SU1104134A1 - Method of obtaining analogs of prostanglandines - Google Patents

Abstract

1. METHOD OF OBTAINING ANALOGUES OF PROSTAGLANDINS F, of the general formula I: OH I (CH2) 3COlt (CHgV A B OR, where R is alkyl, hydroxyethyl, epoxypropyl, -OCHjCH CH2, CHjCFj or a octyl bicycle; n 1 - 5; Y is the lowest alkyl, 3-chlorophenoxy, 1-naphthyloxy, 2,2-difluoro-3methyl-3-butene-1-yloxy, -OCH.CgH-et-Cl, ethoxy, 3-trifluoromethylphenoxy; A is a hydroxyl group or hydrogen; B is hydrogen or a hydroxyl group, moreover, if A is a hydroxyl group, then B is hydrogen or if A is hydrogen, then B is a hydroxyl group, consisting of the lactone of general formula 11: where n and Y have the indicated values; prenodor or .OZ group; A is hydrogen or OZ group, B being moreover, if A is OZ group, then B is hydrogen or if A is hydrogen, then B is OZ group, where Z is a protective t-butyl dimethylsilyl group, 2,5-dioxyhexyl group, 4-methoxytetrahydropyran-4-yl group, 2-methoxy-2-propyl group, 4-phenylbenzoyl group, benzyloxymethyl group, -CH, OSI, CC1, 2 3 (,,, (СНз) 2СОС2Нд, CHjСОС H5-group; CO is reduced to the corresponding lactol, which is then reacted with a ylide of general formula III: (CH (CH2) jCOX, where X has the indicated values, followed by removal of the protective groupsZ by acidic hydrolysis in an aqueous-organic medium to obtain the desired product of general formula I, where X - hydro

Description

xyl group, and A, B, Y and p have the indicated meanings, which are either isolated or converted to ester.

2, Method POP1, characterized in that the target product is converted into an ester by exposing a compound of formula I, where X is a hydroxy group, by a diazoalkane or oxirane derivative in an aprotic solvent

3. Method POP1, characterized in that the target product

134,

The compounds of the formula I, where X is OH, are converted into the silver salt, and then the ester is treated by an apicalizing agent.

4. Method ijon.l, characterized in that the reduction of the lactone of the general formula II is carried out with diisobutyl luminium hydride or sodium bis (2-methoxyethoxy) aluminohydride at a temperature from 0 to 80 ° C.

one

The invention relates to methods for producing prostaglandin analogs FJL, of general formula I:

HE

Asng) zsoh

(CHgU

B

X - OR, where R is alkyl,

hydroxyethyl, epoxypropyl, —OCH ,, or bicyclooctyl; n 1 - 5;

Y is lower alkyl, 3-chlorophenoxy, 1-naphthyloxy, 2,2-difluoro-Zmethyl-3-butene-1-yloxy5 -OCH.CgH-M-Cl, ETOXI-, 3-trifluoromethylphenoxy;

A is a hydroxyl group or hydrogen; B - hydrogen or hydroxyl

a group, and if A is hydroxyl, then B is hydrogen, or if A is hydrogen, then B is hydroxyl.

Most of the known methods for the preparation of prostatic acid derivatives are related to a series of prostaglandins, substances as well.

known for their physiological activity, especially in the range of RZL ° lyche.ts at the last stages of multi-step synthesis by the following sequence of chemical reactions: the reduction of lactondiol (a) to lactiolol (b)

ABOUT

1-f

about

yy

P.-C5H1,

(B)

where T is hydrogen or THP (tetrahydropyran residue); the reaction of lactoldiol (b) with ylide. (c) with the occurrence of prostaglandin Pgob) or if T is TGP, then with the appearance of its TFT-derivative:

  CH (CH2)

(B) (C) 3 and the subsequent release of hydroxyl groups on G-11 and C-15 is simple diene acid if T is TPT: hydrolysis From this it follows that these last stages of prostaglandin synthesis are carried out or with intermediate products, in which the hydroxyl groups present on 11 and 15 carbon atoms are protected in the form of tetrahydropyran derivatives, or with intermediate products in which these hydroxyls are free. The first method, where the hydroxyl groups are stored in the form of a derivative of tetrahydropyran (German patents No. 2709804, No. 2736110, No. 2437388 No. 2234709, No. 234569, US Patent No. 3933892, England Patent No. 1438093), has the disadvantage that the next asymmetric center arises in the molecule and a mixture of isomeric compounds is obtained. As a result, the products obtained are almost all syrupy, which makes them difficult to isolate, purify and characterize, the second method (J.He.Soc. Perkin 1.1973, 2796), which does not protect the hydroxyl group on carbon atoms 11 and 15 before further synthetic processing is characterized by an increased consumption of expensive reagents, and, in addition, the desired product is difficult to isolate because it is contaminated with ballast substances caused by reactions of free hydroxyl groups and excess reagents. These known methods are based on the proposed method, and it eliminates the disadvantages of the known methods. The essence of the method for producing prostaglandin 2 analogs of this general formula is that for a compound of general formula II: (CH2) aT 344 | Where n, Y have the indicated values; A - OZ group or hydrogen; B is hydrogen or OZ group, where A is a group of OZ, then B is hydrogen, or if A is hydrogen, then B is a group of OZ, where Z is a protective tert.butyldimethylsilyl group, 2,5-dioxyhexyl-, group, 4-methoxytetrahydropyran-4-yl group, 2-methoxy-2-propyl group, 4-phenylbenzoyl group, benzyloxymethyl group, -CHjOCHjCClj, (CH3) 2COC2H5-, (CEj) COCRj-, CH3CO2H, y-group after regeneration lactone grouping into lactol, act as a ylid of the general formula (CgHg) (CHj) 3COX, where X has the indicated value, followed by the removal of the protective groups Z by acidic hydrolysis in an aqueous-op anicheskoy medium to obtain the desired product of the general formula I, wherein X - hydroxyl group, aA, B, Y and n are as defined above, which either is isolated by known methods, or converted to an ester. The target product is converted into an ester, preferably by exposing the compound of formula I, where X is hydroxy groups, by a diazoalkane or oxirane derivative in an aprotic solvent or by converting the reaction product to a silver salt, which is treated with an appropriate alkylating reagent. In the production of a prostaglandin analogue by the proposed method, the lactone diol moieties (a) are converted to lacto diol (b), preferably at (0) - (-80) ° C with a complex hydride, preferably diisobutyl aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydroxide. The .Ilide (e) of the general formula (CHg) SOPS is obtained from the corresponding phosphonium salt in anhydrous dimethyl sulfoxide with a strong base, preferably sodium hydride or alkyllithium. The phosphonium salt for X, which is different from OH, is preferably obtained by the reaction of 3-hapogenpentanoic acid esters with triarylphosphine, and the 5-halopentanoBoic acid ester is prepared by reacting the corresponding acid halide with an alcohol.

