SU607550A3 - Method of obtaining prostaglandine derivatives - Google Patents

Description

(541

SUPPLY PREPARATION OF PROSTAGLANDINE PRODUCTION

The invention relates to a method for obtaining new, not open, literature from prostaglan.cyme derivatives (which possess biological activity and can therefore find use in me, cycin ..

Olefins production is widely described in patent and technical literature.

CHs

-Y-f

BUT

  . WITH

RS

from carbonyl compounds and alkylphosphonates by the Wittig reaction Ij.

To obtain new, not described in the literature, compounds with high biological activity, use the above reaction.

The proposed method for producing prostaglandin derivatives of the general formula

SNG CHNG tOOR

OCotHj OH -HO where A, R and Q, - have the indicated values (I react with the compound of the general formula HI OORi (СНзО) - Pg-UO-C-1 where they have the indicated values, in the presence of sodium hydride, in anhydrous an inert organic solvent at a temperature followed by reduction of the oxo group in the 15th position of the obtained compound of formula 1 having the structure of (a) ring 0., using sodium borohydride, and, if necessary, removing the protective acyl group, and isolating the resulting product or after dukadim consistent oxidized hydroxy groups in the U ring of the structure / a / to the keto group and dehydration of the latter. Dimethoxyethane is preferably used in the co-oxidation reaction. Example 1 Methyl ether 9 ° C-acetoxy-11o-oxy-16-methoxy-15 -oxo-prosta-5 (Z), 13 / E / -diene-1-hydroxy acid (16R- and 16S-isomers), A. 1.3 g (30 mmol) of the sodium hydride suspension in mineral oil are washed under nitrogen hexavom is then added with 20 ml of anhydrous dimethoxyethane and at -O ° C 8 g (32 mmo) of dimethyl ester (3-methoxy-2-oxo-hepti-71) fs Background ki lots dissolved in 50 ml of anhydrous dimethoxyethane. The mixture was allowed to sit at room temperature for 15 minutes, cooled to 6.24 g of methyl ester 7-5 ° C-acetoxy si-2 | L-formyl-ZoC-oxycyclopent-1e-5 (E) E-hepten-1- was added. Nova acid (20 i-wiO), dissolved in 100 ml of anhydrous dimethoxyethane. The mixture is then stirred for 4 hours and the temperature rises from approximately to. The mixture is poured onto a saturated solution of sodium hydrogen phosphate, and immediately extracted with ethene. The organic extract is evaporated and 14.1 g of crude product are obtained, with two products holding — the right- and left-rotating isomers at position 16, which are separated using preparative thin-layer chromatography, eluting first with ethyl ether / hexane (7: 3), and then ethyl ester: hexane (85: 15). Thus, 1.38 g of the lower polar isomer and 1.410 g of the more polar isomer are obtained. The less polar isomer is both an oily product with the following physical parameters:, 4 s: 0.985% in CHCfj) UV spectrum in methanol:, la.x (MMKM) 218,., 67 IR spectrum (no impurities) : The most significant absorption bands are observed at the following hours, 3400, 2910, 2860, 1740 (cutting), 1625, 1440, 1370, 1240 ,. 1100. NMR spectrum: the most significant absorption peaks in CDCtj are observed at the following frequencies and are expressed in units of 0: 0.88; 1.08-2.88; 2.03; 3.30; 3.64; 3.67; 3.83-4.32; 4,985, 45; 6.50; 6.90. Microanalytical data correspond to the formula Cji, Hjg, O / j. The more polar isomer is an oily product and has the following physical parameters: o., 8 (with 1.05 snow). UV spectrum in methanol: MAxSmmlm) 218,, 28g IR spectrum (no impurities): the most significant absorption observed at frequencies, cm: 3450, 2920, 2860, 1730, 1700 (cutting), 1620, 1435, 1370, 1320 , 1240, 1100, 1040, 985. NMR spectrum: the most significant absorption peaks in CDCtj are observed at the following frequencies and are expressed in units of S 0.88; 1.07-2.84; 2.05; 3.30; 3.63; 3.67; 3.84-4.28; 4,985, 45; 6.50; 6.90. Microanalytical data correspond to the formula. . B). The crude methyl ester of 7-5c. Acetoxy-2-formyl-3-oC -oxycyclopent-1o.-yl (-5) E -hepten-1-one ACID used as the starting compound is prepared in a known manner described for the related analogue, namely (4-phenylbenzoyloxy) -2-formyl-3 (/ -oxycyclpent-1o (-yl (-5) 2 -hepten-1-one acid acid) methyl ester, the only difference being that 5 the hydroxyl group of the cyclopenta of the new ring is not acylated with 4-phenylbenzoyl chloride, but with acetyl chloride. The product from which the specified starting material is obtained It is obtained by hydrolysis using 60% acetic acid, methyl ester.-acetoxy-2-dimethoxymethyl-Sv - (tetra-hydropyran-2-yloxy) -cyclopent-lot-yl (-5) -hepten-1- Onoic acid is an oil with the following physical parameters:

