CS204595B1 - Process for preparirng analogs of prostaglandin f2alpha - Google Patents

Description

The present invention relates to a process for the preparation of prostaglandin Fg analogs of the general formula I

who

X is hydroxyl or

OR ¹ , wherein R ¹ is alkyl or alkenyl of 1 to 8 carbon atoms, or cycloalkyl, bicycloalkyl, trioycloalkyl, of 5 to 10 carbon atoms, optionally containing in the chain 1 to β hydroxyl groups free or partially or fully protected т in the form of esters, ethers or acetals (or substituents from the group of halogens, trihalomethyl-, nitro-, mercapto-, alkoxy-, groups having 1 to 2 carbon atoms in the alkyl chain, n to 0 to 6,

Y is a hydrogen atom or an alkyl or alkenyl group having 1 to 6 carbon atoms or a cycloalkyl group having 8 to 10 carbon atoms, optionally substituted by 1 to 3 halogen atoms, trihalomethyl-nitrohydroxy-mercapto-alkoxy having 1 to 2 carbon atoms , dialkylamino groups in 1 to 3

204 595 carbon atoms in the aliphatic chain or o

OR group · who R is an aryl group having 6 to 10 carbon atoms, which is optionally substituted with 1 to 3 halogen atoms or hydroxyl · nitrotrihalomethyl- · mercapto-, alkyl · alkoxy or dimethylaminoacids · containing 1 to 3 carbon atoms in the aliphatic chain · Or o

R is C 3 -C 8 alkyl or alkenyl optionally substituted by 1 to 3 halogen atoms, hydroxyl, mercapto or alkoxy groups 8 1 to 3 carbon atoms ·

A is hydroxyl or hydrogen ·

Je is hydrogen or a hydroxyl group · wherein when A is hydroxyl · is vodík hydrogen · If A is hydrogen · В is hydroxyl.

Most known processes for the production of prostadienoic acid derivatives belonging to the group of so-called · proetaglandins · substances with significant physiological effects · especially in the Fg _{8e T} y _Zn series, follow the following sequence of chemical reactions:

reduction of lactondiol (formula a) to lactoldiol (formula b)

where T is hydrogen or THP (denotes tetrahydropyranyl) lactol diol (formula b) and lidide (formula c) to form prostaglandin Fg (formula d) or when T is THP to form its THP derivative

(b) ^(C ? 3 ^{F with} CH (CH ₂ ) ₃ COOH OB > г / а ^ / _э соон / а / от (C) ^£ ot

and the subsequent release of hydroxyl groups on C-11 and C-15 prostadienoic acid in the case that T is THP:

hydrolysis' »----------------- ^{ГОР 2х}

204 595

It follows that these last stages of prostaglandin synthesis are carried out either 8 with intermediates which find hydroxyl groups on 11 and 15 carbon protected by tetrahydropyran derivatives or 8 intermediates having these hydroxyls unprotected.

The first method for protecting hydroxyl groups in the form of a tetrahydropyran derivative (German Patents Nos. 2,709,804 · 2,736,110, 2,437,388, 2,234,709, 2,345,695, U.S. Pat. No. 3,933,892 and British Patent No. 1 438 093) has the disadvantage that another asymmetric center is formed in the molecule and a mixture of isomeric compounds is obtained. As a result, the products obtained are generally syrupy, making it difficult to isolate, purify and characterize.

The second method (J. Chem.Soc.Perkin I 1973, 2796), which does not protect hydroxyl groups on carbons 11 and 15 from further synthetic processing, has the disadvantage of increased consumption of costly reagents and, moreover, the desired product is difficult to isolate because it is contaminated with chemicals formed reactions of free hydroxyl groups and excess reagents ·

These known processes are followed in a positive way by the process according to the invention, which eliminates the disadvantages of the known processes.

According to the invention, the process for the preparation of the prostaglandin Fg4 analogs according to the invention consists in the formation of a compound of the formula II

(II) wherein ц, Y are as defined above, is OZ or hydrogen,

V is hydrogen or OZ, and when A is OZ, V is hydrogen or is

And hydrogen, Is В the OZ group,

Z is a triphenylmethyl radical, optionally substituted with a methoxy group or denotes an alkoxyalkyl group of the type

R where

R is alkyl of 1 to 5 carbon atoms, optionally bearing substituents from the group of halogen, alkoxy of 1 to 4 carbon atoms in the aliphatic chain.