Since according to the proposed method, when protecting hydroxyl groups on 11 and 15 carbon atoms, such compounds are used which do not bring the next asymmetric center into the molecule, crystalline products are obtained in most cases. This makes it easier to isolate or characterize the product, which is obtained in quantitative yield.

The next significant advantage of the protection of the hydroxyl group by the proposed method is the easily feasible elimination of these groups.

from the molecule. For example, the hydrolysis of the 4methoxy-4-tetrahydropyranyl protective group proceeds 5-10 times faster than the hydrolysis of the 2-tetragyropyranyl group used so far. In addition, milder conditions, especially lower temperatures and less acid during the reaction, reduce the amount of by-products and thus often eliminate the difficult release of the desired substance.

The values of the radicals and symbols of the indicated formulas I-IV are given in the table. Note,

P r and m about r. 1. To a solution of 325 mg of a lactone of the formula lid in 25 ml of freshly distilled toluene after cooling down to -78 ° C, 1.06 ml of diisobutyl aluminum hydride in toluene (1.5 and solution) are added over 5-10 minutes. Then the reaction mixture is stirred for 15 minutes at the same temperature and decomposed by adding 2.15 ml of methanol, and then stirred for 20 minutes at room temperature. After adding 18 ml of saturated

of a solution of sodium chloride and 18 ml of water, the aqueous layer was extracted with 3x40 m of ethyl acetate, the combined extracts were washed with 8 ml of the fine sodium chloride solution and dried with anhydrous magnesium sulfate. After distilling off the solvents, the oily product is dried under vacuum (60 Pa) at room temperature. 326 mg of lactol Ilia are obtained.