+26.5 (with 1.02%, CHCfj)

IR spectrum (no impurities): the most significant absorption bands are observed at the following frequencies, cm 2900, 2850, 1730, 1435, 1365, 1240, 1120, 1080-1040, 1020, 870.

NMR spectrum: the most significant absorption peaks are observed at the following frequencies and are expressed in units of S: 1.24-2.48; 2.02 and 2.03; 3.22-4.44; 3.40 and 3.42; 4.54-4.75; 4.90-5.20; 5.22-5.51.

Microanalytical data correspond to the formula C22, HjgOg.

Example 2. 9v, 1 let, 15-trioxy-16-methoxyprost-5 (H), 13 {E) -diene-1-oic acid isomers: {15S, 16b) (15S, 16R), (15R, 16S) and (15R, 16R)

A) To a solution of 1.3 g of more than half of the pH-B-isomer obtained in Example 1 (-19.8) in 150 ml of methanol, 300 mg of sodium borohydride in 15 ml of ice water are added dropwise at -10 ° C. The reaction mixture is stirred at-UC until the reaction is complete, subjected to thin layer chromatography and poured into saturated sodium hydrogen phosphate solution. Extraction with ethyl acetate and evaporation of the organic extract gives 1.15 g of a mixture of isomeric methyl esters 9c-acetoxy-liei., 15-dioxy-16 methoxyprost-5- (2), 13 (E) -dien-1-one acids with the same absolute the configuration at position 16 and the opposite absolute configurations at position 15.

The resulting product is dissolved in. 46 ml of methanol and 30 ml of water. A solution of 2.1 g of KOH in 30 ml of 50% methanol is then added and the mixture is stirred at room temperature for 1 hour, after which the reaction is completely complete.

A saturated solution of sodium hydrogen phosphate is added to the reaction mixture, then extracted with ethyl acetate. The organic phase is evaporated in vacuo to give 1 g of a product consisting of an isomeric mixture of the corresponding prostanoic acids, followed by chromatography on an acid washed column of silica gel. Eluted with ethyl ether (hexane), two isomeric products were obtained in a substantially pure form.

The first product eluted (530 mg) is an oil with the following physical parameters:

  +7.6 (from 0.92%, in CHCfj)

IR spectrum (CDCEj): the most significant absorption bands are observed at the following frequencies (cmM: 3580, 3500, 2960, 2935, 2870, 2830, 2240 (set CDCfj product), 1710

(width), 1600, 1452, 1405, 1240 (width 1090, 1040, 970.

NMR spectrum: the most significant pi absorbances are observed at the following frequencies and are expressed in units of 0; 0.88; 1.12-2.57; 2.84-3.29; 3.40; 3.80-4.32; 4.41, 5.21-5.70.

The second zoned product (200 mg) is an oil with the following parameters:

, 2 (, 05% in CHCfj)

NMR spectrum: the most significant absorption peak of WOCES, is observed at the following frequencies and is expressed in units of (3: 0.88; 1.13-2.62; 3.04-3.37 3.40; 3.72-4; 35; 4.84; 5.21-5.70.

B) In the same way as described above, 1.35 g of the less polar C, g -isomer obtained in Example 1 (i.e., the product with - +85.4), is restored with sodium borohydride, then hydrolyzed with KOH in 50% - with methanol to form 920 mg of a mixture of two corresponding prostanonate isomers with opposite configurations at C15.The first product eluted (300 mg) is an oil with the following physical parameters:

, 2 (with 1.85% CHCfj).

NMR spectrum: the most significant absorption peaks are observed at the following frequencies and are expressed in units of 6; 0.88; 1.11-2.63; 3.04-3.37; 3.40; 3.72-4.35; 4.86; 5.21-5.70.

The second product eluted (200 mg) is an oil with the following physical characteristics:

p.20 31.7 (with 1.25% CHCEj)

NMR spectrum: the most significant absorption peaks are observed at the following frequencies and are expressed in units of 3 0.88; 1.11-2.63; 3.04-3.37; 3.40; 3.72-4.35; 4.86; 5.21-5.70. The microanalytic data of all four isomers correspond to the theoretical formula CjjHjgOg.