204 S9S denotes hydrogen or alkyl radicals * and preferably identical * with 1 to 10 carbon atoms * optionally carrying a substituent from the group of halogen or alkoxy groups containing 1 to 5 carbon atoms or aliphatic chain or R ⁴ together *

with R form an alkenyl radical having four to six carbon atoms, * optionally containing an oxygen atom * optionally carrying substituents chosen from halogen *, alkoxy * having 1 to 3 carbon atoms in the aliphatic chain * after reduction of grouping a lactol above with the ylide of formula (ΟθΗ ₅ ) ₃ ₽ = CH (CHg) ₃ COX * who X is as defined above * after which the protecting groups Z * are removed, preferably in an aqueous organic medium under acid catalysis ·

In the case where OH is represented in formula IX, the novel prostaglandin Fg analogs according to the invention are preferably prepared by treating the reaction product with a C 1 -C 4 diazoalkane or a C 1 -C 6 oxirane derivative in an aprotic organic solvent, or the product is converted to a silver salt * and treated with an appropriate alkylating agent of 1 to 13 carbon atoms * which optionally contains 1 to 6 hydroxyl groups in the chain in the form of sterols * or an ester or substituents * such as halogen.

In the process for producing the prostaglandin Fg _x analogue of the invention, the lactondiol group in the formula is converted to the lactoldiol in formula b * preferably at 0 to -80 ° C with a complex hydride * preferably diisobutylaluminum hydride or sodium bis (2methoxyethoxy) aluminum hydride. ? βΗ *). ₃ Ρ - CH ($) ₃ COX according to the invention is preferably prepared from corresponding to an phosphonium salt (CHG) ^ COX IIIg wherein Hlg represents halogen, in an anhydrous dinetyLsulfoxidu treatment with strong bases * preferably sodium hydride or an alkyllithium · The phosphonium salt for x other than OH is preferably prepared by reacting 5-halopentanoic acid esters with triarylphosphine *, wherein the 5-halopentanoic acid ester is prepared by reacting the corresponding acid halide with an alcohol.

The protecting groups on the hydroxyls C-11 and C-15 of the prostaglandin F ₂ analogue are preferably removed in the aqueous-organic medium under acid catalysis in the process according to the invention.

In the process according to the invention, when protecting the hydroxyl groups on the 11th and 15th carbon atoms of such compounds * which do not introduce another asymmetric center into the molecule *, crystalline products in most cases are interrupted. * which is obtained practically in quantitative yield ·

Another important advantage of protecting the hydroxyl group by the method of the invention is that it is easy to remove these groups from the molecule. For example, the 4-methoxy-4-tetrahydropyranyl protecting group is dehydrolysed 5 to 10 times faster than the hitherto used

2-Tetrahydropyranyl group · In addition, milder conditions * especially lower temperature and less acid in the reaction * reduce the amount of by-products thus removing the often difficult isolation of the desired substance ·

DETAILED DESCRIPTION OF THE INVENTION The invention and its effects are explained in more detail in the following examples * in which the aforementioned symbols in formula A in formulas I to IV below are used to simplify the labeling.

204 595

AND/

II /

III /

β

204 S95

Substance n AND в X Y OF Ia 1 H-0- H- HIM- CPH-0 [0057] Ib AND H-0- H- CH ₃ -0- NPH-O- - Ic 5 H-0- H- BCO-O- H- - Id AND H-0- H- H-0- DFM-0 - Ie AND H-0- H- HET-O- CPH-O- - If 1 H-0- H- EPP-O- CPH-O- - Ila AND - 0 - AND CPH-O- PHB- lib 1 H-0- H- 4 » CPH-O- H- face 1 H- HIM- W CPH-O- H- people 1 MEM-0- H- CPH-O- MEM- Him 1 (H0; H) CPH-O- PHB Uf 1 THF-0- H- CPH-O- THF- 1 MTP-0- H- MPH-O- MTP- of alcohol 1 H-0- H- MPH-O- H- Ili 5 M0P-0- Ht H- MOP- IIJ 5 H-0- H- H- H- Ilk 1 M0P-0- H- DFM-0 MOP- III 1 H-0- H- DMF-0 H- lila AND MEM-0- H- CPH-O- MEM- Illb 1 THF-0- Hk CPH-O- THF- Behold 1 MTP-0- H- NPH-O- MTP- Illd 5 M0P-0- H- H- MOP- Behold 1 M0P-0- H- DFM-0 MOP- IV a 1 MEM-O- H- H-0- CPH-O- MEM- IVb 1 THF-0- H- H-0- CPH-O- THF- IVc 1 MTP-O- H- CH ₃ -0- NPH-O- MTP- IVd 5 MOP-O- H- BCO-O- H- MOP- IVe 1 MOP-O- H- HrO- DFM-0 MOP-