To a solution of 3.23 g of triphenylphosphonium pentanoic acid bromyl in СНН-3-chlorophenyl; MOP - 2-methoxy-2-propyl; MEM 2,5-dioxahex1; DFM is 2,2-difluoro-3-methyl 3-buten-1-yl; PHB — 4-phenylbenzoyl; TNG - 2-tetrahydrofuryl; Vso. - 2- (2,2,2-bicyclooctyl); NPH - 1-naphthyl; NO is 2-hydroxyethyl; IGR - 4-methoxytetrahydropyran-4-yl; EPP is 2,3-epoxypropyl; 9 15 MP of dimethyl sulfoxide, while stirring at room temperature, 5.9 ml of sodium dimethyl sulfoxide (2,., 32 solution) are added over 5-10 minutes. After adding half the volume, the reaction mixture stains with a dark orange color resulting ylide. Over the next 5 minutes, 1.26 g of lactol of Ilia Formula, dissolved in a mixture of 30 ml of anhydrous dimethyl sulfoxide and 3 ml of benzene, are added. The reaction mixture is then stirred for 3 hours at room temperature, after which 32 ml of distilled water is added dropwise with external cooling. The reaction mixture is extracted with 3x30 ml of ethyl acetate and the pH of the aqueous layer is adjusted to 3-4 with the addition of 1.73 and oxalic acid. After re-extraction with a mixture of hexane and ether in a 1: 1 ratio (total 160 ml), the combined extracts are washed with saturated sodium chloride solution, dried with magnesium sulfate and the solvents are distilled off in vacuo. After drying, 0.67 g of a viscous oily acid of formula IVa is obtained. A solution of 0.6 g of the syrup of formula IVa, 5 ml of anhydrous methylene chloride is mixed with anhydrous powdered zinc bromide (2.25 g) and stirred vigorously at 25 ° C for 12 hours. After adding 10 ml of water, the mixture is evaporated in vacuo to evaporate systance paste, which is extracted with 3x30 ml of ethanol. The combined extracts are evaporated to dryness. From the oily residue (480 mg) after chromatography on a column of silica gel with a mixture of benzene, methanol and acetic acid in a ratio of 32: 1, a total of 360 mg (85%) is obtained. An almost pure product of formula 1a. The starting lactone of formula lid is obtained in the following manner. A solution of 4.18 lactone of the formula In in a mixture of 100 ml of tetrahydrofuran and 13 ml of methyl acetate in an atmosphere of argon is cooled to -79. A solution of 3.12 g of tris (2-butyl) lithium borohydride is added with stirring so that the temperature does not exceed -76 ° C After adding the total amount of hydride, the mixture is stirred for 75 minutes at the same temperature. The excess hydride is decomposed by the addition of 25 mp of 40% aqueous acetic acid solution 13410. 280 ml of dichloromethane and 140 ml of water are added to the reaction mixture. The organic layer is separated and evaporated to dryness in vacuo and three times with the addition of 150 ml of methanol. The crude product of formula He (31.99 g) is dissolved in 90 ml of dichloromethane and 200 ml of dry methanol. At room temperature while stirring at room temperature, 6 g of potassium carbonate is gradually added to the solution. The mixture was stirred for another 1.5 h, then 27 ml of 2 N was added. hydrochloric acid, 65 ml of water and 90 ml of dichloromethane. After shaking, the aqueous and organic layers are separated. The organic layer, after drying with anhydrous magnesium sulphate, is evaporated to dryness. The aqueous layer is neutralized with solid acid sodium carbonate and evaporated to dryness. The dry residue is extracted 2 times with 25 ml of chloroform, and after evaporation of the solvent, the syrupy residue is combined with the residue obtained by treating the organic layer. By filtering the crude product through a layer of silica gel, 1.78 g of a crystalline mixture of epimeric diols of the formula lib and Ilc with m.p. 109113 C. The mixture was separated using high pressure preparative liquid chromatography (column 50x0.6 cm, filled with Likhrosorb. Si-5, mobile phase - methylene chloride 85%, acetonitrile 14.9%, water 0.1%, speed 120 ml / h, photometric detection (254 nm), dosage 100 mg of a mixture of alcohols). The less polar epimer of the formula: Not crystallized from ethyl acetate, m.p. 113-115 ° C. The IR spectrum shows characteristic absorption bands at frequencies (CHClj): 3610, .. 3020, 2950, 1771.1598, 1583, 1480, 1285, 1037, 975; (KBG): 2935, 1742, 1598, 1583, 1488, 1380, 1310; 1250, 1081, 1031, 980, 918. The mass spectrum contains the following structural-characteristic ions: m / e 338 (molecular ion), 197 (30), 193 (40), 179 (70), 142 (100) . The more polar epimer of the formula lib crystallizestote from a mixture of acetone, ether and petroleum ether, m.p. 125-127 ° C The IR spectrum shows characteristic absorption bands at the following frequencies (CHCl): 3600, 3015, 2935. 1771, 1598, 1583, 1480, 1285, 111037, 975; (KBr): 2920, 1719, 1597, 1576, U85, 1375, 1251, 1225, 1071, 1030, 980, 909. The mass spectrum contains the following structural-characteristic ions: m / e 338 (molecular ion), 197 (30), 193 (40), 179 (70), 142 (100). In 10 ml. 338 mg of the more polar diol of the formula lib is dissolved in dichloromethane, the solution is protected under a nitrogen atmosphere, 374 mg of chloromethyl (2-methoxyethyl) ether and 387 mg of ethyldiopropylamine 1 in 2 ml of dichloromethane are added and the mixture is stirred at 20–25 ° C for 4 h. Thereafter The reaction mixture is diluted with 10 ml of water, the organic layer is separated and, after washing with 5 ml of the saturated sodium chloride solution, dried with magnesium sulfate, and the solvents are distilled off in vacuum. 510 mg of product are obtained, chromatographically homogeneous (, 4, CFgg silica gel, 2% methanol in chloroAorm), its structure, determined by NMR and MS, is in accordance with the obtained formula and corresponds to formula lid. Example 2. The lacquer tone of the formula Ilf is reduced by diisobutyl aluminum hydride according to the method indicated in Example 1. The lactol of formula Illb thus obtained (1.1 g) after solution in 25 ml of anhydrous dimethyl sulfoxide is added to a ylide prepared by the usual method from 3.25 g of brine triphenylphosphinepentane acid in 15 ml of dimethyl sulfoxide (Example 1). After 3 hours of stirring at room temperature, the reaction mixture is worked up in the usual way (example 1). After thorough drying under high vacuum, they are obtained. 0.76 g of an oily acid of formula IVb. A mixture of 1.3 g of a derivative of formula IVb and 10 ml of a mixture of acetic acid factory-tetrahydrofuran () is stirred for one hour at 25 ° C. Solvents are evaporated under reduced pressure and the product is purified by chromatography on silica gel. 0.77 g of the compound of formula 1a is obtained. - Initial tetrahydrofurylproducer No Ilf is prepared as follows. To a solution of 1.0 g of diol lib in 10 ml of carbon tetrachloride, 1.86 g of tetrahydrofuryl diphenylacetate and O are added, 1 g of p-toluenesulfonic acid. The resulting mixture is stirred at 3412 for 15 h. After adding 20 ml of water, the mixture is shaken three times with 20 ml of heptane. The combined heptane solutions are evaporated to a dosage. Traces of moisture are removed by evaporation from 10 ml of benzene. 1.62 g of a tetrahydrofuryl derivative of formula Ilf is obtained in the form of an oil, the structure of which is in accordance with the interpretation of spectrum. In the IR spectrum, the band at 1775 corresponds to the lactone grouping, and the band at 963 cm corresponds to the out-of-plane diformational oscillations of CH in trans-oleAine, the proton 5IMP signals / 5.72 (2H, trans-olefin), 7.13 (1H) and 6, 85 (MN) aromatic draw. Example 3. Ilg lactone is reduced with diisobutyl aluminum hydride according to the method described in Example 1. A solution of the obtained Bc lactone (2.52 g) in 62 ml of anhydrous dimethyl sulfoxide and 7.1 ml of benzene is added to a solution of the ylide prepared in the same manner as Example 1 of 6.5 g of methyl 5-triphenylphosphonium pentanoate bromide in 31 ml of dimethyl sulfoxide and 11.9 ml of dimethyl sulfoxide sodium (2.32 n solution). The reaction mixture is stirred for 3 hours at room temperature and thereafter 61.8 ml of distilled water is added dropwise with external cooling. The reaction mixture was extracted three times with 60 ml of ethyl acetate and the pH of the aqueous layer was adjusted to 3-4 with the addition of 1.73 n. oxalic acid. After repeated extraction with a mixture of hexane and ether (1: 1), a total of 320 ml, the combined extracts are washed with a saturated solution of sodium chloride, dried with magnesium sulfate, and the solvents are distilled off on a rotary vacuum evaporator. After drying in high vacuum, 1.15 g of substance of formula IVc is obtained, its structure is in accordance with the interpretation of the spectra. The IR spectrum of the 3450-3550 cm band indicates the presence of a hydroxyl group, 1736 cm - stretching CO vibrations in the ester, the proton NMR spectrum shows signals at 8 5.48 (2H, cis-olefin), 5.78 (2H, trans-olefin), 8.3-8.5 (1H). 7.77, 9 (1H), 7.2-7.5 (4H), 6.85-7.09 (1H), which corresponds to aromatic protons, To a solution of 1.1 g of bis (4-methoxytetrahydropyran-4- W1) a derivative of formula IVc in 30 ml of acetone is added 3 MP 0.1 HC1 and the reaction is monitored by thin layer chromatography (chloroformmethanol 100: 2 system). After the starting material disappears, the reaction mixture is neutralized with solid acid carbonate sodium and evaporated to dryness. The dry residue is stirred in a mixture of chloroform and methanol and filtered through a layer of silica gel to remove inorganic salts. A syrphous ester of the formula Ib is obtained with a Rfr value of 0.35 (chloroform-methanol 100: 5), the structure of which is confirmed by MS, for medical ion at 454.2552. Calculated but%: 454.2556. Further, the types of ions were detected at m / Z 436, 327, 309, 297, 157. The starting lactone of formula 11 is obtained by dissolving 700 mg of the corresponding diol of formula Ilh in 20 ml of dichloromethane with traces of P-toluenesulfonic acid in the flask closed with a medical stopper. After cooling to 0 ° C, 5 ml of 5,6-dihydro-4-methoxy-2H-pyran is added from the syringe with stirring over a period of 5 minutes. After 45 minutes, 10 ml of a 1% sodium hydrogen carbonate solution and 10 ml of methylene chloride are added to the reaction mixture. The organic ggloy is separated, dried over magnesium sulfate, and after filtration and distillation of dichloromethane, 0.75 g of slightly crystallizing syrup is obtained, which is used for further reduction without further purification. In the IR spectrum, there are no bands corresponding to OH groups. There is a band at 1778 cm corresponding to the Y-lactone group. Example 4. The lactone of formula Ili is reduced with diisobutylaluminum HYDRIDE using the method described in Example 1. The product of formula Hid is dissolved in 10 ml of anhydrous dimethyl sulfoxide and in 1 ml of benzene and added, with stirring at room temperature, to the solution of the ylide obtained by the usual method ( Example 1) from 1.4 g of 2-C2,2,2-bicyclooctyl) -5triphenylphosphonium pentanoate bromide in 6 ml of dimethyl sulfoxide. After standard treatment, 0.23 g of oily ester of the formula IVd is obtained from the reaction mixture. The protecting groups are removed by the method of Example 3 and in this way a substantially pure syrup-like ester of the formula -Ic is obtained, the structure of which is confirmed by spectra. The proton, NMR spectrum contains signals at 8 5.39 (2H, cisolefin), 5.71 (2H, trans-olefin). In the IR spectrum, the bands 3440-3458, 3600 and 1105 cm correspond to the presence of hydroxyl groups, 1740 cm corresponds to the stretching vibration of the carbinyl group in the ether. In the high resolution mass spectrum, found molecular ion at 462.3329. Calculated,%: 462.3333. The precursor of formula Hi is obtained from solution 1, g of the diol of precursor of formula IIj in 160 ml of dichloromethane, to which 0.05 ml of phosphorus oxychloride is added with stirring and 960 mg of Isopropenylmethyl ether are added at room temperature. The progress of the reaction is monitored by thin layer chromatography. After 30 minutes, 4 ml of a saturated sodium carbonate solution was added to the reaction mixture. The organic layer is separated and washed with 2x10 ml of a saturated sodium chloride solution. After - drying the dichloromethane solution with magnesium sulfate, the solvents are distilled off and syrup-forming. The dried product is dried at 20 ° C and 0.1 kPa. Obtain 2.1 g of the product. Formula Hi. In the IR spectrum, there are no bands corresponding to the presence of OH groups, and an intense band was found at 1775, confirming the presence of the γ-lactone. Example 5. A solution of the lactone of the formula Ilk (645 mg and 10 ml of toluene) is cooled to -60 ° C and then added -; 3 ml of diisobutyl aluminum hydride in toluene (approximately 1.5N solution) are obtained. After standard treatment (Example 1), 642 mg lactone of the formula Ille with a viscous oily consistency. The NMR, mass and IR spectra are in accordance with the proposed structure. To 820 mg of trifenstraponypentanoic acid bromide dissolved in 4 ml of dimethyl sulfoxide (under nitrogen atmosphere) are added with stirring 2.1 tm of sodium dimethyl sulfoxide (1.75 n. solution). To the thus prepared ylide, 261 mg of a lactone of the formula Ille, dissolved in 7 ml of dimethyl sulfoxide and 1 ml of benzene, are added. Then the reaction mixture is stirred for li hours at room temperature and treated with the standard method. 210 oily acid of formula IVe is obtained, the corah structure is confirmed using spectral methods. The F NMR spectrum contains a signal at S107.39 (2F, CFj), the proton NMR spectrum contains signals at fi5.69 (2H, trans-olefin), 5.23 (2H, H - 21) in the IR spectrum - the bands 3390 - 3450 cm confirm the presence of the hydroxyl group, the types of m / Z ions (rel. points%) were found in the mass spectrum: 85 (100 41 (17), 43 (16), 29 (12), 121 ( 10), 67 (9), 86 (8), 27 (6), 39 (5), 84 (5). 210 mg of the indicated acid of formula IVe are dissolved in 13.2 ml of diluted acetic acid (2: 1) and the reaction mixture is heated for 2 hours at 35-40 ° C. After evaporation of acetic acid and water B using a vacuum rotary evaporator (temperature of about 40 ° C, 2660 Pa) from the residue p After standard chromatography, 87 mg of the acid of formula Id is obtained; the proposed structure is in accordance with the spectra. The proton NMR spectrum shows signals at about 1.05-2.83 (18H, S, 2t, H-22, H-12, H- 10, H-8, H-7, H-3, H-4), 5.08-5.83 (6H, t, H-21, cis- and trans-olefin), in the F NMR spectrum of the signal at §107.58 (2F2, CFj, triplet Ij,). In the IR spectrum of the band 3360-3450, 3585, 1100 cm they are responsible for the presence of a hydroxyl group, 1710 cm - corresponds to the valence vibration of CO in the carboxyl function. I .. To a solution of 432.5 mg of lactone of formula He in 30 ml of dichloromethane dob