Example 3. Methyl ester 9d. -acetoxy-11 ° C hydroxy-16-methoxy-16-oxoprost-13 / E / -ene-1-opoP acid (16H- and 16S-isomers).

A) 2 g of methyl ester complex 7- (5 (-acetoxy-2-formyl-Zo - (oxy) -cyclopent-1 (-yl (-hepten-1-oic acid is subjected to interaction as in Example 1A.

Both isomers in position 16 are separated by preparative thin layer chromatography on silica gel plates using the elution system of Example 1. The less polar isomer C of the title product is an oily substance with the following parameters.

 +69 (with 1.04% CHCtj)

IR spectrum (no impurities): the most significant absorption bands are observed at the following frequencies (cm): 3440 (width), 2920, 2850. 2.820, 1740, 1695, 1625, 1460, 1440, 1375, 1240 (width), 1170, 1120, 1100, 10.30, 980.

NMR Spectrum: The most significant absorption peaks are observed at the following frequencies and are expressed in &0.9;2.10;3.48;3.70;3.74; 3,904, 36; 5.12-5.45; 6.6; 7.04.

The more polar isomer C (go oily substance with the following parameters:

, .3 (C5H, 07% CHCEj). The IR and NMR spectra do not show a significant difference when compared with those of the less polar isomer.

B) Methyl ester; .-acetoxy-2J3-one-methoxymethyl 8 r (tetrahydropyran-2-yloxy) -cyclopent-1e (-ilo-5) -hepten-1-oic acid is obtained in accordance with a known method described for the preparation of the corresponding 5 ° C (4-phenyl-6-ethyloxy) homolog using acetyl chloride instead of 4-phenylbenzoyl chloride. ,Cm. Example 1, Item B 32 g of the described product is hydrogenated in 4 L of ethyl acetate at atmospheric pressure and at room temperature in the presence of 10 g of 5% palladium on carbon as a catalyst. By evaporation of the scientific-research institute of the solvent, 32 g of methyl ester of 7 (5- -acetoxy-2-dimethoxymethyl-Zocch- (tetrahydropyran-2-and loxy) -cyclopent-1) -heptan-1-oic acid are obtained; this product with parameter

. 34.3 (s-.1.95% in CHCej) is converted by heating on a steam bath for 30 minutes using 60% acetic acid in 7-5C xy-acetoxy-2-formyl-ZOC (oxy) -cyclopent-. 1o (-yl) -heptan-1-ovic acid used in the condensation step without further purification.

Example 4, Methyl esters of 9,11,15-trioxy-16-methoxyprost-13 (E) -en-1-oic acid isomers {15S, 16S) (15S-16R), (15R, 165) and (15P 16R ).

A) The more polar C, g -isomer obtained in Example 3–3, the product C °, 3, is recovered from sodium borohydride using the method described in Example 2, A. The 9 ° C-Latetate derivative is partially hydrolyzed with K COj-methanol to obtain a mixture of the isomeric esters of the title compound with the same absolute configuration at 15 and opposite absolute configurations at.

Both C isomers are separated by preparative thin layer chromatography, following Example 2 A. The following parameters are obtained:

a) Less polar product (oil) s

c., (s, 47% in CHCCj). The IR spectrum of the most significant adsonational bands is observed at the following frequencies, 3400 (width), 2920, 2845, 1745, 1670, 1460, 1440, 1260 (width), 12 1175, 1095 (broad), 1030, 970.

NMR spectrum: the most significant absorption peaks in CD Ctj are observed at the following frequencies, they are expressed in units of 3: 0.91-1.12; 2.84; 2.90; 3.34-3.46; 3.68-3.80; 4.40; 5.52--5.78.

b) More polar product (oil): WB +19.3 (from 1.21% in CHCEj)

IR spectrum (no impurities): the most significant absorption is observed at the following frequencies, 3380 (width), 2920, 2850, 1740, 1670, 1460, 1440, 1260, 1190, 1170, 1090, 1025, 970, 800.

NMR: The most significant absorption peaks in, / are observed at the following frequencies and are expressed in units of S 0 0.91-1.12; 2.90; 2.95; 3.35-3.47; 3.63-3.84; 4.38; 5.43-5.74.

B) The less polar isomer obtained in example FOR (. +69) is reduced with sodium borohydride 5, then partially hydrolyzed with K, COjjB

methanol to obtain a mixture of isomeric prostanoic acids with the same absolute configuration at C; and g and opposite absolute (configurations at Cff.

