with ether. The combined organic extracts are washed with 5 ml of water and evaporated to dryness. A residue is obtained which is recrystallized from N-hexane and 4.8 g of d, 1-3,7-endodioxybicyc are obtained: (3.3.0) octane-2 exo- (carboxymethyl ester) -7-daTB-silyl th simple ether, so pl. 68-70 ° C. The mother liquor is adsorbed onto 25 g of silica gel; elute with 90: 10n-heptane: ethyl ether. Another 2 g of product is obtained, pure enough to use, without further purification. : A solution of 6 g th, 1-3,7-enlodioxib cyclo (3.3.O) octane-2-exo- (carboxy methyl ester) -7-DMTB-silyl ether in 100 ml of a mixture of 80:20 methanol-water is treated 2 g of potassium hydroxide and heated to boiling point. under reflux for 30 min. After concentration in vacuo, the mixture is acidified to pH 5.1 and extracted with ethyl acetate. After evaporation of the organic layer, 5.1 g of a, 1-3,7-endodioxy-2carboxybicyclo {3.3.0) octane-7-datB silyl ether are obtained. A solution of this compound in 150 ml of acetonite ralla is then treated with 2.81 g (1- (+) ephedrine.) After 4 h at room temperature, 2.9 g of salt is obtained, which is recrystallized twice from acetonitrile, giving 1.85 g ( +) 3, 7-endodioxy-3-exocarboxy-bicyclo (3.3.0) octane-7-DMTB- (silyl ether) -th (+) ephedrine salt. All mother liquors are collected and evaporated to dryness. A residue is obtained, which is dissolved in water and treated with 0.68 g of sodium hydroxide in water. s - (+) Ephedrine is separated into a benzene extract, and the sodium salt solution is acidified the organic phase is evaporated to dryness, a residue is obtained, which is treated with 2.2 g of 1-ephedrine, and after several recrystallizations, 2.3 g of (-) - 3,7-endodioxy-2ecaocarboxybicyclo 3 .3.0) -7-DMTB (silyl ether) -1-ephedrine salt, k1 o -49 °. Frozen. A solution of 6.28 g, 1-3.7-endodiksibitsiklo {3.3.0) octane-7- DMTB- (silyl ether) -2-exo-carboxymethyl layer of ether in 30 ml of anhydrous methylene chloride is treated with 2,19 2,3-dihydropyran and 39 ml of Para-toluene sulfonic acid. After 3 hours at room temperature, the reaction mixture is washed. 5% NaHCO (2-5 ml. By evaporation of the organic phase to dryness, 8 g d, 1-3,7 endodioxybicyclo C 3.3.0) octane-7DMTB- (silyl ether) -3 tetrahydropyranyl (THP) - (ether) - 2- carboxymethyl ester, which is dried by adding anhydrous benzene (2-15 ml) and evaporation to dryness. This product, in 30 MP anhydrous ether, was added dropwise over 15 minutes to a stirred suspension of 0.6 g of LiAiH, in 40 ml of anhydrous ether. Stirring is continued for 30 minutes. Before the excess reagent is destroyed by careful addition of 5 ml of acetone and then with a saturated aqueous solution of ether. Then 10 g of anhydrous sodium sulfate is added. After filtering the organic solution and evaporating it to dryness, 7.2 g of a, 1-3.7-endodioxy2-exooxymethylbicyclo (3.E.0) octan7-DMTB {silyl ether) -3THP-etherJM are obtained. Thus, the following compounds are obtained from optically active starting materials: ent-3,7-ENDODIOXY-2-ECZOOXI methylbicyclo 3 .3O) -Toan-7-DMTB (silyl ether) -3-THG-hydrostatic ether-3, 7-ENDODIOXY-2-EXODIOXY- .. methylbicyclo (3.3.0) “octane-7-DMTB (silyl ether) -3-THP-ether. If 1,4-dioxy-2-ene is used instead of 2,3-di-propyran, then the corresponding 3 (2-diox) ethers are obtained. PRI me R 4. A solution of 3.8 g d, 1-3,7-endodioxybicyclo (3.3.0) octane-2-exo- (carboxymethyl ester) -7-DMTB-silyl ether in 40 ml of benzene First, 3.66 g of benzoic acid and 7.9 g of triphenylphosphine are treated, and then, with stirring, 5.8 g of ethylazobis carboxylate in 15 Pb of benzene. After 40 minutes of stirring, the organic phase is washed with 2N. sulfuric acid {2-20 ml), and then sodium carbonate (3-15 ml) and water until neutral. After evaporation to dryness, a, 1-exo-7 endodioxybicyclo (3.3.0) octane-2-exo- (carboxymethyl ester) 7-DMTB- (silyl ether) -3 benzoate mixture is obtained. NMR: 3-endo (n 5.8B. Multiplet) 2 endo (H 3.25 doublet, doublet CO-2CH) (3N, 3.64S singlet), 7 endo (H 4.45 multiplet) and,, a, 1- 7-endooxybicyclo (3.3.0) oct-3en-2-exo- (carboxymethyl ester) -7-LMTB-silyl ether,. The crude reaction product is dissolved in anhydrous methanol, stirred for 3: 1 and treated with 0.5 g of anhydrous potassium carbonate. Upon evaporation to dryness, a residue is obtained, which is taken up in ethyl acetate and saturated. The organic phase is washed until neutral and evaporated to dryness. The residue is adsorbed on silica gel and eluted with hexane and a mixture of hexane ethyl ether. Receive:
1.01 g a, 1-7-endooxybicyclo (3.3.0) oct-3-en-2- (carboxymethyl ester) -7-DMTB silyl ether, which is dissolved in methanol, is treated with 0.3 g of 5% Pd on CaCO and hydrogenated at room temperature and normal pressure to give a, 1-7-endo-oxybicyclo (3.3.0) octane-2- (carboxymethyl ester) -7 DMTV-silyl ether;
2.01 g (1.1 3-exo-7-endodioxybicyclo (3.3.0) octaH-2- (yarboxymethyl ester) -7-DMTB-silyllorgo ether, which is poured as described in Example 2, 5% potassium carbonate in a mixture of 80:20 methanol: water, to obtain d, 1-exo-7-endodioxybicyclo (3.3 O) octane-2-exo- (carboxylic acid) 7 - DMTB-silyl ether , M °°,. Then it is divided into individual optical antipodes (+) and (-) amphetamine.
The interaction with the ether solution of diazomethane transform (+) - 3exo-7-endodioxybicyclo (S. 3.0) octane 2-exocarboxyacid-7-DMTB-silyl ether into methyl ester. Subsequent interaction with 2,3-dihydropyran followed by reduction of LiAlH In ethyl ether gives (1) -3-exo-7-endodioxy 2-exooxymethylbicyclo 3,3.0) octane-3-THP (ether) -7-DMTB silyl-simple ether,
(-) Enantiometer and racemic mixtures are prepared in a similar manner.
Example 5.5g a, 1-7-endooxybicyclo (3.3.0) octane-7-DMTB (silyl ether) -3-exo-carboxymethyl ester in 100 ml of aqueous methanol was washed with 2 g of KOH at the boiling point under reflux. After methanol is removed in vacuo, the aqueous solution of potassium mud is extracted to remove neutral impurities, acidified and extracted with ether. The extracts of the latter are combined and evaporated to dryness to obtain 4.5 g of d, 1-acids, which are then divided into optical antipodes () and (-) ephedrine,
1.32 g of (-) - 7-endooxybicyclo (5.3.0) octane-7-DMTB- |. The silyl ether-2-exo-carboxylic acid is then expanded into 20 ml of THF and treated with 10 ml of 1 N BH-} and THF. After
4 hours at room temperature, the excess reagent is decomposed by carefully adding 20 ml of 1.5 and. NaOH. The THF is then distilled off in vacuo and the aqueous phase is extracted with ether. The combined organic extracts are washed until neutral and evaporated to dryness. The 1.02 g of (-) 7-endooxy-2-exooxymethylbicyclo (3.3.0) octane-7-DMTB-silyl simple is obtained.
10 ether,
(+) - The isomer and the racemic mixture are prepared in a similar manner.
Example 2.7 g of d, l-7-endooxy-2-exooxymethylbicyclo (3.3.0) 5 octane-7-DMTB-silyl ether in 20 ml of methylene chloride are treated with 0.95 g of 2.3 dihydropyran and 20 g of gtara- toluenesulfonic acid for 3 hours at room temperature. After the organic phase is washed with 7% aqueous NaNSO and then with water, it is evaporated to dryness. Crude d, 1-: 7-endooxy-2-exotetragidropyr5 nyloxymethylbicyclo (3.3.0) octane-7-k DMTP-silyl ether is obtained. It is dissolved in 15 ml of THF and treated with 4.5 g of tetrabutylammonium fluoride for 10 hours with stirring. Then the reaction mixture
 concentrate in vacuo, adsorb on silica gel and elute with a mixture of benzene-ether to obtain 2.1 g of d, 1-7-endooxy-2-exo-THP-oxymethylbicyclo (3.3.0) octane. IR (film):
5 3400, 1280 cm. . A solution of this product in 25 ml of acetone is cooled to (-20) - (- 8) ° C with stirring and treated with 4.2 ml of 8% Jones reagent (aqueous sulfuric acid) for 15 minutes, until light is obtained. pink staining. After additional stirring for 14-20 minutes, 1.5 ml is added dropwise.
g of isopropanol and the resulting green solution is diluted with b volumes of benzene. The organic phase is washed with 20% (N114) 304 until neutralized and the combined aqueous phases are repeated extractions: they are benzene. Unite
 Venous benzene extracts are dried and evaporated to dryness. 1.82 g of d, 1-2-exo-TPH-hydroxymethylbicyclo (3.3.0) 6ctane-7-one are obtained, IR (film): 1740, 1128 cm-.
5 Nat- and enant-isomers are prepared in a similar way ..
Example7. With external cooling and with stirring, to maintain the temperature of the reaction mixture at about 20-22 ° C, a solution of 6.57 g of potassium t-butylate in 65 ml of DMSO is added dropwise to 6.75 g of 4-carboxybutyltriphenyl phosphonium bromide and 2 , 28 g d, l-2-3K3O
5 THP-hydroxymethylbicyclo (3.3.0) octane-7one (from example 6) in 40 ml of D1-1CO. After the addition, the mixture was diluted with an equal volume of water, acidified to pH 5, and re-extracted with 50:50 ether-pentane. These combined organic extracts are concentrated / treated with ethereal diaeomethane until a yellow color is obtained, and then evaporated to dryness. Then the residue is dissolved in 50 ml of acetone, I process 20 ml of 2 and. oxalic acid and kept at 40-45 s for 8 h. Then the acetone is distilled into vacuum
I aqueous phases are extracted with ethyl acetate and the combined organic extracts are evaporated to dryness. Purification of the residue obtained on silica gel using ethyl ether as an eluent yields a mixture of d, 1-5-and, is-trans 2 exoxymethylbicyclo (3.3.0) oct-7 ethylJ-pentenoic acid methyl ester (1.75 g) . Separate isomers. It is possible to isolate, using high performance liquid separation chromatography, up to 5TpoHC-djl- and 5U, MC-d, l-H3OMepOBj, the latter is called methyl ester B-cis-W () - Octanor-12-oxymethyl-9q-methylethylproduct; 5-ene acid, NMR: 5H (14.5, 156 multiplet CO "SI"), 3.67 6 singlet). . .
If in the described procedure, 4-carboxybutyltriphenylphosphonium bromide is replaced by one of the following Wittig reagents: 3-carboxypropyltriphenylphosphonium bromide-5-carboxypentyltriphenylphosphonium bromide, 4-carboxy2-oxobutyltriphenylphosphonium bromide, then methyl compounds are prepared
d, 1-5-Cis-W () octanor-2-nor12p-hydroxymethyl-9a-deoxy-9a-methyleneprostacycl-5-enoic acid; M.
d, l-5-u, “c-W () oKTaHop-2-aromo-12p-hydroxymethyl-9p-methyleneprostacycl-5-enoic acid, M.
d, l-5-u, MC-w () oKTaHOp-3-OKC12p-hydroxymethyl-9a-deoxy-9c | -methyleneprostacycl-5-enoic acid, as well as the 5-trans-isomer and the individual wat and enant-antipodes.
PRI me R 8. A stirred solution of 7.16 g of methyl ester 5-1CIS-W () oKTaHop 13 Joxymethyl-9a-deoxy-9a-methyleneprostacyc-5-enoic acid in 80 ml of a mixture of 75:25 benzene-dimethylsulfoxide 8.9 g of dicyclohexylcarbodiimide are treated, and then 14.2 ml of pyridinium trifluoroacetate solution (obtained by adding 25 ml of a 75:24 benzene: DMSO mixture to 1 trifluoroacetic acid and 2 ml of pyridine). After 4 hours stirring
The reaction mixture is diluted with 10 ml of Bezol and 3 g of oxalic acid in water is added dropwise. Dicyclohexyl urea is removed by filtration, the organic phase is separated and washed with water (5-6 ml). The reduction in volume gives a benzene solution of the 12p-formyl derivative, which is added in one portion to the solution of (2-oxoheptyl) dimethylphospho-.
0 sodium salt. The latter is obtained by adding dropwise 7.58 g of (2-oxoheptyl) -dimethylphosphonate in 40 hl of anhydrous benzene to the stirred solution. 1.02 g of hydride
5 sodium (80% dispersion in mineral oil) in an inert gas atmosphere and continue to stir until H-j release ceases. After adding the formal derivative to the sodium phosphate sodium phonate salt, stirring is continued for 20 minutes. Then the reaction mixture is neutralized with a saturated solution of monosodium phosphate. The organic phase is separated, evaporated to a small volume, absorbed on silica gel and eluted with a mixture of cyclohexane: ethyl ether. 6.4 g of 5-cis-12-1 trans-9adeoxy-9a-methylene-15-oxoprostacyc-5,13-diene acid of methyl ester, M are obtained.
Using similar 12D-hydroxymethyl derivatives of example 7, methyl esters are obtained
The following 5 acids
5-Cis-12-trans-9o-deoxy-9a-methylene-15-oxo-2-nor-prostacycla5, 12-diene acid,
5-cis-13-trans-9a-leoxy-9a-me0 tyylene-15-oxo-2-homoprostacyclic 5, 13-diene acid, M
5-i-13-trans-9a-deoxy-9-methylene-15-oxo-3-oxaprotect 5, 13-diene acid; ,
as well as the 5-trans-geometric isomers of the nat, anat, in d, l forms.
All compounds prepared in Examples 21-23 and 47-52 were prepared in the same manner as in this example.
0
PRI me R 9., Mixing and cooled () a solution of 1.25 g of exooxymethyl-7-endooxybium (3.3.0) octane-DMTB-silyl ether in 0.8 ml of pyridine is treated with 0.82 g of benzoyl chloride. . After 8 hours at room temperature, 2N is added. H2S04 and the mixture was extracted with ether to obtain 2-exobenzoyloxymethyl-7-endo.
0 hydroxybicyclo (3.3.0) octane-7-DMTB-silyl ether. This silyl ester group is removed at reflux in 20 ml of acetone with 8 ml of 2N. oxalic acid. Acetone is removed under vacuum.