5 mg of anhydrous p-toluenesulfonic acid are added and, after external cooling with ice and water, 324 mg of methylisopropenyl ether are added dropwise. After stirring for one hour at room temperature, 150 mg of solid sodium carbonate are added to the reaction mixture, and the reaction mixture is treated as in Example 4. 645 mg of a uniform Ilk oily lactone are obtained, the spectra of which are suspended in accordance with the proposed structure. mixtures of 10 ml of dry ether and 5 ml of absolute ethanol; 150 ml of epichloro hydrina- are added to the mixture. The mixture was boiled under reflux for 50 hours to remove moisture from the air. After cooling, the silver salts are filtered off, washed with ethanol, and the filtrate is evaporated in vacuo. From the remaining oil, chromatography on a column of silica gel (chloroform-methanol) yields 405 mg (84%) of a syrup-like ether form 4 16, there are no bands in the IR spectrum that provide for the presence of OH groups. Example 6. 425 mg of an acid of formula 1a are suspended in a glass ampoule in 10 ml of dried ether, 5 mg of freeze-dried iron trichloride are added to the mixture, the reaction mixture is cooled to 0 ° C, and a solution of 50 mg of ethylene oxide in 2 ml of dried ether is added by syringe. The vial is sealed and left at the laboratory temperature for two days. Then the contents of the ampoule are poured into 5 ml of water, the ether is evaporated under vacuum, 0.5 g of carbonate cation exchanger is added to the solution, the mixture is stirred for an hour, filtered, and the filtrate is evaporated under vacuum. The remaining oily product is purified by silica gel column chromatography (chloroform-methanol) and 390 mg (83%) of the practically pure syrup-like ester of formula 1 is obtained. The proton NMR spectrum contains signals at 3.61 and ii, 25 (4H, -CH, jCHj- in ether), 5.52 and 5.83 (4H, cis- and trans-olefin), 7.10 (1H) and The 6.85 (3N) protons in the aromatic core, in the IR spectrum of the band at 1728 cm, correspond to the presence of the ether function: 3350-3482, 3610, 1050, and 1108 cm correspond to the stretching and deformation vibrations of the hydroxyl groups. In the mass spectrum, the types of ions at m / Z were found: 450, 341, 324, 310, .127, 141 and muscleball ions at 468, 1198 (calculated for - 468, 1200). Example 7. To a solution of an acid of formula 1a in 3 ml of 50% aqueous ethanol is added a solution of 180 mg of silver nitrate in 2 ml of water, the silver salt is filtered, washed with water and ethanol. After drying in vacuum, silver