Both isomers were isolated by preparative thin layer chromatography, giving the following parameters;

c) The less polar product (oil) s d, 5 (p. 0.96% CHCtj,);

d) More polar product (oil):

, 7 (c-0.66% in CHCtj, Both of these isomers differ in the same IR and NMR spectra as in the isomers described in paragraph A.

 Example 5. Methyl ester 9ot-acetoxy-1111C-hydroxy-16-phenoxy-15-oKconpocTa; -5f rl3 E -dien-1-oic acid (16Ki 168-yzo-measures).

An act in accordance with an example. 1, but dimethyl ester of (3-phenoxy-2-oxo-heptyl) phosphonic acid is used instead of the diphenyl ester (3-methoxy-2-oxoheptyl) of phosphonic acid, to give

50 methyl ester 9v4. -acetoxy, -11rC-hydroxy-16-phenoxy-15-oxoprost-5 (Z), 13 E -dien-1-oic acid (isome; ry 16I and 16S) in 66% yield. In the 9th case, the isomers are not separated.

55 Isomeric mixture has the following parameters.

NMR spectrum: the most significant absorption peaks are observed at the following frequencies and are expressed in units of;

60 ()

0.9; 2.05; 3.70; 3, 3; 4.64; 5.15, 5; 6.66; 6.8-7.6.

Microanalytical data correspond to the theoretical formula

Example 6. Methyl esters of 9c., Llvi, 15-trioxy-16-phenoxy-prosp-5 (2), 13 (E) -diene-1-oic acids C isomers 15S, 16S, and 16R) and (15R, 16S, 1b).

Analogously to example 2, the methyl ester of 9-acetoxy-11 A-hydroxy-16-phenoxy-15-oxoprost 5 (Z), 13 (E) -diene-1-oic acids obtained in example 5 was chromatographed on a column of silica gel. Elution with ethyl ether / hexane gave two mixtures of isomeric products. Each of these mixtures consists of multiple products with the same absolute configurations with and opposite configurations with. The first eluted mixture (4.3 g) is an oil with the following parameters;

The NMR spectrum has the most significant absorption peaks at the following frequencies and are expressed in units of C: (GDCt).

The second zoned mixture (2.5 g) is an oil with the following parameters: 2.04; 3.67; 3.7-4.4 5.0-5.8; 6.8-7.5

NMC spectrum: significant absorption peaks in CDCtj are observed at the following frequencies and are expressed in units of €:

2, 4; 3.67; 3.7-4.4; 5.0-5.8; 6,

Both mixtures were hydrolyzed individually, obtaining the named compounds by dissolving in 160 ml or, respectively, 80 ml of menthol, and adding 3.3 g or 1.6 g, respectively, after which the mixture was kept at room temperature for about 20 hours. To neutralize the reaction mixture, it was saturated with NdHjiPOi solutions, and extracted with ethyl acetate, the name of the compound was recovered by evaporation.

The less polar mixture (3.7 g) has the following parameters:

NMR Spectrum: The most significant absorption peaks are observed at the following frequencies and are expressed in units of: &3.68;3.8-4.4;5.3-5.8; 6.8-7.5.

More polar mixture (1.9 g). has the following parameters;

ma-spectrum: the most significant absorption peaks are observed at the following frequencies and expressed in units of V. 3.65; 3.7-4.4; 5; 2-5,8; 6.8-7.5.

Example 7. Methyl ester 9BC-acetoxy-11 (1 (.- hydroxy-16-methoxy-16-methyl-15-oxoprost-5 (Z), 13 (E) -diene-1-ov to 1slota (isomers 16Y and I6S).

Analogously to Example 1 using 1.2 g of sodium borohydride (55% suspension in mineral oil) in 60 ml of methoxyethane, 8.65 g of dimethyl ester (3-methyl-3-methoxy-2-oxoheptyl) phosphonic acid in 60 ppm dimethoxyethane and 5 g of methyl 7- (5b-acetoxy-2 {-fo | "yl-3 goxycyclopent-11g .- (-5) -hepten-1-oic acid in 45 ml of dimethoxyethane get these two products. These two products R and L are allocated as in Example 1.

5 The less polar isomer (2.5 g) oil with the following parameters:

C 3 ° g + 48.7 (c?: B, 98% CHCfj) NMR spectrum: the most significant absorption peaks are observed in the following frequencies and are expressed in units of 6: 1.28; 2.06; 3.20; 3.67; 3.8-4.3; 5.0-5.5; 6.7-7.0.