5 and the resulting residue is extracted with ether. After purification on silica gel, 1.11 g of 2-exobenzoyloxymethyl-7-endooxybicyclo (3.3.0) octane is obtained. IR (film): 3420. It is dissolved in pyridine and then added to a solution of 1 g of CrO} in 10 ml of pyridine. After 6 hours at room temperature, the mixture was diluted with 20 ml of benzene and filtered. The filtrate is evaporated in vacuo and the residue is poured onto 2N. sulfuric acid and benzene. Then washed with 2 n. EqSO / AND WATER BEFORE neutralization, the organic extract is evaporated to dryness, to obtain 0.98 g of 2-exobenzoyloxymethylbicyclo (3.3.0) octan-7-one. IR (film): 1645, 1705 cm. A solution of this compound in 5 ml of anhydrous THF is then added to a solution of (2-oxo-5-trimethoxypentyl) dimethyl phosphonate sodium salt, obtained by adding dropwise a suspension of 0.23 g of 80% - sodium hydride in THF to a solution of 2.12 g of 2-oxo-5trimethoxypentyl dimethylphosphonate in b ml of anhydrous THF. After 10 hours of stirring, the mixture is neutralized with 15% KHjPO. THF is evaporated in vacuo, and the residue is extracted with ether. The combined extracts are concentrated, absorbed on silica gel and eluted with hexane-ether to obtain 1.1 g of 5- 2-benzoylox methylbicycloC 3.3.0) oct-7-enyl} -1,1 1-trimethoxypent-5-en-1- it is either 12R-benzoyloxymethyl-W () octanor-4 oxo-9a-deoxy-9a-methyleneprostacycl-5-enoic acid - orthomethyl ester, M, as a mixture of B-Cys-and 5-trans-olefins, which section high performance liquid separation chromatography. After treatment with aqueous methanol, and then H2SO4, the corresponding methyl ester derivatives are obtained. The interaction of 0.3 methyl ester with 0.25 ml, 1,3-ethanedithiol in methylene chloride and a catalytic amount of; BF j-ether for 15 min at io ° C results in 12L-benzoyloxymethyl-KC) octanor-4, 4; ethylene hydroxy-9a-deoxy-9a-methyleneprostacycl-5-enoic acid methyl ester, P and measures 10. 0.8 g of methyl 12B-benzoyloxymethyl-H- () octanor-4-oxo-9a deoxy-9a-methylene-pro-cycl-5-enoic acid in 10 ml of methanol selectively debenoxylates, processing with stirring 0.15 g of anhydrous KyiCO. After evaporation, the solution Current bodies remains placed in 15% aqueous solution and methylene chloride and after evaporation of the organic phase, 12 | α-oxymethyl and (20-12) octanor 4oxo-9a-deoxymethyl and prostacyclic-5-enoic acid (methyl ester), M. A solution of this compound in 10 ml and 10 ml of ethanol is cooled to -20 ° C, treated with 90 mg of NaOH and stirred for 2 hours. Then the excess reagent is decomposed with a 15% aqueous solution of acetic acid, the solvent is evaporated and the residue is absorbed on silica gel. Elution with ethyl ether to give 0.21 g of methyl ester 12p-oksimetilW () oktaHop-4s-oxy-9o-deokci9a metilenppoctatsikl-5-enovoy acid, and 0.13 g of 4N-hydroxy isomers, individual products are then saponified with 20 % aqueous methanol and 19% potassium carbonate. Obtained after acidification and extraction with ethyl acetate 0.18 g of 1,4-lactone 12 | -oxymethyl-K (20-12) octanor-43-hydroxy-9a-deoxy-9C1-methyleneprostacycl-5-enoic acid and 0.11 g of the 4n-isomer. As a result of the oxidation of these compounds according to the procedure of Example 8, 12-formyl derivatives are obtained. Example 11. About, 28 g of methyl 4,4-ethylenedithio-12-benzoyloxymethyl-W (20-12) octanor-9a-deoxy-9a-deoxy-9a-methylene-pro-cyclic-5-enoic acid methyl ester is selectively benzoylized by methanolysis of KjCO in anhydrous methanol to give the corresponding 12-oxymethyl derivative. It is then oxidized to the aldehyde by the procedure of Example 8. The 12th formyl derivative is obtained. By reacting this compound (0.12 g) in benzene with a phosphonate obtained from 0.177 g (2-oxo-3, 3-dimethylheptyl) dimethylphosphonate and 20 mg of 80% NaOH, as described in Example 8, complex methyl 5.13-16, 1b-dimethyl-4,4-ditioethylenedioxy-15oxo-9o-deoxy-9a-methyleneprostacycl-5, 13-diene acid ester, I „jp 228 MMK; f 9,200. Similarly, using (4-cyclohexyl-2-oxobutyl) -dimethylphosphonate as the phosphonate and 4u-lactone from Example 10 as the aldehyde, 4-y-lactone 5.13t 48-oxy-15-oxo-9a-deoxy is obtained -9O1-methylene-17-cyclohexyl-18, 19,20 tri-orpro-pro-cyclic-5, 13-dienoic acid with (3-phenoxy-2-oxopropyl) dimethylphosphonate, get 1,4-ulactone 5,13t-4s-oxy-15-oxy- 9a-deoxy-9a-methyl-17, 18, l9,20-tetranoper-16-phenoxycaprostacic-5, 13-diene acid.
PRI me R 12. Using as phosphonates (2-oxo-33-methylheptyl) -dimethylphosphonate and (2-oxo3.3-fluoroheptyl) -dimethylphosphonate, and as an aldehyde of boron - 1,4-Sactone-12p-formyl- w (20) octanor4n-hydroxy-9a-deoxy-9C1-methyleneprostacycl-5-enoic acid, according to the method of examples 3 and 11, get 1,4-lactone 5.13-4k-oxy-15-oxo-9a-deoxy-9a -methylene-1BB-methylprostacyclic6, 13-diene acid, 4-U-lactone 5,13-4n-hydroxy-15-oxo-9a-deoxy-9o | methylene-1b-5-fluoroprostacyclic-5, 13dienoic acid.
Example 13. A solution of methyl ester 5c, l3t-15-OKCo9a-deoxy-9C1-methylene-pro-cyclic-5, 13dieneic acid (0.7 g) in 7 ml of methylene chloride and 7 ml of ethanol, cooled to -20 ° C, treated 38 mg sodium borohydride. After 20 minutes of stirring, the reaction was quenched with 2 ml of acetone and 2.5 ml of 20% NaH5P04i. The mixture was then concentrated in vacuo and extracted with methylene chloride. The combined organic extracts are evaporated to dryness and a residue is obtained which is purified on silica gel using ethyl ether as eluent. 0.32 g of methyl ester 5c, 13t-15soxy-9a-deoxy-9a-methyleneprostacycl5, 18-diene acid (52. -2.0 ° /% MD +86 MeOH) and 0.26 g of 15R isomer are obtained (57Mo + 22 °, +54 MeON).
According to the same procedure for the reduction of 15-oxo-derivatives from examples 8, 11 and 12, methyl esters of the following acids are obtained,
5c, 13-throne-9a -deoxy-Ea-methylene-15B-hydroxy-2-norprostacyclo-5, 13 dieneic acid
5-y, is, 13-trans-9a-deoxy-9a-methylene-15z-hydroxy-2-agomoprostacycl5, 13-diene acid
B-cis, 13-GranS-9a-deoxy-9methylene-153-hydroxy-3-oxaprocycl5, 13-diene acid,
5-cis, 18-trans-9s (-deoxy-901-methylene-4, 4-dithioethylenedioxy-15-hydroxyprostacyc-5, 13-diene acid,
and 1,4-lactone following acid
5c, 13t-9a-deoxy-9a-methylylene 43-, 158-dioxy-17-cyclohexyl-18, 19,20-U-trinor-pro-cyclic-5,18-diene acid, M 354;
5c, 13t-9o-deoxy-9a-methylene-4-S, 155-dioxy-16-phenoxy-17,18,20-W-tetranorprostat-5, 13-diene acid, 350
5c, 13-9a-deoxy-9a-methylene-4n, 1B3-dioxy-1bz-methylprostacyc-5.13 dienoic acid, 328;
5c, 131-9a-deoxy-9C | -methylene-4c, 153-dioxy-1b3-fluoroprostacyc-5.13 dienic acid; M + -HjO 332 is the same as their 5-trans-geometric isomers in the nat, enanth and 6,1-forms. PRI me R 14. A solution of 0.35 g of methyl ester 5c, 13t15-oxo-9a-deoxy-9a-methyleneprosta-5,13-diene acid in 10 ml of a mixture of 2: 1 ethyl ether - toluene is cooled before and with stirring, treated with 5 ml of 5% methylmagnesium iodide in ether. After 4 hours with stirring, the temperature of the mixture was adjusted to 0 ° C and the reaction mixture was decomposed with 20% aqueous ammonium chloride. Then the organic phase
washed with water, sodium bicarbonate and water, dried with MeZo, treated with 0.1 ml of pyridine and evaporated in vacuo to obtain a mixture of 153 and 15k alcohols. After separation and on silica gel using 80:20 ethyl ether: isopropyl ether as eluent, 0.1 g of 5c tantyl ester, 13t-15S-oxy-9a-deoxy 9a-methylene-15-methylprostacycla-5, 13dieneic acid M -HjO 344, and 0.1 g of 15k isomer.
Example 15. With the same substrate, but with THF as a solvent, as a result of the reaction. with 8 ml of O, 8m of ethynylmagnesium bromide in THF, after chromatography on silica gel, methyl ester 5c is obtained. isomer.
Using 0.3 M vinylmagnesium bromide, methyl ester 5c, 13g-15-vinyl-153-hydroxy-9 deoxy-9a-methyleneprostacyc-5, 13dienoic acid (J) and its 15K-isomer are obtained,
PRI me R 16 methylene is cooled to (10) - (- 8) ° C and treated with stirring with 0.3 ml of boron trifluoride etherate (1.2-10 M) in anhydrous methylene chloride, and then 5% diazomethane in methylene chloride to obtain a yellow stains. Then the solution is washed with 5%
aqueous NaHCO- and then water until neutralized. 0.21 g of 5c, 13t-9a-deoxy-9a-methylene-4R, 153-dioxy-1b-methylprostacycl-5, 13- (diene acid) -1,4-y-lactone-15-methyl ether m / e.
Example 17. A solution of 1.05 g
d, l-2-exooxymethyl-3-endo-THP-oxy17-endo-DMTB-silyloxybicyclo (3.3.07 octane in 8 ml of a mixture of 65:25 benzene MeOH is treated with 0.89 g of dicyclohexylcarbodiimide, and then with stirring 1.42 ml pyridine trifluoroacetate solution. After 3 hours, 20 ml of benzene and excess carbodiimide were quenched with 0.13 g of shavel acid in 3.8 ml of water, and the benzene phase was separated, neutralized, and concentrated in vacuo. zkzoformil-3-endo-THP-hydroxy 7-end DMTB-silyloxybicyclo (3.3.0) octane d, l-HaT and enanthioformal pro joster are prepared, and This method is used. Under the conditions of Examples 1-3, 7-exoxybicyclo (3.3.0) octane-3-one-7-dimethyl-tert-butylsilyl ether is used and 2-exoformyl-3 endo-THP-oxy- 7-copies of DMTB-siloxybicyclo (3.3.0) octane. Example 18. Each of the ortho-complex esters: 5.13 g-4-oxo-11 (;, 15-dioxy-9adeoxy-9a-methylene-pro-cyclic-5, 13dienoic acid 406, 5 , 13t-4 oco-llo, 15S-dioxy-9a-deoxy-9a-methylene-20-methylprost cycle-5,13-diene acid, 420,. 5,13t-4-oKco-llot, 153-dioxy-9a de 6 x 9-s -methyl-17 (2) -furyl 18,19,20-terinorprostacycla5 tetrahydr 5, 13-diene acid, H 5,131-4-oxo- 11-6,158-dioxy-9c | deoxy-9o-methylene-16-meta-trifluoromethylphenoxy-17,18,19,20-tetranorpro-prostated cycla-5,13-diene acid M-H20, 510, and their 15K-epimer. dl-5t, 13g-4-oxo-11p, 158-dioxy-20-methyl-9a-deoxy-9a-methyleneprostacyclo-5, 13- (diene acid trimethyl ortho ester, IR (pleura): 1700, 1690 cm, 15k- epimer, - 420. It is converted into the methyl ester by boiling under reflux in methanol (15 ml / g with 2 ml of 0.2 and oxalic acid) and isolating the product by extracting it with ether. A sequential saponification of 2% KHCO in 80% aqueous methanol produces the free acid Example 19. A solution of 0.45 g 5, l3t-4-oKco-lla, 153-dioxy-9a-deoxy-9a-methylene-pro-cycla-5, 13 (diene acid) - trimetilorto (complex eff ira) mmk, E 9850c in 6 ml of methanol and 1.2 ml of 0.2N oxalic acid are refluxed for 2 hours. After evaporation of methanol in vacuo and extraction with ether, 0.42 g of the corresponding methyl ester is obtained A solution of this product in b ml of anhydrous ethyl ether is added dropwise to a stirred solution of 0.1 M zinc borohydride (10 ml) over 10 minutes. After 1 hour of stirring at room temperature, the reaction is quenched with 3N. sulfuric acid. The organic phase is isolated, washed until neutral and evaporated to dryness, giving 0.4 g of the ester 5.13 t4 (S, R), 11l, 158-trioxy-9a-deoxy9q-methyleneprostacyclo-5, 13-diene acid. After chromatographic separation on silica gel (using ethyl ether ethyl acetate as the eluent), 0.11 g of 5, 13t-4S, llo6,158-trioxy-9adeoxy-9a-methylene prostacycl-5, 13-dienoic acid methyl ester is obtained. IR (film): 3400 cm (wide) and 0.14 g of 4P.-epimer of methyl ester. A solution of the latter compound in 5 ml of methanol is treated with 0.05 g of lithium hydrate and 0.3 ml, and then stirred at room temperature for 6 hours. Removal of methanol in vacuo, acidification to pH5, b and rapid extraction with ethyl acetate leads to 5.13 t -4E, lloi, 15Strioxy-9a-deoxy-9c | - methyleneprostacycla-5, 13-diene acid. Treatment of a mixed solution of this compound in ethyl acetate with 0.5 parts of a polystyrene sulfone resin (hydrogen ion form) results in a quantitative yield of 1,4-lactone 5 .13t-4R, lloi, 15s-tripiaxi-9C (-dextxy-9bl-methylylenepropac-a 5, 13-diene acid, mp: 51-52 ° C, 333. 48-epimer-y-lactone is prepared in the same way Example 20. A solution of 0.8 g of 5.13 t-4-OKCo-llot., 158-dioxy -20-methi71-9a-deoxy-9a-methylene-pro-cyclic-5, 13- (diene acid) -trimethyl-ortho (ester) -11.15-BisTHP-ether in 20 ml of a mixture of methylene chloride-ethanol is cooled before and processed 50 mg of NaBH4. Pos After 80 minutes of stirring, the reaction was quenched with 2 ml of acetone and 5 ml of saturated monosodium phosphate. Evaporation of methylene chloride and ethanol in vacuo and repeated extraction with ethyl ether results, after combining the organic extracts, drying and evaporating them, 0.75 g of 5,13t- 4 (s, R) 11 6 6,15B-trioxy-20-methyl-9a-deoxy 9a-methylene-pro-cyclic-5, 13- (diene acid) -trimethyl ortho (ester) -11,15-Bis-THP-gprotic ether. This crude product is a solution of yut in 2.2 ml of methanesulfonyl chloride. The reaction mixture was left overnight at room temperature, and then partitioned between glacial 2N sulfuric acid and ether. The combined organic extracts are washed with brine, dried and evaporated at low temperature to obtain 5, 13t-4
(I, R), 1 loc, 155-trioxy-20-methyl-9adeoxy-9a-methylene-pro-cyclic-5, 13 (diene acid) -trimethyl-ortho (ester) -4-meeelate-11,15-bc-tfc .
Without further purification, this product is dissolved in anhydrous ethyl ether and treated with 50 mg of lithium aluminum hydride in ethyl ether. After stirring for 2 hours at room temperature and one hour at reflux, the reaction mixture is quenched with 2 ml of ethyl acetate and then with wet ethyl ether. After drying and evaporation of the ester, 0.5 g of crude 5.13 g-11L, 15z-dioxy20-methyl-9a-deoxy-9a-methylene-pro-cyclic-5, 13- (diene acid) trimethyl-ortho-(ester) -11 are obtained 15bis-tgp-simple ether.
After treatment at reflux with a brother refrigerator with 12 ml of methanol and 4 ml of 0.3 n. oxalic acid, standard treatment gives 2 g of methyl ester, 13t-llo6.15 (s) -dioxy-20-methyl-9-eoxy-9a-methylene-pro-cyclic-5, 13ienoic acid, M - 1CO360. Liquid chromatography suggests that the resulting product is soy-. It is mainly from trans - (85%) and 15% of the Cis isomer.
So get:
5g-11oC, 155-dioxy-9a-deoxy9a-methylene-20-methylprostacycl-5-eM13-inic acid. NMR (CDCl) mln. . (ppm): 0.90 (3H, t); 4.00 (1H, m); 4.40 (1H, triplet), 5.30 (1H, tripet) and its 5 c-isomer, NMR (CDCl3) 8 ppm; 0.90 (3H, t); 4.00 (1H, multiplet); 4.40 (1H, triplet), 5.27 (1H, t), and also: 5t, 15E-dioxy-9-deoxy-9a-methylene-20-methylprostacycl-5-ene-13-inoic acid. NMR (CDCla) S mld: 0.90 (3N, triplet)) 4.00 (1H, multiplet); 4.39 (1H, triplet) 5.30 (1H, triplet) and its 5 c-isomer. NMR (0001) 5 ppm: 0.90 (EF, triplet); 4.00 (1H, multiplet), 4.40 (1H, triplet) 5.28 (1H, triplet).