17

ly if. In the IR spectrum, 1742 cm bands were found, confirming the presence of the ether group; 3380 - 3450, 3605 and 1104 cm correspond to the stretching and deformation vibrations of the hydroxyl group. The proton NMR spectrum contains signals at §5.48 and 5.79 (4H, corresponds to cis- and transolefin), 7, 10 (1H) and 6.82 (3N), which correspond to aromatic protons.

Example 8. To a mixture of 26 g of 1,2, 5,6-di-0-isopropylidene-1C-B-glucfuranose and 50 ml of dry pyridine at -78 ° C are added dropwise 22 g of 5-bromovaleric acid chloride. The mixture was left at -17 ° C for 6 hours, at room temperature for 12 hours, after which it was decomposed with water. The isolated crystals of 3-0- (5-bromonaleroyl) -1,2,5,6-di-O-isopropylideOC-B) -glucofuranose are filtered off, washed with water and dried in vacuo. The crude product (41 g) is dissolved in 24.7 g of triphenylphosphine in 125 ml of dry acetonitrile. The reaction mixture was boiled for 10 hours without access of moisture. After evaporation of the solvents, a glassy mass is obtained which crystallizes on standing. By treating the mixture with chloroform-ethanol ester, 46 g (70%) of the solid phosphonium salt is obtained. The structure of the substance is in accordance with the interpretation of the spectra.

Example 9. A mixture of 1.5 g of 2-adamantanol, 40 ml of dry pyridine is treated with 22 g of bromovaleric acid chloride 5 according to Example 8 The crude product (30 g) is converted in the same way (with respect to the amount of chemicals and method) as in Example 8, 45.5 g of the corresponding phosphonium salt (82%). In the IR spectrum there are bands 2890-2990, 1400 and 1380 cm, the corresponding stretching and deformation vibrations of CH in and CHj-groups, then the band at 1738 cm corresponds to the stretching vibration of CO in the ether. In the proton NMR spectrum, the signals at S 1.55 1, 98 correspond to aliphatic protons, 2.65 (2H, t, CH), 3.5-4.0 (2H, CH) and 7.65-7.90 ( 15 N, aromatic protons).

Example 10. A mixture of 13.5 g of 2- (2,2,2) -bicycloo-octanol and 40 ml of anhydrous pyridine treats 22 g of 5-bromovaleric acid chloride.

0413418

lots according to example 7. The crude product (29.2 g) was dissolved in 75 ml of acetonitrile and the method according to example 7 was allowed to react with 5 26.4 g of triphenylphosphine in 130 ml of acetonitrile. 44 g (79%) of the phosphonium salt were obtained. In the IR spectrum there are bands at 2890-2985, 14601380 cm, corresponding to the valence and.

0 deformation oscillations of CH in methyl and methylene groups, in pro. tone spectrum signal at 57.567, 95 (15H, aromatic protons). Example 11 To a mixture of 13 g,

5 1,2,0-isopropylideneglycerol and

30 ml of anhydrous pyridine at -78 ° C are added dropwise 22 g of 5-bromovaleric acid chloride. The mixture is left for 6 hours at -17 s and for 12 hours.

0 at room temperature, after which it decompose with water. The product is shaken with chloroform (3x100 ml), the combined chloroform extracts are extracted with water, diluted

5 with hydrochloric acid, saturated sodium hydrogen carbonate, water, and dried with anhydrous magnesium sulfate. After filtration and evaporation of the solvents, 30 g of crude 1-0 (5-bromovaleroyl) -2.3.0 isopropylideneglycerol is obtained, which is converted to the phosphonium salt by reaction with triphenylphosphine in 200 ml of acetonitrile by the method according to Example 8. 51 g (85%) of crystalline phosphonium salt.

Example 12. Dimethyl- -3- (2,2difluoro-3-methyl-3-butenoxy) -2-oxopropyl-J-phosphonate.