The more polar product (oil) has the following parameters: 5, 3 (with 0.86% CHCPj).

NMR: The most significant absorption peaks are observed at the following frequencies and are expressed in units of 0; 1.28; 2.06; 3.18; 3.66; 3.8-4.3; 0 5.0-5.5; 6.6-6.70.

Example 8. Methyl esters of 9 ° C, Hot, 15-trioxy-16-methoxy-16-methylprost-5 (Z), 13 (E) -diene-1e acid, isomers: (15S, 16 &), (15K, 16S ), (15R16R) (15S, 16R), (15S, 16R).

A) 2.31 g of the more polar product obtained according to Example 7 (26.8) is reduced with sodium borohydride and, by chromatographic isolation, the 9-acetate compounds of Example 6 are partially hydrolyzed.

Both products obtained are diastereomeric methyl esters of 5–9 ° C, THEIR, 15-trioxy-16-methoxy-16-methylprost-5 (Z), 13 (E) -diene-1-oic acid with the same absolute configurations and absolute configuration 0 at Cf5. Both products are purified by chromatography 1 on an acid-washed silica gel column, eluting with ethyl ether: hexane. The less polar product (310 mg) is an oil with the following 5 parameters.

NMR: The most significant absorption peaks are observed at the following frequencies and are expressed in units of C (C 0 C): 1.07; 3.23; 3.67; 0 3.8-4.3; 5.2-5.7.

, 4 (with 2.67% CHCtj) The more polar product (22Q mg) is an oil with the following parameters:

 (0.8%)

e NMR spectrum: the most significant absorption peaks are observed at the following frequencies and are expressed in units of 0 (CDCti) 1.07; 3.23; 3.68; 3.8-4.3; 5.2-5.65.

B) Proceed as in paragraph A, but using as the starting material 1.5 g of the less polar product obtained in Example 7c + 58, T, the following mixture of diastereoisomeric compounds is obtained with the same absolute configuration at C

eleven

And the opposite absolute configuration at C, 5.

The less polar product (500 mg, oil) has the following parameters:

NMC spectrum; the most significant absorption peaks in CDCEj are observed at the following frequencies and are expressed in units of 5: 1.12; 3.25; 3.67; 3.8-4, 3 5.3-5.8

.9.9 (, 2%, CHCti). The more polar product (300 mg, oil) has the following parameters:

NMR spectrum: the most significant absorption peaks in CDCCj are observed at the following frequencies and are expressed in units of 3: 1.1; 3.25; 3.8-4.3 5.35, 8.

Wp + 23.3 (, 33 CHCEj) Example 9. 11, 15-DIOXI-16-methoxy-9-oxoprost-5 (Z), 13 (E) -diene-1-acid acids and their methyl esters, isomers - (15 S, 16 S) (15R, 16 &), (15 S, 16R), (15 I, 16R).

A) 11.10 g of a mixture of isomeric methyl esters of 9 ° C-acetoxy-11oc, 15-dioxy-16-methoxyprost-5 (Z), 13 (E) -diene-1-oic acid (obtained in Example 2A), in 600 ml of benzene and dried by azeotropic distillation, treated with 72 ml of 3, 4-dihydro-2H-pyran and 102 mg of anhydrous t-toluenesulfonic acid. After 35 minutes, the reaction mixture was neutralized with sodium bicarbonate solution and extracted with ethyl ether. The organic extract is evaporated to give 14 g of the corresponding Hot, 15-bistetrahydropyranyl ether; to 8.46 g of this compound, dissolved in a mixture of 150 ml of methanol and 100 ml of water, add a solution of 21 g of KOH to 100 ml of 80% hydrolyzed methanol, after which the mixture is stirred for 2 hours at room temperature.

A saturated solution is added to the reaction mixture, then extracted with ethyl acetate. The organic phase is evaporated in vacuo to give 6.5 g of 11 °., 15-bis (tetrahydro-2H-pyran-2-yl) oxy-9-oxy-16-methoxyprost-5 (L), 13 (E) -dieno 1-acid acid. Compound is an oil with the following parameters.

NMR spectrum: the most significant absorption peaks in CD Ctj are observed in units (5: 1.4-1.9; 3.1-4.5; 4.7-5.0; 5.3-5.8; 3 , 40-3,41; 3,44-3,4

To 22 g of Collin's reagent () dissolved in 400 ml of anhydrous methylene chloride, 20 g of celite and a solution of the above-described compound (6.5 g, dissolved in 100 ml of anhydrous methylene chloride) are added.