Example 21. In an inert gas atmosphere, a stirred suspension of 0.4 g of NaH (75% mineral oil, dispersion) in 13.5 ml of DMSO is heated to 60-65 ° C for 4 hours. Then, the resulting mixture is cooled to room temperature and maintained at At the same time, 2.6 g of 4carboxybutyltriphenylphosphorium bromide, b ml of DMSO and 0.85 g of 2-exo- (35oxy-non-1-tro1ns-1-enyl) -3-endooxybicyclo (3.3.0) -Octane-7-one-3,3 bis-TGP-simple ether. After stirring for 3 hours, the mixture was diluted with 35 ml of water and the aqueous phase was extracted with ether (512 ml and ether: benzene (ml), the combined organic extracts were re-extracted with 0.5 N, NaOIi (3-15 ml), then water to neutralize, and then poured. The combined aqueous alkaline extracts are acidified to pH 5.3 and extracted with a 1: 1 mixture of ether: pentane, washed until neutralized, dried with tJajSO and the solvent removed, after which 0.86 5, 13t-llct, 15S-dioxy-9a-deoxy-9a-methylene-20-methylprostacyclo-5, 13- (diene acid) 11, 15-Bis-TGP-ether.
five
The resulting product is esterified with diazomethane, and the pyranyl protecting groups are removed as follows.
The methyl ester is dissolved in anhydrous methanol and treated with a solution of 10 molar equivalent of t-toluenesulfonic acid vapor. After 4 hours, pa-toluenesulfonic acid is neutralized with pyridine and
5, the mixture is evaporated to dryness. After purification on silica gel, methyl ester 5.13 t− is obtained. 11o (, 155-dioxy-9a-deoxy-9a-methylene20-methylprostacyclo-5, 13-diene acid (M 360), which is then separated into individual 5c, 13t and 5t, 131 isomers by liquid chromatography.
Using the same technique, receive:
five
5t-llo (;, 153-dioxy-9a-deoxy-9methylene-20-methylprostacycl-5-en-13-tonic acid - NMR (CDCl) mld: 0.90 (3N, triplet); 4.00 (1H, multi -. Tiplet)} 4.40 (1H, triplet); 5.30
0 (1H, triplet); 4.00 (1P, multiplet), 4.40 (1H, triplet); 5.30 (1H, triplet) and its 5c-isomer - NMR ()) (1H, triplet),
five
5t-ll, 153-dioxy-9y-deoxy-9 ) 5 mld: 0.90 (3N, tri0 plet), 4.00 (1H, multiplet); 4.40 (1H, triplet); 5.23 (1H, triplet). Example 22. With stirring and cooling from the outside to maintain the reaction temperature at
5 20-22 ° С solution of freshly obtained potassium tert.-butoxide in 12 ml of anhydrous DMSO is treated successively with 1.8 g of 4-carboxybutyltriphenylphosphonium bromide in 10 ml of DMSO and 0.65 g
0 2-exo- (2-bromo-3-oxyoct-1; 1-yl) -3-endo-oxybicyclo (3.3.0) octan-7-one; 3,3-BIS-THP-ether in 5 ml DMSO After stirring for 8 hours at room temperature, the mixture was diluted with 5 of the same amount of water, acidified to pH 5 and extracted with 1: 1 ethyl ether: pentap. The acidic aqueous phases are drained and the combined organic extracts are extracted with 0.8 n. Kaon (5-20 ml), and then with water until neutralized. When these organic phases are drained, the aqueous alkaline extracts are acidified to pil 5 and the mixture is extracted with a 1: 1 ethyl ester of pentane. The combined extract was dried with Ka2S04, filtered, and treated with ether diazomethane to a yellow color. After evaporated}; dry, Hot, 153-dioxy-9a-deoxymethyl lenprostat-5-ene-13-inova acid (methyl ester of group 11, 15-Bis-THP-simple ether) is obtained after removal of the pyranyl protecting group and subsequent separation by liquid-liquid chromatography get 5t-11o6,15 in-dioxy9a-deoxy-9o (5th 13-inic acid methyl methane-pro-cyclic methyl ester (M + 344} 0 m: -H, 2O - CfHfi 279) and 5g-geometric isomer. Using the described procedure , the compounds listed in Example 21 are prepared. Example 23. If bicyclob (3.3.0) -oct 7-one-3,3-BIS- is used in Examples 22 THP-ethers, methyl esters of the following acids are controlled: 5c, 13g-11p, 153-dioxy-9yg-deoxn. 9p methylene-pro-cyclic-5,13-dioic acid, M-Hjp 346-, 5c-11l, 15z- Dioxy-9a-deoxy-9 1-methylene-1bB-fluoroprocyclic-5-en13-inoic acid, M 362 5c-11os, 153-dioxy-9o | -deoksz1-9amethylene-1b5-fluoroprostacyc-5-ene-13-one acid, 362 5 c-Hot, 15z-dioxy-9a-deoxy-9 1-methylene-17 (2) -tetrahydrofuryl-18.1 20 trinorprostacyc-5-ene-13-Povo acid, M-HgO 386, 5c-11oC, 15z- Dioxy-9a-deoxy-9-methylene-pro-cyclic-5-ene-13-inoic acid, -H-2O 344, 5c, 13t-llcC, 15S-diox-9q-dioxi 9C | -methyleneprostacyc-5, 13 -dienoic acid, M -HjO 346, 5c, 13 -11 ° C, 153-dioxy-β-deoxy9a-methylene-1b S-methylprostacycl-5.1 dienic acid, ZbO 5c-13gg-11s6,158-dioxy-9a-methyls 20 -methylprostacycla-5,13-dienoic acid, M 360, 5c, 13g-11Y, 158-dioxy-9a-deoxy 9a-methylene-17-cyclohexyl-18,19,20 trinorprostacic-5, 13-diene acid, M 372, 5c, 13t-llflt, 153-dioxy-9a-deoxy 9o-methylene-17-phenyl-18,19,20-trinor of prostatocycle-5,13-diene acid, m zso; 5c, 13t-l 1oC, 153-dioxy-9a-deoxy9o-methylene-16-yyu-SGs-phenoxy-17, 18,19,2O-tetraNorprostat-5,13-dienoic acid, M 450, 5c, 13 ± -11o, 158-dioxy-9a-deoxy9a-methylene-16-methyl-1b-butoxy-18, 19,20-trinorprostacic-5,13-dioic acid, M., in the form of a BIS trimethylsilyl ester, as well as their 5- trons-geometric isomers, in particular methyl ester 5t-ll "t, 153-dioxy-9a-de6xy-9methylene-prostacycl-5-ene-13-inoic acid, plus 15H-isomers of both, in particular methyl ester 5t-llet, 15Rioxy ZD -deoxy-9a-methyleneprostacycl-5-ene-13-inoic acid. All methyl esters are then oiled with kgg to produce free acids, in particular: 5t-llrt, 155-dioxy-9a-deoxy-9a-methyleneprostacycl-5-en-13-inic acid - NMR (CDCls) S mcd: 0.90 (3N, t) 4.00 (1H, t), 4.10 (1H, wide triplet), 5.28 (1H, wide triplet) and 5t-llo (;, 15R-dioxy-9a-deoxy-9C1-methylene-pro-cycl-5-en13 -anoic acid - NMR (CDCl-j) mp g 0.90 (3N, t); 4.00 (IH, multiplet) 4.39 (1H, broad triplet)} 5.29 {1H, broad triplet). PRI me R 24. A solution of 0.37 g of methyl ester 5c, 13t-llol 155-dioxy-9c | -deoxy-9a-methyleneprostacyc-5, 13-diene acid in 10 ml of benzene is heated to 250 mg 2 , 3-dichloro-5,6-dicyanobenzoquinone for 3 hours. The precipitate is isolated by filtration and the benzene solution is purified on a short column of alumina. Obtain 0.29 g of methyl ester 5c, 13t-lloi, hydroxy-15-oxo-90-deoxy-90-methylen-pro-stethalc-5,13-dienoic acid, M -HjO 344. A solution of this product in a mixture of ethyl ether- toluene is cooled to and treated with 1.2 ml of 1M methylmagnesium bromide in ethyl ether. After 2.5 hours at -20 ° C, the reaction is quenched with a solution, the organic phase is separated, the volume is reduced and purified on silica gel (ethyl ether: ethyl acetate is used as eluent), resulting in 0.1 g 5c, 13g- 11th, 15B-dioxy15 methyl-9o | -deoxy-9a-methylene-pro-cyclic-5, 13 dienoic acid methyl ester, M 360 m / e and 0.072 g of 15n-hydroxy-isomer. . Example 25 A solution of 2.2 g of 3-endo-oxybicyclo (3.3.0) octan-7-one in 100 ml of anhydrous benzene is treated with 4 ml of ethylene glycol and 0.2 g of para-toluene sulfonic acid monohydrate and boiled in reverse refrigerator for 12 hours, while taking away the water that is formed during the reaction. Then add
0.25 ml of pyridine and the mixture is cooled. The organic phase is washed with water, NaHCO, then again with water and evaporated to dryness. 2.32 g of 3-endooxybicyclo (3.3.0) octan7-one-7, 7-ethylene dioxide, IR (film): 3450 cm and no absorption at 1745 cm are obtained.
A solution of this product in 40 ml of acetone is cooled at 1745 cm to -5 s and treated at this temperature with 4.1 ml of Jones reagent. After 20 minutes at -5 ° C, the excess oxidant is quenched with 4 ml of isopropyl alcohol. 150 ml of benzene are added and the benzene phase is successively washed with 20% (NN4), water, 5% NaHCO-j and water. After evaporation to dryness, 2.1 g of d, l-bicyclo (3.3.0) -octane-3,7-dione-7,7 ethylene dioxide, m.p. 40-42 0.
According to the procedure of Example 1, this compound is reacted with methyl carbonate to give d, l-bicyclo (3.3.0) octane-3,7-dione-2 carboxymethyl ether-7,7-ethylene dioxide; YamaKS 254 MMK, 7000.
According to the method of Example 2, a solution of this product in 20 ml of CH, 2C1 and 20 m of ethanol is reduced to NaBH4 at -20 ° C, resulting in 1.72 g of d, 1-endooxybicyclic (3.3.0) octan-7-one 2-exo (carboxymethyl ester) -6,7-ethylene dioxide. IR (film): 3400, 1720 cm.
A solution of 1.57 g of this compound in 3 ml of dimethylformacchmide is treated with 1.3 g of dimethyl tert-butylsilyl chloride and 0.885 g of imidazole, and then kept at for 5 h. After cooling, water is added and, as a result of conventional processing, I obtain 2.3 g of a, 1-3-endo-oxybicyclo (.3. 3.0) octane-7-oi-2-exo- (carboxymethyl ester) -7,7-ethylenedioxide- Zdimethyl tert. Butylsilyl ether. IR (film): 1710 cm Subsequent reduction of LiAlH in anhydrous ethyl ether (as described in Example 3) gives a, 1-3-endooxy-2-exooxymethyl-7, 7-ethylenedioxybicycloC 3.3.6) octan-7-one-3-dimethyl-tert-butylsilyl ether with quantitative yield, IR (film): 3400
EXAMPLE 26. Using ethylene glycol in place of ethylene glycol, the corresponding 7,7-ethyleneditio analogue is obtained.
EXAMPLE 27 Ethylene glycol (15 ml) and Para-toluene sulfoxylose (0.9 g) were added to a solution of 2-exobrom-3-endooxybicyclo (3.3.0) heptan-b-it in benzene and the resulting mixture boil for 12 hours to remove the water that forms during the reaction. Then add to the mixture
are pyridine (0, b ml) and cooled to room temperature.
The organic phase is washed with water, 2.5% aq. And water, then dried. Benzene (100 ml) is partially removed in vacuo, then the resulting mixture is treated with tributyltin hydride (41 g) under nitrogen at 55 ° C for 1 h. After cooling to room temperature, the organic phase is washed with saturated aqueous solution, dried and evaporated to dryness. After purification of the residue obtained (240 g) with benzene: ether, 14.9 g of 3-endooxybicyclo (3.3.0) hepten-6-on6, 6-ethylene dioxide, IR (film): 3460 cm, in the form of trimethylsilyl ether are obtained.
Example28. A stirred solution of 12.75 g of 3-endooxybicyclo (3.3.0) heptane-6 / -one-6,6-ethylenedioxide (in benzene), 340 ml, and D1-1CO (112 ml) is treated with dicyclohexylcarbodiimide (465 g) , pyridine (5.9 g) n trifluoroacetic acid (5.4 g). After 6 hours, the resulting mixture was diluted with benzene (600 ml) and water (50 ml), filtered from dicyc: oxylurea and the organic phase was washed with water, dried with MgSO4 and evaporated to dryness. Get bicyclo (3.2.0) heptane-3,6-dione-6,6t diethylene dioxide, IR (film): 1742 cm
A solution of the crude product in dimethyl carbonate (70 ml) was added to a suspension of sodium hydrate (80% in mineral oil, 4 g). The resulting mixture is stirred until hydrogen appears at room temperature and then heated for 40 minutes at 75-80 ° C.
After cooling, the reaction mixture was diluted with benzene (350 ml) and acetic acid (8.4 g), washed with water, dried and evaporated to dryness to obtain a mixture (1: 1) a, 1-bicyclo (3.3.0) -heptan-3 , 6-Dione-2- (carboxymethyl ester) -6,6 | ethylene dioxide, II, (,) and d, 1-bicyclo (3.2.0) -heptan-3, b-dione4 (carboxymethyl ester) 6, 6-ethylene dioxide, which is separated by chromatography on SiOj, using a mixture of hexane and ethyl ether as eluent.
Example 29 According to the method of example, 28 out of 14.85 g of 3-endo-oxybicyclo (4.3.0) -nan-7-on-7-ethylenedioxy, 13.9 g of bicyclo (4.3.0 ) nonan-3,7-dione, 7-ethylene dioxide, Sic (film): 1740 cm M 196 M / eJ, which gives 4.2 g of d, 1-bicyclo (4.3.0) -non-3 for carboxymethylation, 7dione-2- (carboxymethyl ester) -7,7-ethylene dioxide and 4.8 g of d, l-bicyclo (4.3.0) nonane-3, 7-di (en4- (carboxymethyl ester) 7, 7-ethylene dioxide , also called d, 1 bicyclo (4.3.0) nonan-3,8-dione 2- {carboxymethyl ester} 8, 8-ethylene dioxide. EXAMPLE 30 Stirring Solution bicyclo (4.3.0) yonan-7-en-3ona (90 g) in dimethyl carbonate; (350 ml) is added to a suspension of hydr; and sodium (80% dispersion in mineral oil, 42 g) in dimethyl carbonate (550 ml). After the evolution of hydrogen is complete, the resulting mixture is heated for 4.5 hours at 75-8.0-C, cooled at room temperature, diluted with benzene (2.7 l) and washed with a 25% aqueous MaH2P04 solution, evaporated to dryness, get bycyclo (4.3.0) nonan-7en-3-one (carboxymethyl ester) (91 g), 252 mmk, (G 8200 A solution of this compound in methylene chloride (1.2 l) and ethanol (1.2 l) cooled to -20 ° C and while stirring, it is treated with NaBH (14.4. The mixture is stirred for 30 minutes again at -20 ° C, then it is treated with acetic acid (23 ml), warmed to room temperature, and the solvents are evaporated in vacuo. The residue is partitioned between ethyl acetate and water, the organic phase is dried and evaporated in vacuo. 64 g of pa a-ester, 1-bicyclo (4.3.0) nonan-7-one-3-endooxy-2-exo-carboxymethyl are obtained in the form of trimethylsilyl ether, which is dissolved in dry tetrahydrofuran (THF) and treated with 2,3-dihydropyran (33 d) and a pair of tol / -olsulfonic acid (0.63 g) for 3 hours at room temperature. 0.4 g of pyridine was added to the reaction mixture. Then, after cooling to 0 ° C with stirring, a solution of 1.2 m HBV and THF is added over 45 minutes. Stirring is continued for 1 h at, then water is added to decompose the remaining hydride. With vigorous stirring and with external cooling to (-5) (- 0) ° C, the resulting borane is oxidized by the slow joint addition of 110 ml of 0.3 M sodium hydroxide and 110 MP to 30% hydrogen peroxide, maintaining the internal temperature at 20-25 C. The oxidized mixture is diluted with benzene (2-l) and the layers are separated. The aqueous layer was extracted with benzene (2-50 ml), the organic layers were combined, washed successively with 1% sodium carbonate, saturated with sodium sulfite and sodium chloride, and then dried with MgSOij. After evaporation of the solution, a crude mixture of 7- and 8-hydroxy compounds is obtained, which are separated by chromatography on SiOj (300 g), using ethyl ether as eluant and obtaining, respectively, a.x-bi- 1 cyclo (, 4.3.0 ) nonan-3-endo, 7-dioxy-2-exo- (carboxymethyl ester) -3-THP-ether (24 g) in the form of trimethylsilyl ether and d, 1-bicyclo (4.3.0) nonan-3-endo- 8-dioxy-2-exo (carboxymethyl ester) -3-THP-ether (27 g), M, as trimethylsilyl ether. A solution of 7-hydroxy alcohol (24 g) in dry DMF (30 ml) is treated with dimethyl-tert-butylsilyl chloride (15.8 g) and imidazole (8.85 g), then heated for 5 hours at, cooled to room temperature temperature, diluted with water (90 ml) and extracted with ether. The organic layers are collected, taken up in water and evaporated to dryness. d, 1-bicyclo (4.3.0) nonan3-endo-7-dioxy-2-exo (carboxyme. ethyl ester) -3-THP- (ether) -7-DMTB-silyl ether,, to the mixture to be stirred of this compound in dry toluene (220 ml), cooled to -70 ° C, a 1.4 M DIVA solution in toluene was added in 45 minutes, maintaining the temperature between (-70) - (- 80) ° C, stirring was continued for 2 hours, the rest of the hydride decomposed by adding 2 M isopropyl alcohol in toluene. The reaction mixture is warmed to room temperature and 30% aqueous aH 2 PO 4 (60 ml) and (50 g) are successively added. After filtration, the organic phase is washed with water and evaporated in vacuo to give d, 1-bicyclo- (4.3.0) 3-ENDO-7-DIOXI-2-EXOFORMIL-3-THP (ether) -7-DMTB-silyl ether . Using the 8-compound in this procedure, d, 1-bicyclo (4,3,0) nonan-3-eido-, 8-dioxy2-exo- (carboxymethyl ester) -TGP- (ether) -8- DMTB-silyl ether, d, 1-bicyclo (4.3.0) nonan-3-endo-3-dioxy-2-exoformyl-THPg (ether) - 8-DMTsilyl ether. Example 31 Using the procedure of Example 27, 30 g of 2-acetoxyperhydroazulene-b-it is converted into its ethylene dioxide (29.1 g), then the compound is saponified by treatment with 2% KjCOj in aqueous methanol. 3-endooxybicyclo (5.3.0) deca8-one-8, 8-ethylene dioxide is obtained, which, after oxidizing in example 2 and treating with dimethyl carbonate (example 28), gives d, 1-bicyclo (5.3.0) decah-3,8dione-2 - (carboxymethyl ester) -8,8-ethylene dioxide (21.2 g); I am 254 nm, e 7000.