To a solution of methylphosphoric acid complex dimethyl ether (4.96 g) in anhydrous tetrahydrofuran (80 ml) with vigorous stirring and a temperature of (-75) - (-80) C, 35.9 ml of c-butyl lithium in hexane (concentration 1.13 mol) at such a rate that the temperature of the reaction mixture does not exceed -66 C. After 15 minutes, 4.16 g of ethyl ester (2,2-difluoro-3-methyl-3-butenoxy) acetic acid is added to this mixture acid dissolved in 15 ml of tetrahydrofuran, and the temperature of the mixture was maintained at -70 ° C for 2 more hours, and 5 after heating the mixture to O C and the mixture was acidified with 3.1 ml of glacial acetic acid. After dissolving the inorganic salts in water (approximately 15-20 ml) and evaporating the solvents, the aqueous phase was extracted 3 times with 20 ml of ether, the combined organic phases were washed with 10 ml of sodium hydrogen carbonate and dried over magnesium sulfate. After distillation of the solvents by distillation, I obtain 3.5 g of an oily product with m.p. 119-124 with a pressure of 53 PA. (286.2). Calculated,%: C 41.97; H 5.99; R 10.82. Received,%: C 42,19; H 5.48; R 10.50. The IR spectrum shows the band at 1728 cm, corresponding to the stretching vibration of the carbonyl group in the ether, the mass spectrum shows the characteristic types of ions at m / Z (rel. 152 (100), 41 (73), 93 (70). 109 (64 ), 96 (55), 100 (42), 40 (42), 124 (36), 65 (M. 286 (0.15). P-NMR signals with Sl07.64 (t, 2F in CFj-rpynpe ), the proton NMR spectrum is also in accordance with the proposed structure. Example 13. Ethyl- (2,2-difluoro-3-methyl-3-butenoxy) acetate. Sodium alcohol prepared from 21 g of 2,2-difluoro- 3-methyl-3-butenol and 5.15 g (80% sodium hydride) in 100 ml of anhydrous dimethoxyethane are added to a solution of ethyl bromoacetate (28.4 g) in 20 ml of the same solvent at such a rate that the temperature of the reaction mixture does not exceed 40 ° C. After three hours of stirring, the reaction mixture is left overnight at room temperature. After that, the salt added is dissolved in 35 ml of distilled water. The organic phase is separated, and the aqueous phase is extracted 4 times with 50 ml of ether. The combined organic phases are dried with magnesium sulfate and the usual method of isolation by distillation of the residue at 2.27 kPa. 14.0 g of product are obtained with a bale. 102-104С. C ,, N. (208.2). Calculated,%: C, 51.92; H 6.78; F 18.25. - Received,%: C 50.2; H 6.76; F 18.55. The following types of ions were found in the mass spectrum: m / Z (relative int.%): 59 (1 21 (72), 41 (59), 61 (52), 31 (41), 39 (38), 27 (34 ), 89 (31), 106 (31), 118 (24). In the IR spectrum, the band at 1755 cm corresponds to the presence of CO-g 3420 on the air. The H- and F-GMP-spectra are also in accordance with the proposed Example 14. To a suspension of sodium hydride (0.115 g, 69.4% in paraffin oil) in 5 ml of dimethoxyethane in a nitrogen atmosphere was added 1.159 g of the phosphonate from example 12 in 20 ml of the same solvent at such a rate that the temperature did not exceed -5 ° C. The resulting solution of ylide, after stirring for one hour, is cooled to (-15) - (-20) c and add an equivalent amount (3,3aa, 4p, 5od, 6, 6afl.) - 5-1, l-biphenyl4-carboxyloxy-4-formylhexahydro2H-cyclopenta (b) -furan-2-one. After 20 minutes stirring at this temperature, the reaction mixture is stirred for another 2 hours at room temperature, and finally decomposed by 10 ml of fine solution of ammonium chloride and water (10 mi). After evaporation of the solvent on a rotary vacuum evaporator, the aqueous phase is extracted 4 times with 10 ml of ethyl acetate. After the usual treatment of the extract, 1.164 g of an enone of the general formula II is obtained, where OCH2CP2C (CH3) CH2; A + B 0; Z C6H5CgH CO-, with m. Pl. 75-76 0. In the mass spectrum there are types of ions m / Z (relative int.%): 198 (100), 181 (98), 177 (95), 152 (95), 153 (83), 182 ( 71), 41 (60), 149 (57), 57 (54), 121 (46), molecular ion lii / z 510 (5.7). In the IR spectrum, characteristic bands of 1775 cm (γ-lactone grouping), 1717 cm of the ovalent vibration of CO in the ether, and 1705 cm of the stretching vibration of CO in the keto group were found. In the F NMR spectrum - signals at 107.51 (2F, CFj). The proton NMR spectrum is also in accordance with the proposed structure — signals at S 1.68 (S, 3N, H-22), 1.99–3.10 (in, 6H, H-7, H-8, H- 10, H-12), Z., 80 (t,, 2H,), 6.87 (2H, trans-olefin) 7.35-8.15 (9H, aromatic protons) Example 15. To enrna solution from example 14 (510 mg, 1. millimole) in anhydrous tetrahydrofuran (20 ml) under argon at (-77) - (-74) were added a tris-sec solution. lithium butylborohydride (2 ml of 1 M toluene solution, i.e. 2 millimole), and the reaction mixture is stirred at this temperature for 43 minutes. After removing the cooling bath 21 and heating the reaction mixture to O-Slc temperatures, add 30 ml of 30% acetic acid, then diluted with water (20 ml) and. 30 m dichloromethane is added. After separating the organic layer, the aqueous phase is extracted with the same solvent 2 times 15 ml each time, the combined dichloromethane solutions are washed with water (10 ml with a saturated sodium hydrogen carbonate solution and dried with magnesium sulfate, and the solvents are evaporated in a vacuum on a rotary evaporator. The crude oily product is evaporated 2) with 10 ml of methanol and the residue (547.9 mg) is chromatographed on a silica gel column (20 g of silica gel, eluent is chloroform). 451.5 mg (88%) of the chromatographically pure lactol of formula II is obtained (and its epimer is and 45:55), where Y OCHjCFjC (CH3) CHj; Z QHrCcH CO;), whose structure is determined using the spectral methods: NMR-spectrum at S 106.84 (2F, CF,, t,), NMR at 8 1.84 (3N, S, H-22), 3.23-3.94 (4H, mt, H-16, I-18,), 5.53-5.79 2P, trans olefys 7.17-8.15 (9H, aromatic protons In the IR spectrum, bands at 3580 cm are replaced by OH-group 1770 cm (y-lactone and 1713 cm carbonyl in ether |) group. Mass spectrum m / z (rel. points%) 151 (100), 110 (58), 166 (43)., 42 (43), 44 (37), 124 (35), 125 (31), 77 (21), 39 ( 2), molecular ion m / z 512 (07) Example 16. To a solution of diastereoisomeric alcohols of the formula II (Y OCH2CF, C (CHj) CH,; from example 15) in dichloroethane (770 mg, 1.5 millimole in 20 ml dichloromethane) and absolute methanol (41 ml) pounded calcined potassium carbonate (544 mg, 3.94 millimol) was added, and the mixture was stirred at room temperature for 2.5 hours, then the oxides are oxidized with hydrochloric acid (0.7 ml) and the pH of the reaction mixture is adjusted with acidic sodium carbonate. After evaporation of the solvents on a rotary vacuum evaporator, the distillation residue is extracted with dichloroethane to separate the inorganic salts, after evaporation of the dichloroethane solution, glacial acetic acid and ethyl acetate are added to the residue, filtered with carborafin and again stripped. 3422 The distillation residue (1692 mg) is chromatographed on a silica gel column (eluent chloroform-methanol) to obtain 401 mg (80%) of the product of formula II (Y OCH2CF ,, C (CH3) CH2;). The spectral characteristics are - in accordance with the proposed structure: F Я№spectr at S 107,46 (2F, CF, t, 1cr 13), the IR spectrum in 3580 cm and 3420-3480 cm bands corresponds to the hydroxyl group, 1770 corresponds to - lactone grouping, the prrtonic NMR spectrum does not contain aromatic protons, then at 5 1.86 (3N, S, 5,49-5,63 (2H, trans-olefin). I Example 17. Lactone of formula II (Y c- C5H gF) is reduced with diisobutyl aluminum hydride according to the method described in Example 1. A solution of the resulting lactol of the formula III (ZC H5CHjOCH; Y c-CgH F) with (2.2 g) in 50 ml of anhydrous dimethyl sulfate oxide and 5 ml of benzene are added to a solution of ylide prepared from 6 g of triphenylphosphonium pentanoic acid bromide in 30 ml of dimethyl sulfoxide in the same way as in example 1. The reaction mixture is stirred for 3 hours at laboratory temperature, then it is decomposed with water during external cooling (60 ml) and treated in the same manner as in Example 1. From the combined extracts, 1.4 g of a syrupy substance of formula IV (Z C5H5CH20CH2, oF) was isolated, which was immediately dissolved in 20 ml of liquid ammonia and reduced by gradual addition of sodium (100% excess). After treatment in