Peanut stir the mixture at room temperature for 30 minutes, after which the reaction is complete. The reaction mixture is poured into 1 liter of ethyl ether, then filtered and washed with water.

12

The organic phase is concentrated in vacuo to dryness.

The oily residue is chromatographed on a column of silica gel, eluting with ethyl ether: hexane with an increasing amount of ethyl ether; 3.4 g of Hot are obtained; 15-bis (tetrahydro-2H-pyran-2-yl) oxy-9-oxa-16-methoxyprost-5 (1), 13 (E) -diene-1-oic acid.

1.650 g of this acid is dissolved in 250 ml of a solution of acetic acid: water: tetrahydrofuran-19: 11: 3. The reaction mixture is heated to 40 ° C for 24 hours, after which the reaction is complete.

The reaction mixture is saturated by adding sodium chloride, and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated in vacuo to obtain 1.4 g of a mixture of diastereomeric compounds in position 1

An appropriately prepared mixture of diastereomeric prostanoic acids is chromatographed on an acid-washed silica gel column, eluting with ethyl ether: hexane with increasing amounts of ethyl ether, and obtaining 2 of 4 isomeric acids of the title compound in pure form. These acids have the same absolute configuration at C, g and the opposite configuration at C.

The first product eluted (630 mg, oil) has the parameters:

, 9 (, 77% CHCej).

NMR Spectrum: The most significant absorption peaks in CHCtj are observed at the following frequencies and are expressed in units of (5: 3.47; 3, 8-4, 4; 5, 3-5, 5; 5.6-5.8; 5 2-5.6.

IR spectrum (solution in CDCtj): the most significant absorption bands are observed at frequencies, 3380, 305, 2955, 2930, 2870, 2660, 2240, 1747, 1715, 1610, 1510, 1455, 1410, 1265, 1240, 1155, 1090 , 970.

B) 1.35 g of a mixture of isomeric methyl esters of 9 ° C-acetoxy-11, 15-dioxy-16-methoxyprost-5- (2), 13 (E) -diene-1-oic acid, obtained by reduction of sodium borohydride less polar the isomers of example 1 (see also example 2B) are converted into the corresponding llot, 15-bis-tetrahydropyranyl ether as in paragraph A.

1.30 g of 11H, 15-bistetrahydropyranyl ether is dissolved in 50 ml of anhydrous methanol, then 800 mg of anhydrous is added. The reaction mixture is stirred at room temperature for 24 hours, after which the reaction is generally complete. The reaction mixture is neutralized by the addition of a strongly acidic resin, which is easily removed by filtration. The filtrate is concentrated to dryness in vacuo to give

13

1.18 g of a mixture of two .diastereomeric methyl esters of 9 ° C-hydroxy-1 15-bis- (tetrahydro-2H-pyran-2-yl) OKCHJ-9-oxa-16-methoxyprost-5 (2,), 13 (E ) -diene-1-acid acid.

Similar to the method of paragraph A, the resulting mixture is converted into a mixture of two diastereoisomeric 11 ° C, 15-dioxy-16-methoxy-9-oxaprost-5 (2), 13 (E) -dien-1-oic acid. These esters have the same absolute configuration at C, which is the counter half of that of the two acids obtained according to point A, and the opposite absolute configurations C ;, The mixture of diastereoisomeric esters is chromatographed (see point A for two C g isomeric acids),. getting two products virtually pure. The first eluted ester (oil) has the parameters:

, 85 (with 0.82% CHCfj)

NMC spectrum: the most significant peak is 6 (values in are observed at the following frequencies and recorded in units of 53.48; 3.72; 3.8-G, 5; 5.3-5.6; 5 7-5 9

.7 (with 0.67% CHCfj).

The second eluted ester (oil) has the parameters: 3.43; 3.68; 3.9-4.4; 5.2-5.5; 5.6-5.8.

NMR spectrum: the most significant absorption peaks in CDCtj are observed in the following frequencies and are expressed in units of 6: 3.43; 3.68; 3.9-4.4; 5.25, 5; 5.6-5.8.

IR spectrum (no impurities): the most significant absorption bands are observed at frequencies, cm:

3400, 3005, 2950, 2930, 2870, 2240 1740, 1450, 1440, 1405, 1250, 1220, 1155, 1090., 970.

Example 10. Methyl esters of IoC, 15-dioxy-16-methyl-16-methoxy-9-oxoprost-5 (Z), 13 (E) -diene-1-oic acid isomers- (15S, 16 S), ( 15R, 16S), (15S, 16R), (15I, 16I).