PRI me R 32. Bicyclo-keto (ester) ethylene dioxide, prepared in Examples 28.29 and 31, is reduced as follows. To a stirred solution of bicyclo-rocket complex ester (ethylene dioxide) 2.5102 m / m in a 1: 1 mixture of methylene chloride / ethanol (50 ml), cooled to -20 ° C, is added in portions of 0.9 g of NaBH-. After further stirring for 30 minutes, the remaining hydride is decomposed by adding 12 ml of acetone. The reaction mixture is warmed to room temperature, treated with aqueous 20% KH, 2PO4 after removal of the solvent, diluted with water (20 ml) and extracted with methylene chloride. The organic phases are combined, washed until neutral with water, dried and evaporated to dryness in vacuo. The residue is treated with absolute methanol (20 ml) and sodium methoxide (0.54 g) for 12 hours at room temperature, 0.59 g of acetic acid is added, then the solvents are evaporated and extracted with methylene chloride. About 0.22-10 moles of the following bicyclo-oxy (ester) ethylenedioxides are obtained:
d, 1-3-endooxybicycl6 (3.2.0) heptane-b-on-2-exo- (carboxymethyl ester) -6, b-ethylene dioxide,
 d, 1-3-endooxybicyclo (3.2.0) heptane-6-OH-4-exo- (carboxymethyl ester) b, b-ethylene dioxide, also called d, l-3-endooxybicyclo (3.2.0) heptane 7-one-2-exo (carboxymethyl ester); 7,7-ethylene dioxide;
d, l-3-endooxybio (4.3.0) nonan7-one-2-exo- (carboxymethyl ester) -7,7-ethylene dioxide
d, l-3-endooxibibicyclo (4.3.0) nonan8-OH-2-EXO- (carboxymethyl ester) 3,8-ethylene dioxide,
d, l-3-endooxy-cyclic (5.3.0) decane-8-one-2-exo-(carboxymethyl ester) -8,8-ethylene dioxide.
Then a solution of each of these compounds in dry methylene chloride (25 ml) is reacted with 2,3-dihydropyran (2 g) and para-toluene sulfonic acid (38 mg, M) for 2 hours at room temperature. The reaction is stopped by adding 0.1 ml of pyridine, and the resulting mixture is evaporated to dryness in vacuo to obtain the corresponding. corresponding 3-THP ethers, which are used without further purification.
EXAMPLE 33. 3-ENDOOXI-2-ECO-carboxymethylene esters and their 3-THP ethers, prepared according to Example 32, are reduced to the preparation of the corresponding eco-oxymethyl derivatives.
as follows. A solution of 2-102 and p-keto ester (both alcohol and 3-THP ether) in dry ethyl ether (25 ml) is added dropwise to a stirred suspension of L1H4 (0.4 g) in dry ethyl ether (50 ml) . After further stirring for 30 minutes, the residual hydride is decomposed by adding acetone (5 ml) and ethyl ether,
0 saturated with water. Then 12 g of dry MpSO are added, then the organic phase is filtered and evaporated to dryness. The following 3-endooxy-2-exooxymethyl derivatives are obtained:
bicyclo (3.2.0) heptan-6-one-6,6 ethylene dioxide}
bicyclo (3.2.0) heptan-7-one-7, ethylene dioxide;
bicyclo (4.3.0) nonan-7-one-7.70 ethylenedioxide,
bicyclo (4.3.0) nonan-3-one-8-one8, 8-ethylene dioxide,
bicyclo (5.3.0) deci-8-one-8.8 ethylene dioxide
five
and their 3-endo-hydroxy-THP ethers of both the racemic and optically active forms (nat, ent).
Example 34. A free ketone is obtained by treating a solution of 30 endooxy-2-exooxymethylbicyclo (5.3.O) decane-3-one-8,8-ethylene dioxide (5 g, 2.10 M) in methanol (20 ml) and water (2. ml ) para-toluenesulfonic acid (0.3 g) for 2 hours at reflux temperature. The solvent is evaporated in vacuo and the residue is filtered through a short SiC column.
A solution of Z-endooxy-2-exooxymethylbicyclo (5.3.O) -3-one (4.7 g) in
0 dry DMSO (17 ml) is reacted with a ylide obtained from potassium tert.-butylate (27 g), DMSO (280 ml) and 3-carboxypropylphosphonium bromide for 5 hours at 5p ° C. The Fe5 mixture is diluted with water (300 ml) and extracted with an 80:20 ethyl ether-benzene mixture to remove the triphenylphosphoxide. These extracts are drained and the alkaline phases are acidified to pH 5, re-extracted with ethyl ether (8-200 ml) and a mixture of 5: 1 ethyl ether: ethyl acetate (4100 ml). The combined organic extracts are dried, concentrated
5 to a small volume (100 ml), treated with ether diazomethane to obtain the methyl ester, and then evaporated to dryness.
The crude material is chromatographed on SiO (2 (100 g) with ethyl acetate
0 (as eluent) and get 5 (Z-E) W () octanor-12 | -oxymethyl-11 ° C hydroxy-9a-deoxy-9a, 9p-7-homotrimethylene-2-nor-prostacyclic-5enoic acid (complex methyl; ether) (4.1 g), in vidavis-tr methylsilyl ether. By treating this compound in dry DMF (12 ml) with dimethyl-treg.-butylsilyl chloride (2.2 g) and imidazole (1.55 g) at 15 ° C for 24 hours, followed by dilution with water (24 ml) and extracting ethyl ether with chromatographic purification at 810.2 (25 g) with ethyl ether-cyclohexane (as eluent), get it mono-12p-DMT-silyloxymethyl ether (4.31 g 80%). M. Treatment with 10 ml of pyridine and 5 ml of acetic anhydride at room temperature for 12 hours and hydrolysis with aqueous methanol and pdra-toluene with sulphonic acid results in 5- (Z, E) -W (20 -12) -octanor-12p -oxyl tyl-11 ", - hydroxy-Z-de-6-axi-9a, 9b-7-ag mootrimethylene-2-nor-prostacyclic-5en kielota- (methyl ester) -11-acetate,. Using preparative chromatography (using a device of high performance bone chromatography) on SiO and treatment with 3% AgNO (with methylene chloride ethyl acetate as elk tant), individual geometric 5c and 5t dimensions are obtained. Similarly, 5 (Z, E) -W () octanor-12H-hydroxymethyl-11-hydroxy-9adeoxy-9o1, 7a-homodimethylene-pro-cycl-5-enoic acid (methyl ester) -11-acetate and their 5c- and 5t -individual geometric isomers are obtained when 3-endooxybicyclo (4.3.0) -non-7on-2-exb- (carboxymethyl with a false ester) -7,7-ethylenedioxide is used instead of the corresponding perhydrogen roazulene compound and 4-carboxybutylphosphonium bromide is used instead of 3- carbsxypropylene. Example 35. Starting from 2-exo-oxymethyl-TGP-ethers Example 33 and 12 | The oxymethyl 11-acetate of Example 34 is prepared by matching the aldehydes using the following oxidation procedure: 0.64 g of dicyclohexylcarbodiimide OD ml of pyridine and 0.05 ml of trifluoroacetic acid are successively added to a stirred solution of hydroxymethyl compound (2. M in mixture 75: 25 benzene-DMSO (6 ml). After 4.5 hours the reaction mixture is diluted with benzene (20 mp) and water (10 ml) and stirred again for 30 minutes, the dicyclohexyl urea is filtered off and the organic layer is washed with water until neutralized and concentrated to 10 ml getting solution p in benzene of the following aldehydes: Z-endo-TGP-oxo-2-exoformingbicycloC 3.3.0) heptane-6-one-6,6-ethylenedioxide} Z-endo-TGP-oxy-2-exoformalbicyclo (3.2.0) heptane -7-one-7,7-ethylene dioxide, Z-endo-THP-hydroxy-2-exoformalbicyclo (4.3.0) nonan-7-one-7,7-ethylenedioxide} Z-endo-TGP-hydroxy-2-zkzoformalbicyclo (4.3.0) nonan-3-one-8,8-ethylene dioxide} 3H-endo-THP-hydroxy-2-exoformalbicyclo (5.3.0) decane-8-one-8,8-ethylene dioxide; H () octanor-12 / $ - formyl-111yoxy-9a-deoxy-9L-7-homotrimethylene-2-nor-prostacyclic-5- (enoic acid methyl ester) -11 acetate Q5 (z, E), 5c , 5tl; W {20-12) octanop-12p-formyl-1S-9q-deoxy-9Q, 70-homodimethylene-pro-cyclic-5- (enoic acid methyl ester) -11-acetate 5 (z, E), 5c, 5t; i. These compounds are used in the Wittig-Horner reactions without further purification. Example 36. A solution of (2-oxoheptyl) dimethylphosphonate (0.49 g) in b ml of benzene is added dropwise to a stirred suspension of .NaH (80% dispersion in mineral oil, 66 mg, 2 , M) in 15 ml of benzene. After additional stirring for 45 minutes, a solution of 2.10 M 5t-W (20-12) octanop-12p-fcrmyl-llot-oxy-9a-deoxy-9a, 9b, 7a-gromo-methylmethylene-2-noproptocyclic-5 is added. methyl ester) -11-acetate v. benzene (10 ml), after another hour, the reaction is stopped by adding a solution of 132 mg of acetic acid in 5 ml of benzene; the organic phase is washed with water until neutralized, dried and evaporated to dryness. The residue (1.2 g) is absorbed on 810-2 (10 g), and then eluted with a mixture of diclohexane-ethyl acetate. Obtain 0.76 g of 5t, 13g-11 ".-Hydroxy-15-oxo-9adeoxy-9a, 9b-7a-homotrimethylene-2normprostatocycle-5, 13- (diene acid, methyl ester) -11-acetate; L 228 MMK ,, M 418, and 358. The following ot, p-decayed ketones are obtained using other aldehydes in the procedure described / 5c, 13t-II (track-15-oxy-9a-deoxy-9a, 9b, 7a-homotrimethylene-2-nor -prostacycla-5, 13- (dienoic acid methyl ester) -11-acetate, I 228 MMK, E 9900. and mixtures of 5 - () - isomers) M 418, OCO "H 358. 5c, 13t-ll ( t-oxy-15-oxy-9a-deoxy 9a, 701-homodimethylene-pro-cyclic-5, 13 (diene acid methyl ester) -11-acetate (229 (imc, e 1000 0), M 418, 358 / and its 5t and 5 (Z, E) -isomers and the following 2-exo-3-oxo-oct-1-trans-en13-endooxy-THG-simple efnry, bicyclo C 3.3.0) heptan-6-one-6,6-ethylenedioxide, bicyclo (3 .2.0) heptan-7-o7, 7-ethylenedioxide, bicyclo (4.3.0) but nan-7-one-7,7-gtilenediokgid; bicyclo (5.3 .0) decan-3-one-8,8-ethylene dioxide. EXAMPLE 37 An ether solution of 5% methylmagnesium iodide (5 ml) is added to a stirring solution of 5t, 131-11c-hydroxy-15 -OXo-9a-deoxy9a, 7a-homo-dimethylene-pro-cyclic-5, 13- (methyl ester of dienoic acid) (0.4 g) in a mixture of 2: 1 ether: toluene (12 ml) and. cooled to -30 ° C. After stirring for another 4 hours, the reaction mixture is heated to 0 ° C and the remaining reagent is decomposed by adding 20% aqueous. The organic layer is separated, washed with water, dried and after adding pyridine (0.1 ml) is evaporated to dryness. The residue was dissolved in dry methanol (10 ml) and stirred with anhydrous (0.1 g) for 2 times. The solution was filtered, evaporated in vacuo. And the resulting raw material was partitioned between ethyl acetate and .20% NaH, jP04 The organic layer after the usual treatment is concentrated to a small volume, the residue is absorbed at 8162 (20 g). Elution with an 80:20 mixture of ethyl ether: isopropyl ether gives 5t, 13t-llflt, 153-Dioxy 15-methyl-9a-deoxy-9c1, 7a-homodimethylene-pro-cyclic 5,13 (dienoic acid methyl ester), M 392, ( 0.1 g) and its 15-isomer (0.085 g). According to the same procedure, 5t, 13t-llL, 15S-15-methyl-9c-deoxy-9ccl, 9H-momo-rimethylene-2-nop-prostacic5, 13-dienoic acid methyl ester, M 392 and 15N-epimer, M 392 and 15N-epimer 5 Mn and 15N-epimer 5 Mn and 15N-epimer 5, 13-dienoic acid are obtained. Under reflux, a solution of methyl esters in a 80:20 mixture of methanol-water. in the presence of 2%. The solvent is evaporated in vacuo and the residue is separated by melon with ether and water. The organic salts of the phase are re-extracted with 0.5% KjCOj and drained. The combined alkaline phases are acidified to pH 6 and extracted with ether. The combined organic phases are washed, dried with MgSO4 and evaporated to dryness, free acids are obtained. EXAMPLE 38 Using ethylene magnesium bromide, vinyl magnesium bromide and ethyl magnesium bromide instead of methyl magnesium iodide in approx. 