Legend: CPH 3-chlorophenyl MOP 2 'aetoxy> 2' propyl MEM 2,5-dioxahexyl DFM 2,2'-Difluoro-3-methyl-3-butene PHB 4-phenylbenzoyl BCO 2- (2,2,2-bioyltyl) «HF tetrahydrofuryl НЕТ 2-hydroxyethyl кга 1-Naphthyl БРР 2,3-epylpropyl MTP 4-Methoxy-tetrahydropyran-4-yl

204 S9S

Example 1

To a solution of 325 mg of lactone of formula IId in 25 l of freshly distilled toluene, after cooling to -78 ° C, was added within 5-10 minutes 1.06 ml of diisobutyaaluminium hydride in toluene (1.5 H solution). Then the reaction mixture was stirred for 15 minutes at this temperature and quenched by addition of 2.15 ml of methalone, and finally stirred for 20 minutes at room temperature. After addition of 18 ml of saturated sodium chloride solution and 18 ml of water, the aqueous phase was extracted with 3 x 40 ml of ethyl acetate, the combined extracts were washed with 8 ml of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After the solvents had evaporated. The oily product was dried under vacuum (60 Pa) at alisnoot temperature. 326 mg of the lactol of the formula IHa were obtained in the form of a viscous hoji, whose iC- and afternoon spectra were in accordance with the proposed structure.

To a solution of 3.25 g of trieenyllosoneonepentanoic acid bromide in 15 ml of dimoyl sulfoxide was added 5.9 ml of dimethyl sulfoxide (2.32 M solution) over 5 to 10 with stirring at room temperature. emerging ylideo. After a further 5 minutes, 1.26 g of the lactol of formula IIIa dissolved in 30 ml of anhydrous diolyl sulfoxide and 3 ml of benzene were added. Then the reaction mixture was stirred at room temperature for 3 hours and finally 32 ml of dottled water were added dropwise under external cooling. The reaction mixture was extracted with 3 x 30 mL otylacotate and the aqueous pH was adjusted to pH 4 to 4 by addition of 1.73 N hydrochloric acid. After re-extraction with hexane-salt 1: 1 (total 160 mL) the combined extracts were combined. Washed with saturated rotttokeo common salt, dried over magnesium sulphate and the solvents evaporated in vacuo. After drying, 0.67 g of an oil viscous acid of the formula IVa was obtained, the structure of which was confirmed by the high and infrared spectrum.

A solution of 0.6 g of a syrup of the compound of formula IVa, 5 ml of anhydrous ethylene chloride was mixed with anhydrous zinc bromide powder (2.25 g) and stirred vigorously at 25 ° C for 12 hours. After addition of 10 ml of water, the mixture was evaporated in vacuo to a paste which was extracted with 3 x 30 ml of otanulum. The combined extracts were evaporated to dryness to give a total of 360 mg (85%) of a practically pure product of Formula Ia from the oily residue (480 mg) after chromatography on a 8 µg column with benzene, oethanel and acetic acid (32: 1: 1). yeah in accordance with the interpretation of Spoktor.

The starting lactone of formula IId was prepared as follows:

a solution of 4, 18 lactone of formula IIIa in a salt of 100 ml of totrahydrofuran and 13 ml of ethyl acetate was cooled to -79 ° C under argon. While stirring, a solution of 3.12 g of tri8 (2-buly) lithium borohydride was added at such a rate that the temperature did not exceed -76 ° C. After addition of the entire hybrid sequence, the mixture was stirred at 75 ° C for the indicated temperature. The excess hydride was quenched by the addition of 25 ml of a 40% aqueous acetic acid solution. 280 ml of dichloromethane and 140 ml of water were added to the reaction mixture. The organic phase was separated and evaporated to dryness in vacuo and then evaporated three times with 150 ml of ethanol. The crude product of Formula III (3.99 g) was dissolved in ~ 90 mL of dichloro-isotane and 200 mL of dry ethanol. To the solution, 3.6 g of potassium carbonate was gradually added over 2 hours with stirring at ambient temperature. The mixture was stirred for a further 1.5 hours, after which 27 ml of 2 N hydrochloric acid, 65 ml of water and 90 ml of dichloromethane were added. After shaking, the aqueous and organic layers were separated. The organic layer was evaporated to dryness after drying with magnesium sulfate. The aqueous phase was neutralized with solid sodium carbonate and evaporated to dryness. The residue was extracted twice with 25 ml of chloroform, and after evaporation of the solvent, the syrupy residue was combined with a portion of the organic phase by treatment. Filtration of the crude product through a layer of HCl provided 1.78 g of crystalline opioid diol salt of formulas IIb, m.p. 109-113 ° C. SpeOtrál8

204 59 Measurement proved correctness of the proposed structure. The mixture was partitioned by preparative, high-pressure liquid chromatography (column 50 x 0.6 cm, packed with Lichrosorb. Si-5, petroleum phase 10% 85%, acetic 14.9%, water 0.1%, flow rate 120 ml) 1 h, photometric detection (254 nm), injection of 100 mg of the alcohol mixture).

The less polar epimer of formula IIc was crystallized in ethyl acetate, mp 113-115 ° C. The 1C-spectrum shows characteristic bands at the following frequencies: (CHCl ₃ ).

010, 3020, 2950, 1771, 1598, 1583, 1480, 1285, 1037, 975;

$ KBr) 2,935, 1,742, 1,598, 1,583, 1,488, 1,380, 1,310, 1,250, 1,081, 031, -980, 918,

In the hmoonest spectrum, these structurally characteristic ions are: (·, (molecular ion), 197, (30), 193 (40), - 179 '(70), 142 (100)).

The more polar epimer of formula 1 H was crystallized from mixtures of acetone, ether and petroleum ether, m.p. Mp 125-127 ° C. The IR spectrum showed the characteristic bands at the following frequencies: (CHCC) 3 600, 3 015, 2 935, 1 771, 1 598, 1 583, 1 480, 1 285, 1 037, 975; KBr 2,920, 1,719, 1,597, 1,576, 1,485, 1,375; 1 251, 1 225, 1 071, 1 030, 980, 909, The following are structurally characteristic ions in the mass spectrum: M / e- 338 (moocular ion), 197 (30), 193 (40), 179 ( 70), 142 (100).

In 10 ml of dry dichloromethane, 338 mg of a more polar diol of formula IIb were dissolved, the solution was protected under nitrogen, 374 mg of chloromethyl / 2-meeooylethyl / ether and 387 mg of ethyldiopopoppyaamine in 2 ml of dichloromethane were added and the mixture stirred at 20-25 °. C for 4 hours. The reaction mixture was then diluted with 10 ml of water, the organic layer was separated and, after washing with 5 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solvents evaporated in vacuo. 510 mg of a product which was chromatographically uniform (Ry 3 0.4, silica silika 10 254 254 * ² * methanol in chloroform) were obtained, the structure of which, determined by NMR and MS, was consistent with formula IId.

Example 2

The lactone of formula IIf was reduced with diisobutyaalamine hydride as described in Example 1.

The thus prepared lactol of formula IIIb (1.1g) was dissolved in 25 ml of anhydrous dimethylsulfoxide and added to the ylide prepared in the usual manner from 3.25 g of triphenylphosphine pentanoic acid bromide in 15 ml of dimethylsulfoxide (see Example 1).

After stirring at room temperature for three hours, the reaction mixture was worked up in the usual manner (Example 1). After thorough drying under high vacuum, 0.76 g of oleic acid of formula IVb was obtained, the structure of which was consistent with the interpretation of spectral data.

A mixture of 1.3 g of the derivative of formula IVb and 10 ml of acetic acid-water-tetrahydrofuran (3: 1: 1) was stirred at 25 ° C for 1 hour. The solvents were evaporated under reduced pressure and the product purified by silica gel chromatography. 0.77 g of formula (Ia) was obtained, which was identified with an authentic preparation by thin layer chromatography and high-pressure screening.