BUT). 310 mg 9 o.-acetate precursor of the more polar product of Example 8A

dissolved in 30 ml of benzene and dried by azeotropic distillation. To the dried product, 1 ml of 3,4-dihydro-2H-pyran and 30 mg of p-toluenesulfonic acid are added.

After 15 minutes, the reaction is generally complete. The reaction mixture is neutralized by agitation with sodium bicarbonate solution and washed with water. The organic phase is concentrated to dryness in vacuo to give a residue of 410 mg of the derivative 11., 15-bistetrahydropyranyl ether. To this product, dissolved in 100 ml of anhydrous methanol, 400 mg of anhydrous is added. After 24 h, the mixture is neutralized.

14

adding acidic resin and filter. The filtrate was concentrated to dryness in vacuo to give 360 mg of methyl ester 9 "C-C1Xi-11, 15 bis. (tetrahydropyran-2-yl) oxy - 16-methyl-16-methoxy 11-5-Z (Z),. 13 (E) -diene-1-oic acid. To 50 ml of anhydrous methylene chloride are added with mechanical stirring 2.5 g of Collins reagent (), 2 g of zeolite and 360 mg of the compound obtained above.

After 2 hours, the reaction mixture is poured into 200 ml of ethyl ether, filtered and washed with sodium bicarbonate solution and water. Ether phase

concentrated in vacuo to give a residue of 350 mg of methyl esters of 11o, 15-bis (tetrahydropyran-2-yl) oxy-16-methyl-16-methoxy-9-oxoprost-5 (Z), 13 (E) -diene-1 - acid

150 mg of the obtained compound are dissolved in 2 ml of a CHJCOOH: H20: THF mixture: 19: 11: 3 and heated at 40 ° C for 2 hours. Thereafter, the reaction

the mixture is neutralized with solid sodium bicarbonate and extracted with ethyl ether. The organic phase is concentrated to dryness in vacuo to afford a residue, which is chromatographed on an acid-washed silica gel column. The compound obtained is one of the 4 isomeric esters of the named compound and has the parameters:

 (with 0.46% CHCJj

B) Following the method of point A, from

630 mg less polar 9c -acetate

the precursor of Example 8A,

G, C d ° +6, 0 /, get 400 mg of one

of 4 isomeric named compounds with the following parameters:

  60.6 (with 1.15% CHCfj) B) Follow the procedure described in point A, out of 600 mg less polar 9c C-acetate

predecessor product of example 8B

 ° +9, 9, get one of the 4 isomeric compounds mentioned (400 mg) with the following parameters:

 -62 (with e 2.52% sleep ,,)

d) Following the method of paragraph A, from 700 mg of the more polar 9-acetate precursor of the product of Example 8B, оС 23.3), 420 mg of one of the 4 isomeric compounds mentioned above are obtained

following parameters:

 , ° -48 (sec, 029 SNS (i),

Example 11. llei, 15-DIOXI-16-methoxy-9-oxaprost-13 (E) -en-1-yonic acids isomers: (15S, 16S), (15R, (16S), (15S, 16Я), ( 15R16R).

A) 1.7 g of the 9-acetate precursor of the less polar product of Example 4B f t +13 5 is converted, analogously to the method of Example 10A, to the corresponding methyl ester llei.

15

15-xi-1b-methoxy-9-oxaprost 13 (E) -en-1 oic acid. Output 1.02 g „

The compound is characterized by the following parameters:

C -67.6 (with 1.08%,) NMR spectrum: the most significant absorption peaks in CDCtj are observed at the following frequencies and are expressed as units: 0.93; 3.47; 3.69; 3.8-4.5; 5.6-5.9.

B) Proceed in point A and proceeding from the 9 ° C-acetate precursor of the more polar product of Example 4B, o4. °: +19.7, the corresponding Hot, 15-dioxy-1b-methoxy-9 - oxaprost-13 (E- en-1-oic acid with the following parameters:

, 6 (s, 1.07% CHCej) NMR spectrum: the most significant absorption peaks in CDCtj are observed at the following frequencies and are expressed in units of C: 0.93; 3.48; 3.70; 3.8-4 |, 3; 5.6-5.9.

By proceeding in the same manner as described above and using the two diastereoisomers obtained in accordance with Example 4A as the starting material, the corresponding methyl esters of lleC, 15-dioxy 16-methoxy-9-oxaprost-13 (E) -e -1-oic acid are obtained.