37 instead of methyl magnesium iodide, 15-ETHINYL-, 15-vinyl- and 15-ethnyl-pro-cyclcanic acid are obtained. Example 39. Starting from the p-unsaturated ketones of Example 36, secondary allyl alcohols are prepared according to the following procedure. Solutions of p-unsaturated ketone (2-10 M) in dry ethyl ether (20 ml) are added to a stirred solution of 0.25 M zinc borohydride (48 ml) in dry ether (dropwise 30 min.). After further mixing in The unreacted hydride is decomposed for 2 hours by adding saturated HaCl. The organic layer is separated, washed until neutral, the cyijaT is evaporated and evaporated to dryness. Using preparative high-performance liquid chromatography on SiO using a mixture of methylene chloride and ethyl acetate as an eluant, you get: 5c, 13g- 11a: 15z-dioxy-9a-d eoxy9a, 9b, 10a-homotrimethylene-2-nor-prostacyclic-5, 13-1. dienoic acid methyl ester) -11-acetate, M 420 m / e and its 5 (2, E) and 5g-geometric isomers , 5t, 13g-11 (X, 15 3-dioxy-9a-deoxy-9a, 7a-homodomethylene-pro-cycl-5.13 (diene acid methyl ester) -11-acetate, M 420 m / e and its 5 (z, E) and 5c-geometric isomers of the following 2-exo- (3 Ztoxy-oct-trans-enyl) -3-endo-THP-hydroxy: 3-endo-THP-hydroxy: bicyclo (3.2, 0) hept H-b -one-b, 6- ethylene dioxide; bicyclo (3.2.0) heptan-7-one-7,7 ethylene dioxide; bicyclo (4.3.0) nonan-7-one-7.7 ethylene dioxide / bicyclo (4.3.0) nonan-8-one-8.8 ethylene dioxide; and the following 3-endo-THP-hydroxy, 2-exo- (2-bromo-3 S-OKCH-4 R-fluoro-oct-1 -trans-enyl-bicyclo (3,2,0) -heptan-7-one 7,7-ethylene dioxide /,., 2-exo- (2-bromo-3 3-hydroxy-4 S-fluoro-oct-1-trpns-yln) -bicyclo (3,2,0) heptan-7-one-7 - ethylene oxide, M + 476, 4/8; 2-exo- (2-bromo-3 3-hydroxy-non-1 trans-enyl) bicyclo- (3,2,0) -heptanb-one-6, b- ethylene dioxide, M 427, 474 J 2-exo- (W S-OKCH-HOH-l-transenyl) -bicyclo (3,2, O) -heptan-6-one 6, 6-ethylenedioxide, 394 {2-exo ( 3 8-hydroxy-5-phenylpent-1 trans-enyl) bicyclo- (3,2,0) -heptan 7-OH-7, 7-ethylene dioxide, M 414) 2-exo- (2-bromo-3 3-hydroxy -oct-1 trans-enyl) bicyclo (4,3,0) -non-7on-7, 7-ethylenedioxide, M 486, 488J 2-exo- (3-hydroxy-4S- methyl oct1-trans-yl) bicyclo (4,3-, O) -non-7-OH-7,7-ethylenedioxide, M422; 2-exo-{38-hydroxy-4P-methyl-octtrach-enyl) bicyclo- {4.3.0U-nonan-T-it, 7-ethylene dioxide, M 422, 5c, 13b-11 (, 15b-dioxy- 9a-deoxy 9a, 9b, 7a-homo-trimethylene-2-nor-pro-stationic-5,13- (diene acid, Hfcjfl methyl ester) -11 acetate, M 4 and its 5 (Z, E) and 5t-hemetic isomers, 5t, 13t-ll (, 15E-dioxy-9adeoxy-9a, 7a-homodimethylene-pro-cyclic-5, 13- (diene acid, methyl ester) 11-acetate and its 5 (Z, E) and 5c-geometric isomers are the following 2 -exo- (Zn-hydroxy-octl-Trans-enyl) -3-endo-THP-hydroxy: bicyclo (3,2, o) heptane-6-one-b, 6 ethylene dioxide, 380; bicyclo (3,2,0 ) heptan-7-one-7,7 ethylene dioxide, bicyclo C 4,3, O) non -7-one-7.7 ethylene dioxide, M 408; bicyclic (4.3, O) nonan-8-OH-8.8 ethylene dioxide, M 408, and the following 3-endo-TGP-oxy: 2-exo- (2 -3 E-hydroxy-4 R-fTor-oct 1 - trons-enyl) -bicycles {3,2,0) -heptan-7-one-7, 7-ethylenedioxyl, M 476 478 ,. 2-exo-{2 -3 to-hydroxy-4 R-fluoro-oct l - trans-enyl) -bicyclo (3.2.0) -heptan-7-one-7, 7-ethylenedioxide, M 476 478; , 2-exo (2-bromo-3 R-OKCH-HOH-l trans-enyl) bicyclo- (3,2,0) -heptanb-on-b, 8-ethylenedioxide, M 472.474, 2-exo (LC-hydroxy -non-1-rane-enyl bicyclo (3,2,0) -heptan-b-one-6, b-ethylenedioxide, M 394, 2-exo- (3E-hydroxy-5-phenyl-pent-1 tra NS a-yl) -bicyclo (3,2,0) -hept, ai7-one-7, 7-ethylenedioxide, M 414J 2-exo (2-bromo-3n-oxy-oct-1 TpqH-enyl) bicyclo- (4 , 3, O) -nanan7-one-7, 7-ethylene dioxide, M 486.488 2-exo- (3k-hydroxy-4s-methyl-oct1-trans-enyl) -bicyclo (4.3.0) -nonane 7- he-7,7-eTylenedioxide, Mf 422; 2-exo (3H "hydroxy-4n-methyl-oct1-throms-enyl) -biiiklo (4.3.0) -nonane 7-one-7,7-echylenedioxide M 422. PRI me R 40, Individual methyl esters of 11-acetates tprocyclacienic acids are converted into their 11-hydroxymethyl esters by transesterification in dry methanol with anhydrous (0.5 mol, eq.), and their 11-free acids by treating in 80% aqueous methanol. from the bicycle, the THP-hydroxyethylene dioxides obtained in Example 39 are converted into the corresponding prostacyclycic acids, by the following method. A solution of 1-10 M and bicyclo-THP-oxyethylene dioxide in acetone (15 ml) is refluxed with 1N. oxalic acid (10 ml) for 8 hours. The acetone is evaporated in vacuo and the aqueous phase is extracted with ether. The combined extracts after conventional treatment are evaporated to dryness, yielding about 0.6-1-10 M of oxyketone. A solution of this compound in dry DMSO (2 ml) is added to a solution of the ylide prepared as follows. Potassium t-butylate (1.35 g) is added to a 15 mb daso under nitrogen and then 4-carboxybutyltriphenylphosphonium bromide (2.6 g) is added to it to obtain a dark red solution of ylide. After the ketone is added, the reaction mixture is heated at 40-42 ° C for 6 hours, cooled, diluted with water (20 ml), acidified to pH 5.1 and extracted with ether (5-5 ml). The aqueous phase is drained, the organic extracts are collected, washed with WATER (5 ml) and extracted with 0.5N. NaOH (66 ml) and water until neutral. The combined alkaline extracts are combined, acidified to pH 5 and extracted with ether. The combined organic extracts are washed with water (2 ml), dried over and evaporated to dryness to obtain a mixture of 5Z-and 5E-acids. Individual geometric isomers are obtained after chromatographic separation on acidified SiO2 (Fe, Fe, free) using ethyl acetate (SiO / j 30 g, for every 0.2 g of acid) as eluent. In this way, 5t, 13t-lloC, 15s-dioxy-9o-deoxy 9a-nor-methyleneprostacyclo-5, 13-diene acid, M CH-j, 537, M -Cj-H 481 as a trimethylsilyl ester are obtained; 5t, 13t-llol, 15S-dioxy-9a-deoxy 9-nor-methylene-20-methylprostacycla5, 13-diene acid, M 566, M- -CHg 551, M-CfeH, 481 as trimethylsilyl ether, St-llb C, 15s-dioxy-9a-deoxy-9anor-methylene-20-methyl-prostacycla-5ene-13-inoic acid, M 564, M -CH 549, M 479 as trimethylsilyl ether, 5t, 131-11og., 158-dioxy -9a-deoxy9c (-methylene-8a-nor-methyleneprostacycla5, 13-dienoic prostateopaemopaemoprophycidine neoplasty; 5g, 13t-llot, 15S-dioxi-9a-deoxyxi9a, 7a-hydroximethylamine prostate; , M 364, M-HoO 346 M -2H2 328; St, 13t-liVC, 15S-diox-9Q-deoxy9a, 9H-dimethylene-pro-cyclo-5,13 dienoic acid, M -HO 346, M 348, 5t-lld, 153-dioxy-9C | -deoxy-9 1 m-1-m-7-ior-methylene-1b-fluoropro-cyclic-5-ene-13-inic acid, M 352;
5g-11,155-dioxy-9a-deoxy-9methylene-7a-normethylene-16K-fluoroprocycl-5-one-13-inoic acid, M- 352;
 5t, i3t-110b, 153-dioxy-9a-deoxy9a-mtstilen-7a-nor-methylene-17-phenyl-18, 19,20-trinorprocycl-5,13 dienic acid, M
5g, 131-11o (,, 153-dioxy-9a-deoxy9C |, 7a-homodimethylene-163-methylprostacycla-5, 13-diene acid, M 378, -N / 20 ZbO;
5t, 13t-llo6,15s-dioxy-9a-deoxy; 9a, 7a-homo-dimethyl-lbs-methylproductive cycle-5,13-diene acid,
m 360;
; 5t-lld., 15s-dioxy-9a-deoxy-90, 7a-homodimethylene-pro-cyclic-5-en13-inic acid, M 362
5c, l3t-ll (t, 153-dioxy-9a-deoxy-9a-nor-methyleneprostacyclo-5,13-diene acid,
5c, 13t-il "-, 15z-dioxy-9a-deoxy9a-nor-methylene-20-methylprostacyclo-5,13-diene acid, 350;
5c-11oC, 153-dioxy-9a-deoxy-9-anan-methylene-20-methylprostacyc-5-ene-13-inoic acid, M 348 /
5c, 13b-11 (L, 153-dioxy-9a-deoxy9a-methylene-7a-nor-methyleneprostacyc-5, 13-diene acid, M — H O 318;
5c-13t-llo.
5c-11o1., 153-dioxy-9a-deoxy-9C | methylene-7a-normethylene-16z-fluoroprostacyclic-5-ene-13-inoic acid,
Sc-lld, 153-dioxy-9a-deoxy-901 methylene-7a-nor-methylene-1bb-fluoroprostacyc-5-ene-13-inoic acid, M-HdO 334
5c-13g-11ob, 153-dioxy-9 (I-deoxy9a-methylene-70-normethylene-17-phenyl18,19,20-trinorprostacic-5.13 dieneic acid, M 352;
5c, 13t-llot, 133-dioxy-9v-deoxy9a, 7a-homodimethylene-1b3-methylprostacycla-5, 13-diene acid, M 378,
5c-13t-lloi, 153-dioxy-9a-deoxy, a, 7a-homodimethylene-16z-methylprostacyc-5, 13-diene acid, M 378;
5c-11b, 153-gdioxy-9a-deoxy-9o, 7a-homodimethyleneprostacyc-5-en13-inic acid and their 15P, isomers, M 362.
Example42. O, 32 g of dicyclohexylcarbodiimide, 0.044 ml of pyridine and 0.022 ml of trifluoroacetic acid are sequentially added to a stirred solution of 0.39 g of methyl 1O ester 5t, 13t-ll "i, 153 dioxy-9a-deoxy-9a, 7a-homodimethylen15-methylprostaclic-15a-deoxy-9a-7a-deoxy-9a, 7a-homodimethylen15-methylprostancyl , 13-diene acid in a mixture of 65:25 benzene-DMSO i (6 ml). After 5 h the reaction
the mixture was diluted with benzene (20 ml) and 1.2 g of oxalic acid in water (10 ml). Stirring is continued for another 20 minutes, the mixture is filtered, and the organic phase is washed until neutral, dried and evaporated to dryness,
After chromatographic purification on SiO (4 g) using ether as the solvent, 0.26 g of methyl ester 5t, 1Gr-11o, -oxo-15h-oxy-9a-deoxy9a, 7a-homodimethylene-15-methylprostacyclic 5, 13-dienoic acid, M 390 which is hydrolyzed with 2% Vedoc to obtain the free acid.
Example 43 2.5 g of sodium borohydride are added in portions to a stirred solution of a bicyclic (4.3.0) nonan-7-en-3-one (11.42 g) in 80 ml of ethanol. After further stirring for 2 hours, 5 ml of acetic acid was added and the mixture was evaporated to dryness. The residue was partitioned between water and the organic layer was evaporated to dryness. The solution obtained bicyclo (4,3,0) nonan-7-ene-3-hydroxy (11 g) in dry DMF is heated sequentially with dimethyl-tert.-butylsilyl chloride (15.6 g) and imidaeol (10.35 g), heat at 60 ° C for 6 hours, cool and dilute with water. After extraction with ether and curing, bicyclo (4.3, nonan-7-ene-3-hydroxy-3-DMTB-silyl ether (19.1 g) is obtained. Its solution is dry THF (100 ml), cooled to treated (with stirring under an atmosphere of nitrogen) with a solution of BH in THF (75 ml) After 2 hours, during which the temperature is maintained, 1N of IOH (25 mp) and 25 ml of 30% hydrogen peroxide are added. for 2 h, cooled and diluted with benzene (400 ml). The organic layer is washed with 1% saturated sodium sulfate solution, saturated with NaCl, evaporated to dryness, unpurified bicyclone (4,3,0) nonan-6 (3) -3-dioxy-3-DMTsilyl ether (20.3 g). The solution of the obtained alcohol in a mixture of 75:25 benzene-DMSO (150 ml) is treated sequentially 16 g of dicyclohexylcarbodiimide, 2 ml of pyrimidine and 1 ml of trifluoroacetic acid with stirring.After 5 h, the resulting mixture is diluted with benzene (400 ml), water (50 ml), solution of oxalic acid (6 g) in water (75 ml) and after additional stirring for 30 minutes, filter. The organic phase is washed with water until neutralized. 18.25 g of bicyclo (4.3.0) nonane-7 8) -one-3-ox-1-dBA-silyl-ether are obtained, which are dissolved in methanol (60 ml and treated with 1.8 g of a pair of toluenesulfonic acid). For 12 hours, the resulting mixture was treated with 1.95 mp of pyridine and evaporated to dryness. The resulting residue was filtered on SiO (ether / ethyl acetate was taken as the eluent) and 10 g of bicyclo (4.3.0) nonan7 (8) -on-3- Ola, A solution of this compound in benzene (50 ml) is boiled with a reverse chiller in the presence of dry egylene glycol (5,2) and para-toluene sulfate (0,62 g), remove water, about 5 times during the reaction In 14 hours, 2 pb of pyridine was added, AND: the organic phase is cooled, washed with water, 2% and saturated bicyclo (4.3.0) nonan 7 (8) -On-hydroxy-7, 7 (8, 8) ethylene dioxide, oil, IR (film): 3400 cm M 198.
Example 44. Saponification of 2% in 80% aqueous methanol d, 1-3endooxybicyclo (4.3.0) nonan-8-one8, 8-diethylenedioxy-2-exo-carboxymethyl ester (4.5 g) gives 4/2 g free acid. , Add (+) ephedrine (2.3 g) to a solution of free acid ((4.2 g) in 120 ml of acetonitrile. After 4 hours at room temperature, 2.8 g of B1 crystallized salt is given after further recrystallization from acetone 2.15 g (+) bicycles 6 (4; 3,0) nrnan-8-one-8,8-ethylenedioxy-3-endo-oxy-2 exo- (carboxylic acid) d "() -ephedrine salt. All mother liquors.connect and evaporate to dryness; the residue is dissolved in water and (Processed with 1 and. -NaOH until alkaline. pH (12-13). d (+) -ephedrine is extracted by extraction with ether, the alkaline aqueous solution is acidified to pYa 5, extracted with ethyl acetate The organic layer and the organic layer are combined, evaporated to dryness. The residue is diluted with acetylnitrile and the procedure is repeated using (-) ephedrine. (-) - BiCl 2: Clone (4.3.0) nonan-8-one-8, 8- ethylene cyoxide-8-endo-oxy-2-exo- (carboxylic acid) -1-ephedrine salt. Each salt is separately dissolved in a water / NaiOH mixture, optically active: the base is separated by extraction with ethyl ether, the aqueous alkaline phase is acidified to pH 5-5.1 and extracted with ethyl acetate to obtain (+) bi-cyclo (4.3.0) nonan-8-one-8.8-ethylenedioxide-3-endociCi-2-exo-carboxylic acid; (-) Bicyclo (4,3,0) nona-8-one-8, 8-ethylenedioxy-3-endocoic-2-exocarboxylic acid, which is converted into complex methyl ethers, treating with diazomethane.
Example 45, A solution of 26 g of d, 1-3-endooxybicyclo (4.3.0) nonan2-kzzo (carboxymethyl complex ether) -7-one-7.7-ethylene dioxide in acetone (100 ml) is refluxed with 2n. H2S04 (20 1 hl) for 4 h.
The acetone is evaporated in vacuo and the aqueous phases are extracted with ethyl acetate. The combined organic extracts are washed until neutral, dried and evaporated to yield 21.2 g of d, 1-3-endo-oxybicyclo (4.3.0) nonan-2-exo (caroxymethyl ester) -7-one. To a solution of this ketone in dry acetonitrile (250 ml) was added 12.1 g of 1,1-phenyl-1-ethylamine and the solvent was slowly distilled off. Add 50 ml over 30 minutes. The resulting mixture is slowly cooled to room temperature, and then after filtration, 12.12 g of (n -) - endo-hydroxy-7,7- (1-phenyl-1-ethylenediimo) -2-exo- (carboxymethyl ester) -bicyclo ( 4,3,0) nonan. The stock solutions are concentrated, 6 g of racemic material are obtained. Further concentration to 8 ml gives 11.42 g of (-) - Zendo-hydroxy-7, 7 (1-phenyl-1-ethylenediimo) -2-exo- (carboxymethyl ether) -bicyclo (4.3.0) nonane.
Separately, two Schiff bases are cleaved at reflux in a 80:20 mixture of methanol 2N. H2S04 (200 ml) for 2 hours. The solvent is evaporated in vacuo and, after extraction with ethyl acetate, the combined organic phases are washed until neutral, dried and evaporated in vacuo. Get 8.1 g
() -3-endooxybicyclo (4,3,0) nonan- 2-exo- (carboxymethyl ester) -7-one- and 7.2 g 2-exo- (carboxymethyl ester) -7-one, respectively.
In this procedure, the bicyclo - (- hydroxy (carbonic ester) - ethylene diirxides of Example 32 are separated into optical isomers.
Get the following 3-endo-oxyspirits
() -) bicyclo (3.2.0) heptane-b-on-2 exocarboxymethyl ester
(+) bicyclo (3.2.0) heptan-7-one-2 exocarboxymethyl ester,
(4-) bicyclo (4,3,0) nonan-7-one-2 exocarboxymethyl ester,
(+) 6-cyclo (4.3.0) nonan-8-one-2-exo-carboxymethyl ester /
(-) bicyclo (5,3,0) -decan-8-one-2 exocarboxymethyl ester /
(-) bicyclo (3.2.0) heptane-b-on-2 exocarboxymethyl ester;
(-) bicyclo (3,2,0) heptane-7-OH-2 exocarboxymethyl ester;
(-) bicyclo (4.3.0) nonan-8-one-2 exocarboxymethyl ester,
(-) Bicyclo (5.3.0) Decane-8-one-2ecocarboxymethyl ester. In Example 31, these ketones are converted into their ethylene oxide prod.one.