The starting derivative of formula (Uf) was prepared by adding 1.86 g of tetraltdroflrtldiphenylacetate to a solution of 0.1 g of diol of formula IIb in 10 ml of anhydrous carbon tetrachloride.

0.1 g of p-toluenesulfonic acid. The resulting mixture was stirred at 40 ° C for 15 hours.

After addition of - 20 ml of water, the organic layer was separated, shaken three times with 20 ml of n-hexane.

The combined organic extracts were evaporated to dryness. More traces have been removed. evaporation with 10 ml of benzene. 1.62 g of the compound of formula IIf are obtained in the form of an oil whose solid is filtered off

204 595 the structure is in line with the spectrum interpretation.

Example 3

The lactone of formula lig was reduced with diisobutylaluminum hydride as described in Example 1. A solution of the resulting lactone of formula IIIc 2.52 g in 62 ml of anhydrous dimethylsulfoxide and 7.1 ml of benzene was added to a solution of the ylide prepared analogously to Example 1 from 5.5 g of methyl- Of 5-triphenylphosphonium pentanoate bromide in 31 ml of dimethylsulfoxide and 11.9 ml of dimethylsulfoxide sodium (2.32 N solution), The reaction mixture was stirred at room temperature for 3 hours and finally 61.8 ml of distilled water was added dropwise by external cooling 60 ml of ethyl acetate and the pH of the aqueous phase adjusted to 3-4 by addition of 1.73 N scalic acid. After re-extraction with hexane-ether (1: 1) for a total of 320 ml, the combined extracts were washed with saturated brine, dried over magnesium sulfate. and the solvents evaporated on a rotary evaporator. After drying in a high vacuum, 1.15 g of a light oil of formula IVc was obtained, the structure of which was consistent with the NMR, IR, UV-interpret and mass spectra interpretation,

To a solution of 1.1 g of the bis (4-methoxytetryhydropyran-4-yl) derivative of the formula IVc in 30 ml of acetone was added 3 ml of 0.1 N HCl and the progress of the reaction was monitored by thin layer chromatography (chloroform-methalone 100: 2 L system). After disappearance of the starting material, the reaction mixture was neutralized with solid sodium bicarbonate and evaporated to dryness, the residue was stirred with a mixture of chloroform and methanol and filtered through a pad of silica gel to remove inorganic salts. chloroform: methanol 100: 5) for which the structure was confirmed by mass spectra.

The starting lactone of formula lig was prepared by dissolving 700 mg of the corresponding diol of alcohol in 20 ml of dichloromethane with a trace amount of p-toluenesulfonic acid in a flask sealed. After cooling to 0 [deg.] C., 500 ml of 5,6-dihydro-4 * methoxy-2H-pyran was added from the syringe with stirring over 5 minutes. After 45 minutes, 10 ml of a 1% sodium bicarbonate solution and 10 ml were added to the reaction mixture. methylene chloride · The organic layer was separated, dried over magnesium sulfate, and filtered and evaporated to give 0.75 g of a slowly crystallizing syrup which was used for reduction without further purification.

Example 4

The lactone of formula IIi was reduced with diisobutylaluminum hydride as described in Example 1. The product of formula II3d, the spectra of which were consistent with the proposed structure, was dissolved in 10 ml of anhydrous dimethylsulfoxide and 1 ml of benzene and added under stirring at room temperature to the ylide solution prepared in conventional manner (see Example 1) from 1.4 g of 2-2,2,2'-bicyclooctyl-5-triphenylphosphonium pentanoate bromide in 6 ml of dimethylsulfoxide. After standard work-up, 0.23 g of oily ester of formula IVd was obtained from the reaction mixture.

The protecting groups were removed as described in Example 3 to give a practically pure syrupy ester of formula Ic, the structure of which was confirmed by RMR-, UF and mass spectra.

The starting derivative of formula IIi was prepared from a solution of 1.5 g of the diol of formula IIj in 160 ml of dichloromethane, to which 0.05 ml of phosphorus oxychloride was added under stirring and 960 mg of isopropenylmethyl ether was added dropwise at room temperature. The progress of the reaction was monitored by thin layer chromatography, after 30 minutes 4 ml of saturated sodium bicarbonate solution was added to the reaction mixture, the organic layer was separated and washed

2x10 ml of saturated sodium chloride solution. After drying the dichloromethane solution with sulfur19

204. 595 magnesium magnesium solvents were evaporated and the syrupy product was dried at 20 ° C and 0.1 kPa. 2.1 g of the product of formula III were obtained. Spectral measurements confirmed the correctness of the proposed structure.