Example 12. Methyl esters of 15-hydroxy-1b-methyl 16 - methoxy-9-oxaprost-5 {2.), 11, -13 (E) -triene-1-oic acid isomers (15 S, $ 16), (155, 16R), (15R, 16Y), (15 R., 16 I). .

A) 300 mg of methyl ester, 15-bis- (tetrahydro-2n-pyran 2 - yl) QKCvi -1b-methyl-16 methoxy - 9 oxoprost-5 (2.), 13 (E) -diene 1 ov The acids obtained in Example 10D are dissolved in a mixture of 2 ml of 2N. brilliant acid and 2 ml of tetrahydrofuran (TEF), then heating up to 48 h,

The reaction mixture is neutralized with solid sodium bicarbonate and extracted with ethyl ether. The organic phase is concentrated in vacuo, the residue is chromatographed on an acid-washed silica gel column, eluting with ethyl ether: hexane to give a partially pure product (150 mg) with parameters;

, 2, (with 1.68% CHCfi) B) Similarly to the same method / but used as starting material obtained in example 10, B methyl ester, 15-bis- {tetraHydro-2-H-pyran-2-yl ) hydroxy-16-methyl-1b-methoxy-9-oxoprost-5 (2g), 13 (E) -diene-1-oic acid. 15-ox-16-me "tilmethoxy-9-" isomeric esters are obtained. oxaprost-5 (J) -11,13 (E -trien-1-ovyh acids with parameters;

0. + 74.1 (with 1.3% CHcij), the other two isomers are prepared in the same way as the same method, but used as starting material

sixteen

two isomeric methyl esfr 11o4, 15-bis- (tetrahydro-2H-pyran-2-yl) oxy-16-methyl-1b-methoxy-9-oxoprost-5- (1) 13 (E) -oic acid, obtained in example 10, points B and G.

Example 13. Methyl esters of 15-hydroxy-16-methoxy-9 oxaprost-5 (E), 11.13 (E) -triene-1-oic acids, isomers: (15S, 16S), (155, 16R), (15R, 16b) (15R, 16I).

D. Analogously to the method of example 12 and using as a starting material a mixture of isomeric AND; 15-bis-tetra-RCHr-2-H-pyran-2-yl) oKCHj-1b-methoxy-9-oxaprost-5 (2) i

The 13 (E) -diene-1 acidic acids obtained in Example 9A give the corresponding mixture of diastereisomers. 15 hydroxy-16-methoxy-9-oxaprost-5 () 11, 13 (E) -triene-1-acidic acids.

The mixture is distinguished by the NMR spectrum: the most significant absorption peaks in the SES are observed at the following frequencies and are expressed in units of 3.47; 3.68; 3.8-4.3; 5-5,5; 6.16; 7., 45.

B) Following the same method of Example 12 and using a mixture of methyl esters 11 "C, 15-bis (tetrahydro-2H-pyran-2-yl) oxy-1b-methoxy-9-oxaprosega-3 ( ,), 13 (E) -diene 1 nd xylode 5, obtained in Example 9B, the corresponding mixture of diastereoisomeric esters is obtained. Both diaste eoisomers are separated by preparative thin-layer chromatography. Elution with hexane: ethyl ether Parameters:

a) Less polyp product

at 1,2 (with -1/02 / S SNSE,)

b) More POLAR product

. 170.8 (0 0.35% in SNCA.)

45

Claims (2)

Invention Formula 1, method for producing prostaglandin derivatives of general formula J  - "" W n / su P ACHj-CHj or cis-CH CH-; B - trans-SP SI-; K is hydrogen or methyl; K is methyl or phenyl; R is n-butyl, j is hydrogen or methyl, R ,, is hydrogen Hj- hydroxy group, imitative with that. what cyclopentanaldehyde of general formula II  x% CIS tOOR where A, d - have the indicated meanings, are reacted with a compound of the general formula U (eNaO), Р ftHi-10- C- W,, H, 18 where they have the indicated values, in the presence of sodium hydride, in an anhydrous inert organic solvent at a temperature followed by reduction of the oxo group at the 15th position of the obtained compound of formula 1 having the structure (a) of the ring CL using sodium borohydride and, if necessary, removing protective acyl group, and the selection of the obtained product or the subsequent sequential oxidation of the oxo group in the ring (X structure (a) to the keto group and dehydration of the latter. 2. The method according to claim 1, characterized in that dimethoxyethane is used as the anhydrous inert organic solvent. Sources of information taken into account in the examination: 1. Waygide-Hilgatag, Methods of experiment in organic chemistry M., ed. Chemistry, 1968, p. 312.