Example 46. To a suspension of 80% NaH (40 mg) in anhydrous bezole (4 ml) is added dropwise a solution of 2-oxoheptyldim: tylphosphonate (280 mg) in anhydrous benzene (4 ml) at room temperature. After stirring for 30 minutes, N-bromosuccinimide (230 mg) was added and after 10 minutes methyl 5c-11l-acetoxy-I () octanor-12-formyl-9a-deoxy-9a-methi: leprostacyclic-5- enoic acid (250 mg). The reaction mixture is stirred for 60 minutes at room temperature and then poured into 30% aqueous NaFlJPO H extracted with ethyl acetate. The combined organic phases are washed with 30% aqueous NaH2P04 and water, dried over Na-S and evaporated to dryness to give methyl ester 5c, 131-11L-acetoxy-14-bromo-15-oxo-9a-deoxy-9a-methyleneprostacyc-5 , 13-diene acid (140 mg).
To a solution of methyl ester 5c, 13t-ll) (, - acetoxy-14-bromo-15-oco 9a-deoxy-9a-methylene-prostacycla5, 13-diene acid (GDT mg) in anhydrous methyl alcohol (5 ml added dropwise, suspension of NaBHj (100 mg) in anhydrous methyl alcohol (5 ml) at -10 ° C. After stirring for 30 minutes at -10 ° C, the reaction mixture is poured into .30% aqueous solution - (100 ml ) and then extracted with ethyl acetate. The organic extracts are washed with a saturated solution of (NH4) 2SO) until neutral environment, then dried with Na 30 and evaporated to dryness to give methyl ester 5c, 13t-llcC-acetoxy-15s-ox-14bro -9a-deoxy-9 o | -metilenprostatsikla-5, 13-dienoic acid (130 mg) and the corresponding 15H-isomer (80 g).
A solution of methyl ester 5c, 131-11L-acetoxy-153-hydroxy-14-bromodeoxy-9a-methyleneprostacyclo-5, 13dieneic acid (80 mg) in anhydrous dimethylsulfoxide (1 ml) is treated with potassium tert-butoxide (200 mg).
After stirring for several minutes, the reaction mixture is poured into a 30% aqueous solution. The aqueous mixture is extracted with diethyl ether and the combined ether extracts are washed with water and evaporated to dryness to give, after treatment with KjCO-j, in 80% aqueous methanol and the usual treatment with methyl ester 5c, 15S dioxy-9a-deoxy-9 -5-en-13-new acid,
344, -N / 70-СЛН, О 300;
); M -N ,, 0 SUN, 273.
Example 47. With stirring and external cooling to maintain the temperature at 20-22 with dicyclohexylcarbodiimide (12.7 g), pyridine (1.65 ml) and trifluoroacetic acid (0.83 ml) are added to solution 2-exooxymethyl-3 -endooxybicyclo (3.3.0) octan-7-one-7,7-ethylenedioxid-3-THP-ether (12 g) in a mixture of benzene-DMSO 75/25/80 ml). The reaction mixture is diluted
5 with benzene (50 ml), filtered, washed with water until neutral and dried with sodium sulfate. The solvents are evaporated to a volume of 30 ml and. this solution is added with stirring to a solution of sodium phosphonate obtained by adding a solution of 2-oxooctyldimethylphosphonate (10.8 g) in benzene (30 mp) to a suspension of 80% sodium hydride
5 (1/35 g) in benzene (125 ml). After 15 minutes, the reaction is complete and the reaction mixture is heated with acetic acid (6 ml), washed with water until neutral and dried with sodium sulfate. The solvent is evaporated to dryness in vacuo, the residue is chromatographed on a SiOj gel. By elution with i-hexane ethyl acetate (80:20) 2g-exr- (3-oxo-non-1c trans-1 (-enyl) -3-endooxybicyclic
(3.3.0) Octane-7-one-7,7-ethylenedioxy-3-THP-ether is obtained (12.7 g) as a yellow oil. IR (film) cm: 2970-1690-1670-1625. NMR (CDCl 3) 0.88 (3N, t), 3.2-4.2 (7H, multiple 0 plet), 4.60-4.75 (1H, multiplet), 6.18-6.20 (1H , doublet), 6.79-6.89 (1H, two doublets).
To a solution of this compound in dry pyridine (100 ml), pyridine bromide hydrobromide 24 g is added with over-stirring. After 1.30 h, the mixture was diluted with a 30% aqueous solution of NaH2PO (500 ml) and extracted with ethyl acetate. Organic
0 extracts are collected, washed until neutral, dried and evaporated to dryness in vacuo. The residue is purified on a SiO-j gel (eluent hexane / ethyl ester 30:20) with a compound of 2-exo-3 (2-bromo-3-oxo-non1-trans-1-enyl) -3-endooxybicyclo (3.3 , 0) Octan-7-one-7,7-ethylene dioxid-3-THP-ether (13 g), IR (-; cm-M: 2940-1685-1610.
 A solution of the resulting bromoketone (12.6 g) in methanol was added dropwise to a solution of NaBH4 (4.2 g) in methanol (65 ml) cooled to. Recovery is complete
5 in an hour. The reaction mixture was diluted with an excess of 30% aqueous solution and extracted with ethyl acetate. The organic extracts are collected, washed with oil, dried over, and the solvents are evaporated to dryness in vacuo. The residue (12 g) is taken up in acetone (100 ml) and then worked up with 1N. an aqueous solution of oxalic acid (50 ml) for 12 hours at. After removal of the acetic acid at vacuum, the aqueous suspension is extracted with ethyl acetate. The organic extracts are collected, washed in brine, dried and, after evaporation of the solvent, the traces are purified by chromatography on a column of silica gel. After eluir of aani with n-hexane ethyl acetate (50:50, the following ketospirits are obtained, 2-ekso- (2-br, ohm-3 H-hydroxy-non-1-transsenyl) -3-enddoxybenzo (3,3,0) octane 7 - ohms. (3 g) and 2-exo- (2-bromo-33-oxy-non-1-trans-1-yl) -3 end6-oxybits 1clo (3.3.0) octan-7-one (: 4.2 g.) In an inert gas atmosphere (Nj, 4 carboxybutyltriphenylphosphonium bromide (32.4 g) was added to a solution of potassium β-butylate (18 g) in dry (DMSO / 180 ml) to give a red solution of ylide. Then, a solution of the obtained 3S-alcohol (4.2 g) is added in 5 minutes. The reaction mixture is kept for 15 hours with stirring The reaction mixture was diluted with an excess of 30% aqueous NaHP04 solution (350 ml) and extracted with ether (5X50 ml). The ether extract was collected, washed with brine (15 m and then extracted with 1N NaOH solution (5У15 ml) and water BEFORE the PFR until the wash liquid is neutral, the main extracts are collected, acidified to PY 5 and then E1 is strained with ethyl ether (3X30.1 and 15X10 ml). These organic extracts are collected, washed with brine, dried with Na2SO4 and the solvent is evaporated to dryness in a vacuum. The residue is placed on a chromatographic silica gel column and using ethyl ether.-acetic acid (100: 0.5) as eluent. The compounds are obtained in the following order:. , 15z-dioxy-9a-deoxy-9ame (gilen-20-1 1-methylprostacyc-5-en131-inic acid (1.21 g). NMR (CDCl-) mln .: 0.90 (G, triplet) 4, 00 (1H, multiplet) / 4.40 (1H, triplet); 5.27 (1H, triplet) i 5E-11 (nd, 153-dioxy-9a-deoxy-9me9ylene-20-methylprostacycl-5-ene 1 3 inoic acid (1.84 g). IR (-)), cm-M: 3350, 2115, 1705, NMR (scantc) b 0.9 (3N, triplet); 4.00 (1H, multiplet), 4, 40 (1H, triplet); 5.30 (1H, triplet) | 6.38 (3N, multiplet); Thus, using as the starting compound 3 R alcohol prepared by the Wittig reaction with 4-carboxybutyltriphenylphosphonium bromide and chromatographic separation on silica gel with using ethyl ester-acetic acid (99.5: 0.5), the following compounds are obtained: 5g-11 ° C, 15K-dioxy-9a-deoxy-9methylene-20-methyl-prostacyclic-5-ep13-inic acid (0, 4 g) NMR (CDC15) 6 ppm: 0.90 (ZN, triplet) 4.00 (1H, multiplet); 4.40 (1H, triplet), 5.28 (1H, triplet) / 5E-llot , 15R-Dioxy-9a-deoxy-9Cl-methyl-20-methyl-prostatecl-5-en13-one acid (0.8 g). NMR (CDCl5) 5 ppm: 0.90 (ZN, triplet), 4.00 (1H, multiplet)) 4.39 (1H, triplet); 5.30 (1H, triplet). Example 48. Using the procedure of Example 47, substituting 2-oxooctyldimethylphosphonate for 2-oxononyl dimethylphosphonate, the following compounds are prepared: 5Z-11C6, 15S-diox-9q-deoxide-9q-methyl-20-ethylprostacyl-5-e-cycl-9-methyl-20-methyl-20-ethyl-20-ethyl-proctyl-5-e-9-methyl-20-ethyl-20-ethyl-20-ethyl-20-methyl-phosphonate. () 340 (M -2H70); NMR (CDC13): 0.88 (EH, triplet)) 2.37 (2H, triplet), 3.98 (1H, multiplet), 4.40 (1H, triplet)} 5.30 (1H, broad triplet) , 5,98 (ZN, wide). 5E-11th., 155-dioxy-9a-deoxy-9o | methylene-20-ethylprostacyclo-5 en13-inic acid: m / e 358 (-H „0) 340 (), NMR (CDClI): 0.88 ( ZN triplet), 2.36 (2H, triplet), 3.98. (1H, multiplet); 4.39 (1H, triplet) J 5.30 (1H, wide triplet), 5.62 (3N, broad) and their 15K epimers: 5Z-llct, 15H-dioxy-9a-deoxy-9methylene-20-ethylprostacycling --5-en13-inic acid; m / e 358 (M) 340 (), 5E-11o6,15 in dioxy-9a-deoxy-9 methylene-20-ethylprostad. Acyl-5-ene-13-inic acid J m / e 358 (M-NyO),. 340 (-2H20-). Example 49. Using the procedure of example 49 from the following osfonatov: 2-oxodecyldimethylphosphonate; 2-oxo-isodecyl dimethyl phosphonate f 2-oxoundecyl dimethyl phosphonate; 2-oxoisoundecyldimethylphosphonate; The following compounds are obtained: 5E-11c, 15z-dioxy-9a-deoxy-9c1 (ethylene-2-n-propylprostacyc-5-en13-inoic acid, m / e 372 (m) MP (CDCl) S ppm): 0.88 (ZN, t.), 4.37 (IH, t.), (Hi, t.), 7.21 (ZN, wide); 5Z-llo (, 155-dioxy-90 | -deoxy-9C | methylene-20-h propylprostacyc-5-en13-inoic acid, m / e 372 (M NMR {CDC13) S ppm: 0.88 (ZN, t.) 4.36 (1H, t.), 5.23 ( 1H, t.), 7.34 (3N, broad); 5E-lloi ,, 158-dioxy-9a-deoxy-9h-methylene-20-isopropylprostacycl-5-ene 13-inova acid, m / e 372 (M NMR ( CDCl) S ppm: 0.86 {6H, d.) 4.38 (1H, t.), 5.24 (1H, t.), 7.52 (ZN, broad)}. 52-11-6,153- Dioxy-9a-leoxy-9methylene-20-isopropylprostacycl-5ene-13-inic acid, m / e 372 (M -H-2O) j NMR (CDCl-i) fi ppm 0.85 (bN, d), 4.36 (1H, t.), 5.25 (1H, t.), 6.24 (3N, broad); 5E-11a, 153-dioxy-9a-deoxy-9c | methylene-20-n-butylprostacycl-5-en13-inovaic acid, m / e 386 (M NMR (CDClo) S ppm: 0.89 (ZN, t.), 4.39 (1H, t.), 5.28 (1H, t.), 7.88 (ZN, broad), 52-11L, 15z-dioxy-9a-deoxy -9methylene-20-n-butylprostacycl-5-en13-inova acid, m / e 386 (M -H / NMR (CDCl) 5 ppm: 0.89 (MN, t 4.39 (1H, t.), 5.25 (1H, t.), 6.70 (3N, broad) i 5E-11-6,158-dioxy-9a-deoxy-9s | methylene-20-isobutylprostacycl-5-en13-inic acid, m / e 386 (M NMR (CDCl / i) S ppm: 0.86 (bN, d.) 4.34 (1H, t.), 5.26 (1H, t.), 7.32 (ZN, broad) , 52-11o, 153-dioxy-9a-deoxy-9hmethylene-20-isobutyl prostacycl-5-en13-inoic acid, m / e 386 (M NMR (CDCI / I) 5 ppm: 0.86 (6H, d. 4.32 (1H, t.), 5.27 (1H, t.), 6.54 (3N, broad)} 5E-11os, 15n-dioxy-9a-deoxy-9a methylene-20-H-propylprostacycl-5-en13-inic acid, m / e 372 (M NMR (CDCla ) S MLN.DOL .: 0.88 (ZN, t.), 4.38 (1H, t.), 5.26 (1H, t.), 6.25 (ZN, wide) J 5 Z -116 , 15H-dioxy-9a-deoxy- 90 methylene-20-n-propylprostacycl-5-en13-inic acid, m / e 372 (M-IDO NMR (CDClo) S ppm: 0.88 (GTH, t. ) 4.38 (1H, t.), 5.24 (1H, t.), 6.02 (3N, broad), 5E-llot., 15k-dnoxy-9a-deoxy-9methylene-20-isopropylprostacyc-5-ene 13-inoic acid, m / e 372 (M NMR (CDCl-) S mpn.dol: 0.86 (6H, dL 4.37 (1H, t.), 5.27 (1H, t.), B, 68 (ZN, wide) , 52-11 ° C, 15P-dioxy-9o-deoxy-9methylene-20-isopropyltrogstatsikl-5-ene, 13-inovy acid, m / e 372 (NMR (CDC1)) 5 ppm: 0.86 (6H, d.), 4.36 (1H, t.), 5.27 (1H, t.), 6.63 (3N, broad), 5 E-Nose, 1H -dioxy-y-deoxy-9-methylene-20- p-butylprostacyc-5-en13-inoic acid, m / e 386 (M) NMR (CDCl) S ppm, dol: 0.89 (3N7t.), 4.39 (1H, TJ, 5.26 / 6.40 (ZN, wide); 5g-11c (, 15p, -dioxy-9a-deoxy-9chmethylene-20-and-butylprostacycl-5-en13-inova acid, m / e 386 (), NMR (CDCl) fi MN.dol, 0.89 ( ZN, t.) 4.39 (1H, t.), 5.25 (1H, t.), 6.43 (ZN, broad), 5E-11o (,, 15n-dioxy-9a-deoxy-9methylene -20-isobutylprostacyc-5-en13-inoic acid, m / e 386 (), NMR (CDCl) 5 MN.dol .: 0.86 (BN, d,), 4.38 (1H, t,), 5.25 (1H, t.), 6.58 (3N, broad), 5Z-110I ,, 15E-dioxy-9a-deoxy-9methylene-20-isobutylprostacycl-5-en13-inic acid, m / e 386 ( ), NMR (CDCl-) 5 ppm DOL .: 0.87 (6H, d.), 4.37 (1H, t.), 5.25 (1H, t.), 6.04 (ZN, broad Example 50.With use in Example 47 2-oxo-3K-methylheptyldimethylphosphonate and d, 1-2-exooxymethyl-3-endooxyb cyclo (3.3.0) octan-7-one-7, 7-ethylenedioxide-3-TGPether, after bromination of the intermediate C, p-unsaturated ketone with hydrotromobromide pyridine, reduction using NaBH, removal of protective groups and chromatographic separation, get d, l- 2exo (2-bromo-ZZ-hydroxy-4 R-methyloct-1-trans-1-yl) -3-endooxybicyclo (3.3.0) octan-7-one. NMR (SPS1e) 8 million dollars: 0.76 (GD, d.), 1.00 (GTH, d.), 3.73 (1H, d.), 5.83 (1H, d.), 5.85 (1H, d.), And its 3; epimer These intermediates are converted to the following compounds in accordance with the method of Example 47: d, (z, E) -ltf., L5 8-dioxy-9a-deoxy) a (-methylene-16 H-methylprost 1 Cycle-5-en13-inic acid and d, l-5 (Z, E) -lloC, 15k-dioxy-9o | -deoxy-9a-methylene-1bEmethyl-pro-cycl-5-ene-13-inic acid, NMR (CDC1) 8 MLN.DOL .: 0, 97 (MN, d.), 4.27 (1H, broad d.), 5.25 J1H, broad m.). GP ID and measure 51. a, 1-16 (K, B) Fluoro20- methylcarboprostacyclin (dl-5E-13E11o (, 155-dioxy-9a-deoxy-9a-methylene 16 (R, 3) fluoro-20-methylprostacycl-5,13 dienoic acid. 320 mg a, 1-Zo {-oxy-2p- ( 3 -5-hydroxy-. 4 - (R, 3) fluoro-1-trans -nonenyl-7-oxobicyclo (3.3.0) octane t per reaction in accordance with Example 22 to obtain 103 mg of the target compound, as well as its 52-isomers d, l-5Z, 13E-llo, 15S-diox-9a-deoxide 9a-methylene-16- (K, 3) - fluorine-20-methylprostacyc-5, 13-diene acid and 15k-epimers. Thin layer chromatography for the target compound (ethyl 4-2% AcOH5, 25 NMR (CDCla) (M ppm): 0.89 (GH, t .), 3.77 (1H, m.), 4.0-4.3 {1.5H, m.), 467 50.5N m.), HB C.: 1
50 Hz, 5.27 (1H, t.).
Example52. Following examples 21 and 22 and using appropriate bicyclo. 3. 0) octan-7-on3, 3-BIS-TGP-esters get the following methylene esters:
Sz-Ilot methyl ester, 15S-dioxy 9q-deoxy-9a-methylene-lbR-fluoroprostatocycle-5-en 13-inovoy acid, M -% 0 362
5g-11 methyl ester (X, 158-dioxy-9q-deoxy-9o | -methylene-lbs-fluorocomplot cycle-5-ene-13-inoic acid, M -H, 20,362;
methyl ester 5E-11 ", 15-dioxy 1 9c-deoxy-9a-methylene-16k-fluoroprost 1 cycle-5 eM-13-inoic acid, M-H, 0 362;
methyl ester WE-I, 155-di, oxy-9r-doxy-9a-methylene-16s-fluoroprocycl-5-ene-13-inoic acid, M-HdO 362
methyl ester SZ-llol, 15E-dioxy-9a-deoxy-9a-methylene-16H-fluoroprostacycl-5-ene-13-inoic acid, M - HgO 362,
methyl ester of SZ-llot, 15k-dioxy-9a-deoxy-9a-methylene-16 & - fluoropro-stacic-5-ene-13-inoic acid,
m - 362;
methyl ester 5E-11o (;, 15k-dioxy9a-deoxy-9C1-methylene-16k-fluoroprostacycl-5-en-13-inoic acid, 5 M -HjO 362;
 methyl ester 5E-11, 15k-dioxy9a-deoxy-9a-methylene-16z-fluoroprosTacyl-5-ene-13-inoic acid / M, 362.
All methyl esters are then washed down with free acids.