the usual way and purification using preparative liquid chromatography (column 450x10 mm, filled with Li-Sirosb Si-10, mobile phase Y-hexane - ethanol - acetic acid 89: 1-0: 1, duct 200 ml / h, detection UV (Varichrome) obtain 1.0 g of a pure syrup-like product of the formula I ((, F;), homogeneous in all chromatographic systems used. (413.5). Calculated,%: C 63.90} H 8.29; F 4, 59. Received,%: C 63.72; H 8.45; F 4.40. In the proton NMR spectrum there are signals at “6.98-7.28 (10 And, aromatic protons), 5.68 - 5.82 (2H, trans-olefin), in the IR spectrum of the floor ca at 1775 cm confirms the presence of the β-lactone circle. The initial lactone of formula II (ZC HjCHjOCH2;, H, (3F) is prepared by the reaction of 3.1 g of the lactone of formula II (, H..R;) dissolved in 20 ml of freshly distilled ethyl diisopropylamine, with 2.5 equivalents of benzyl chloromethylene ether at 5 ° C. The reaction mixture is left at room temperature for 12 hours and then treated by conventional shaking between water and dichloromethane. Example 18. A solution of the lactone of the formula II (Y OC2Hc; Z CHjOCH2CCl3; reduced in toluene with diisobutyl aluminum hydride. The resulting lactol reacts with a ylid prepared from methyl 5-triphenylphosphonium pentanoate as in Example 3. The protective groups from the product of example 14 (j ;, OCH2CCl3;,, Y OCjH5) is eliminated in the usual way by reduction with zinc in acetic acid, buffered with triphenylamine. The product is purified by liquid chromatography as in Example 5. Sira methylether of formula 1 (Y OCjH5-;) shows H-NMR and mass spectra identical with out The initial lactone of formula II (, Z CH20CH2CC1 ,;) is prepared by reacting the corresponding diol with chloromethyltrichloroethylether in tetrahydrofuran in the presence of lithium iodide in the usual way. Example 19. The lactone of formula II (Y CPH CHjO;) is reduced as in Example 1. The product of formula III (Y CPH-CH20;) (0.3 g,) is dissolved in 10 ml of anhydrous dimethyl sulfoxide and in 1 ml of benzene, then added to a solution of ylide prepared from 0.7 g of methyl 5-triphenylphosphonium pentanoate bromide, 5 ml of dimethyl sulfoxide by reaction with 1.2 ml of sodium dimethyl sulfoxide (2.3 and. solution). The reaction mixture was treated as in Example 1, the crude product of formula IV (X OCHs; Z THF-0; Y CPH-CH2-O) 1 4 (0.3 g) was dissolved in 10 ml of a mixture of acetic acid and water in 3: 1 and left at room temperature for 2 hours. The solvents are stripped off and the product of formula I (X OCHs; CHjO;) is purified by chromatography on a column of silica gel in a chloroform-methanol-acetic acid system. 100: 5: 1: 1. Substances detected in the eluent detector at 254 nm. A syrupy substance of the formula I is obtained (X-OCHj; Y CPHCH20;). С24Нз2С10б (452.0). Calculated,%: C 63.77; H C1 7.84. Received,%: C 63,50; And 7.28; C1 7, 50. In the proton NMR spectrum, signals at about 3.53 (2H, CHj in the group), 3.71 (OG, CH, on the air), 4.46 (2H, in the OCHjCgHjCl group), 7.17 (1H) and 6.97 (ZN) are aromatic protons, in the IR spectrum, the bands 3590 and 3400-3480 cm correspond to hydroxyl groups, the band 1725 cm confirms the presence of the ether group. / The starting lactone of formula II (Y OCH2Cj, H -M-Cl;) is prepared by the following method. A mixture of 1.7 g of a lactone of formula II (Y OCH2CgH-A (-Cl;), 20 mg of P-toluenesulfonic acid, 4.5 g of 2-tetrahydrofuranyl ether of diphenylacetic acid and 100 ml of carbon tetrachloride is stirred at 40 ° C until the starting material disappears. The reactions are monitored by chromatography (thin layer). The mixture is neutralized with solid sodium carbonate, after one hour stirring the sodium salts are filtered, the solution is stripped and the resulting product of formula II (Y OCH2CgH Cl;) is used in the reduction with diisobutyl aluminum hydride. Example 20. To a solution of 536 m of substance of formula II () in 15 ml of anhydrous dichloroethane, cooled before, 400 mg of dry ethylvinyl ether in 1 ml of 1,2-dichloroethane, saturated with O, gaseous anhydrous hydrogen chloride is added at 2 ° C after the disappearance of the starting material from the reaction mixture (chromatography on a thin layer of silica gel C, eluent benol-eta25 NOL 100: 5) the reaction mixture is filtered through alumina and the Syrupy-like product of formula II is stripped to dryness (g CH2SNOC2I5; weighing 800 mg does not show bands in the 11K spectrum in the region of 3200-3600 cm (there is no OH group), but shows an intense band at 1771 cm corresponding to the γ-lactone group. In the mass spectrum, the molecular appearance of the ion was detected at m / z 412, The resulting β-lactone is reduced to diisobutyl with pyumahydride as described in Example 1, and then (The resulting lactol, under normal conditions (Example 5), translates the effect of ylide to the desired product of formula IV (Z CH3 CHOC3H5;,;). 412 mg of oily product, the structure of which was confirmed using spectral methods. The IR spectrum contains bands of the 3595 cm stretching vibration of the hydroxyl group, 2890-2960 - the stretching vibration of the CHB CH-, and CH., - group, 1355-1460 - the deformation vibration of the CH-group, 965 cm of the deformation vibration of the CH trans CH and 710 cm — deformational fluctuation of CH in cis-CH CH-group Example 21. 380 mg of an acid of formula IV (Z CHjCHOSOSH) are dissolved in 10 ml of aqueous dimethylformamide in a flask wrapped in aluminum foil. 200 mg of freshly prepared dry silver oxide are then added and the reaction mixture is stirred for 12 hours, after which 140 mg of newly distilled bromohexane is added to the reaction mixture. The progress of the reaction is monitored by thin-layer chromatography on silica C in the system chloroform-isopropyl alcohol-ammonia / water in a ratio of 10: 15: 0.5: 1.5. After 6 hours, the reaction mixture is filtered through a layer of supercell, from the filtrate the volatiles are distilled off at a temperature of up to 60 ° C at a pressure of 2 Pa. The distillation residue is chromatographed on a column of 30 g of cage gel (100-160, in the chloroform system ethanol 100: 5). Mg of the compound of formula IV (, H,;; E CH3 CHOCJH) is obtained, the structure of which is in accordance with the interpretation of the spectra. 3426 Example 22. 440 mg of a substance of the formula II (In CH 3 CH 2); Z (CH3) 2CQCjH5; ) prepared from a compound of formula II (CH 3 CH 2;) by exposure to methyl isopropenyl ether, dissolved in 25 ml of freshly distilled toluene, and the reaction mixture is then cooled in a bath to (-76) - (-80) ° C. Then, with stirring, 1.1 equivalents of diisobutylaluminum hydride are added, and after further 25-30 minutes of stirring at this temperature, the reaction mixture is decomposed with 3 ml of methanol and, finally, after heating to room temperature, 20 ml of water. After separating the organic layer, the aqueous phase is extracted with 3x25 ml of chloroform, the combined extracts are dried with anhydrous magnesium sulfate and, after stripping the solvents on a vacuum rotary evaporator, 410 mg of oily product is obtained, the mass spectrum of which is in accordance with the proposed structure. Then the substance is processed without further purification. After dissolving in 10 ml of anhydrous dimethyl sulfoxide, the solution is added (under nitrogen atmosphere) to a solution of ylide prepared from 525 mg of 2,2,2-trifluoroethyl 5-triphenylphosphonium bromide and 1.1 ml of a 2.32 M solution of dimethyl sulfoxide in 9 ml of dimethyl sulfoxide . After the addition of lactol, the reaction mixture is stirred for 5 hours at room temperature, then 6 ml of water is decomposed with water cooling and the aqueous layer is extracted with 6x10 ml of ethyl acetate. The combined extracts are washed with a high-grade sodium chloride solution (3 ml), dried and stripped of solvents. 390 mg of the product Formula IV (X OSHGSG; Y CH2CHj; Z (CH3) 2COC2H5;) is obtained as a viscous oil. C, .Oj (608.7). Calculated,%: F 9.36. Received,%: F 8,89. In the IR spectrum, a band was detected at 1735 cm, corresponding to the stretching vibration of the CO group in the ether, and a narrow band at 3569 cm, corresponding to the presence of a free OH group. Example 23: To a solution of 0.536 g (2 millimole) of the compound of formula II () in 20 ml of anhydrous tetrahydrofuran is added