权利要求:
Claims (1)
[1]
The method of obtaining 9-deoxy 9a-methylenisosterov P01 ₂ General formula
CH ( "H _{2) m1} B (BH _{2) m2} K
(camping ₂ 5Гй ^н гЧ. ^С1)
H GT ^H Β _δ | 5
V. "'* -" H T-C- (CH ₂ ) _P , * =
Where B is free or esterified carboxyl, C (0Bc) s, where Ββ is lower alkyl or CH ₂ B ^, where K _h is hydroxy or C ₇ –C7 alkoxy, formyl or CHSx BD,) ₂ , where X <- oxygen or sulfur; In 40, an alkyl or two together form C | -C $ = alkylene,
ϋ -methylene, hydroxymethylene, cis - or 'Trans-CH = CH, C = C, C = O or oxygen, one of B <and and independently one
from K-, and K4-hydrogen, C; -Cb-alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or phenyl, and the other is hydrogen, hydroxy, C ^ -C ₆ -alkoxy or K ₄ and B _g and independently B and HZ together form an oxo group)
HZ and HZ - the same or different, hydrogen, С <-Сб = alkyl or halogen;
Υ - CH _g CH ₂ , C-C, W - or trans CH = CH ',
X - (CH <2) tz (where t s - 0 or 1). Cis or trans-CH = CH or oxygen; t ₄ , w , Η ₄ u ₂ 0, at 1-12
provided that _{ + т ₂ and п ₄ + п ₂ <15 ',
p and <ι - 0, 1-3, provided that
Ρ + ς 1-6;
H ₇ - hydrogen, C ^ -C ^ -alkyl,
C5- (¾ = cycloaliphatic radical, phenyl, unsubstituted or substituted by halo-C ₄ -C ₆ -alkyl, tetrahydrofuryl,
or lactones obtained by intermolecular condensation of compounds of formula I, where H is carboxyl and ϋ is CHOH or salts of a compound of formula Ϊ, where B is carboxyl, characterized in that the compound ’of the general formula _ V
• Y
*,
SP
WITH
"H
where k, 4 - carboxyl, free or
esterified, or in the form of a salt, or C (S ₆ ) , CH ₂ B4 ₂ ,
where K '4 ₂ - esterified group or C -C ₇ alkoxide, or CH {,
ONE IE B 4 AND B2 is hydrogen, C ^ -C ₆ alkyl, C ₂ -C £ alkenyl, C ^ -C ^ alkyn or phenyl, and the other is hydrogen, hydroxy, Cu - (-alkoxy or C ^ -Datsyloxy group
1053745 A
1053745
-X- (CH ₂ ) „ ₂ -B ₇
b
β * - methylene, cis - or trans-CH = CH C = C, C — 0 SNOSOND or oxygen or 0 ', E _n and (CH ₂ ) p, _g form the group -CH- (cn
Oh =
X _d , Ββ, Ε _ί0 and m ₂ have the indicated, values
subjected to interaction with the compound of the General formula
"6
Е - СН-С- (<ЗД _{l Г} | -Х - (<5Н ₂ ) l ₂ - * 7 2, 0 Βθ
where ζ is hydrogen or halo,
E - (C ^ H ₅ ) ₃ P or (H ₀ op P (0), where H ₁₃ -C-alkyl or phenyl;
'η <, η ₂ , Κ -Κγ and X have the indicated meanings
to give a compound of the general formula
[ead ^ sh ^
“J.
^{4 to} 2 about
where r _{,, }, W ₂ , B, p, p, P |, P , H}, K *, Ζ, nd ₅ , £ £, Xi Εγ have the indicated values,
and, if desired, restore with obtaining, if desired, after the separation of free hydroxy groups from esterified hydroxy groups, which may be present in the compound of the Formula! where Υ is CH ₂ CH $, and H ₃ and H4 together form an oxo group, or, if desired, a compound of formula I, where th ₃ and H4 together form an oxo ·, group, is reacted with a mixed hydride to obtain a compound of formula I, where one from K ₃ and yd is hydroxy, and the other is hydrogen, or is reacted with an organomagnesium compound, followed by obtaining a compound of formula I, where one of K ₃ and Y 4 is hydroxy, and the other is alkyl, alkenyl, alkynyl, or phenyl, and, if desired, a compound of formula I, where Υ -trans = CH = cr, Ζ is halogen, and the presence of oxygr They can be free or esterified, dehydrohalogenizing ^, with obtaining, if it is desirable, after separation of the free oxyl groups of the compound, of formula I, where Υ is C = C, or, if desired, the compounds of the formula! where one of H <C and K ₄ is a hydroxy group which can be etherified to give a compound of formula I, where one of E ₃ and Ed - C <-C £ alkoxyl, or, if desired, a compound of formula I, where one from H <- and B ₂ - hydrogen, and the other - hydroxy group and / or B-oxymethylene, is oxidized to obtain the compound of the formula! where EU and kρ together form a hydroxy group and / or P - C = 0, or a compound of formula I, where one of EU and E ^ is hydrogen, and the other is hydroxy group and / or B is hydroxymethylene, is converted to methanesulfonic acid ester or L- toluenesulfonic acid and then restore, if necessary, the compound of formula I, where E is carboxyl, is esterified, or the compound of formula I, where E is complex, the ester group, is hydrated, followed by isolation of the target product in; free form or lactone,
¹ or salt.
Priority on the grounds: ί 26.01.78 - when the radicals have all the indicated meanings, except when one of p and и is 0.2 or 3, and the other is 0, 1, 2 or 3, moreover, ρ + =
= ι-e;
12/21/78 - when one of p and d is 0.2 or 3, and the other is 0, 1, 2 or 3, with p + d = 1-6.
one

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同族专利:

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公开号 | 公开日

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KE3262A|1983-03-25|

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JPS54119444A|1979-09-17|

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FR2466445B1|1983-04-22|

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IE790145L|1979-07-26|

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AU530571B2|1983-07-21|

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GB2040928A|1980-09-03|

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GB2038333A|1980-07-23|

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NO790257L|1979-07-27|

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DK35779A|1979-09-06|

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DE2902442A1|1979-08-30|

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CA1209133A|1986-08-05|

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FI72509C|1987-06-08|

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NO153926C|1986-06-18|

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SE453289B|1988-01-25|

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NL7900369A|1979-07-30|

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FR2422634A1|1979-11-09|

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SE8303479L|1983-06-17|

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PT69129A|1979-02-01|

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US4307112A|1981-12-22|

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AT374165B|1984-03-26|

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NZ189461A|1982-03-23|

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FR2466446A1|1981-04-10|

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SE7900685L|1979-07-27|

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ATA45279A|1983-08-15|

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NO153926B|1986-03-10|

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MY8400104A|1984-12-31|

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IL56468A|1986-08-31|

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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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IT7819616A|IT7819616D0|1978-01-26|1978-01-26|9-DEOXY-9A-METHYLENE-ISOSTERES OF PGI 2.|

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IT3107378A|IT1160370B|1978-12-21|1978-12-21|9-Deoxy-9a-methylene analogues of prostaglandin=i-2 - useful in human and veterinary medicine esp. as thrombocyte aggregation inhibitors|

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