Claims (4)

1. METHOD FOR PRODUCING ANALOG GOW OF PROSTAGLANDINS F _{2K <} general formula I: · hydroxyethyl, epoxypropyl, -OCH ₂ CH = CH ₂ , CH ₂ CF ₃ or octyl bicyclic; η = 1 to 5; Υ - lower alkyl, 3-chlorophenoxy, 1-naphthyloxy, 2,2-difluoro-Zmethyl-3-buten-1-yloxy, -OCH ₂ C _b H ₄ -m-C1, c ₆ h ₁₀ f, ethoxy, 3 trifluoromethylphenoxy group; A is a hydroxyl group or hydrogen; B is hydrogen or a hydroxyl group, and if A is a hydroxyl group, then B is hydrogen or if A is hydrogen, then B is a hydroxyl group, namely, that the lactone of the general formula 11: where η and Y have the indicated meanings; A is hydrogen or a group 0Ζ; B is hydrogen or a group 0Ζ, and if A is a group 0Ζ, then B is hydrogen or if A is hydrogen, then B is a group 0Ζ, where Z is a protective tert-butyldimethylsilyl group, 2,5-dioxyhexyl group, 4-methoxytetrahydropyran-4- alkyl group, 2-methoxy-2-propyl group, 4-phenylbenzoyl group, benzyloxymethyl group, -CH ₂ OCH ₂ CC1 ₃ , (CH ₃ ) ₂ COC ₂ H ₅ , (CH ₃ ) ₃ COC. H ₂ , CH ₃ SOS ₂ H ₅ group; 'restore in the corresponding lactol, which is then subjected to interaction with the ylide of General formula III: SU „„ 1104134 >> (с ₆ н ₅ ) ₃ р = СН (СН ₂ ) ₃ СОХ, where X has the indicated meanings, • followed by removal of the protective groups by acid hydrolysis in an aqueous organic medium to obtain the target product of the general formula I, where X is a hydroxyl group , and A, B, Y and η have the indicated meanings, which are either isolated or ester. 2. The method of pop. 1, characterized in that the target product is converted into an ester by exposure to a compound of formula I, where X is an oxy group, a diazoalkane or an oxirane derivative in an aprotic solvent. 3. The method of pop. 1, characterized in that the target product is converted into the silver salt of the compounds of formula I, where X is OH, and then into the ester by treatment with an alkylating agent. 4. The method of Pop. 1, characterized in that the recovery of the lactone of the General formula II is carried out using diisobutyl Dumohydride or sodium bis (2-methoxyethoxy) aluminum hydride at a temperature of from Odo 80 ° C.