Example 5

A solution of the lactone of formula II (645 mg in 10 ml of toluene) was cooled to -60 ° C and then 3 ml of diisobutylaluminum hydride in toluene about 1.5 N solution was added and after standard work-up (see Example 1) 642 mg of lactol of formula As a viscous oil. The NMR, mass and infrared spectra are in accordance with the proposed structure.

To 820 mg of trifluoromethylphosphonic acid bromide dissolved in 4 ml of dimethyl sulfoxide (nitrogen atmosphere) was added, with stirring, 2.1 ml of di-sulfonyl sulfoxide (1.75 N solution). 261 mg of the lactol of formula III dissolved in 7 ml of dl-naphthyl sulfoxide and 1 ml of benzene were added to the thus-prepared ylide. The reaction mixture was then stirred at room temperature for 4 hours and worked up in a standard manner. 210 mg of oleic acid of formula IVe were obtained, the structure of which was confirmed by spectral methods.

210 mg of the above-mentioned acid of formula IVe was dissolved in 13.2 ml of dilute acetic acid ((: 1)) and the reaction mixture was heated at 35-40 ° C for 2 hours after evaporation of acetic acid and water using a rotary evaporator (temperature). about 40 ° C, 2666 Pa) 87 mg of the acid of formula Id was obtained from the standard residue, the proposed structure being in accordance with NMR, IC and HS spectra.

To a solution of 432.5 mg of lilane of formula IIIa in 30 ml of dichloromethane was added 5 mg of anhydrous p-toluenesulfonic acid and 324 mg of methyl isopropene ether was added dropwise to the reaction mixture with ice and water. After stirring at room temperature for 1 hour. 150 mg of solid sodium hydrogencarbonate and the reaction mixture worked up as in Example 4. 645 mg of a uniform oil lactone of formula Ik were obtained, the spectra of which were in accordance with the proposed structure.

Example 6

425 mg of the acid of formula (Ia) was suspended in 10 ml of dry ether in glass amine and 5 mg of ferric chloride were added to the mixture, and the reaction mixture was cooled to ⁰ DEG ^C. and the pH of the solution was adjusted ^{. to} 50 mg of the suspension in 2 ml of dry ether. The ampoule was sealed and left at room temperature for 2 days. The contents were poured into 5 ml of water, the ether was evaporated in vacuo, 0.5 g of carbonate cation exchanger was added to the solution, the mixture was stirred for one hour, the filtrate was evaporated and the filtrate evaporated in vacuo. The residual oily product was purified by column chromatography. to ailtkagtl.1 - (chloroformanol) to give 390 mg (83%) of practically pure syrup ester Ie. - ЮЮ-, IC-, 0F-, and HS spectra are consistent with the proposed structure.

Treasure 7

A solution of 180 mg of silver nitrate in 2 ml of water was added to a solution of the acid of formula la in 3 ml of 50% aqueous ethanol, the silver salt was aspirated, washed with water and et mol. After drying under vacuum, it was suspended in a mixture of 10 ml of dry ether and 5 ml of absolute ethanol, 150 mg of epichlorohydride were added to the mixture, and the mixture was refluxed to avoid air humidity. for 50 hours. After cooling, the silver salts were aspirated, washed with ethanol and the filtrate evaporated in vacuo. Column chromatography of the residual oil (chlorolorp-petanol) yielded 405 mg (84%) of syrupy oil.

11.

204,595 ester of formula If. whose structure is consistent with the interpretation of spectra.

Example 8

To a mixture of 26 g of 1,2,5,5-di-O-isopropylidene-o-glucofuranose and 50 µl of dry pyridine was added dropwise at -78 ° C 22 g of 5-brombaaeric acid chloride. The mixture should pon ^{la <echoes and} when n ^»17 ° C β H ^{o n} says. in ^te p ^l o níítnosti. 12 o'clock ar ^o zl ^o that ^{at v} odou. The precipitated crystals of 3-0- (5 Xbronvelerol) 1,2,5,6-dioO-isopropylpyrrole-D (guucofuranose) were aspirated, washed with water and dried in vacuo. The crude product (41 g) was dissolved in 70 µl of dry acetone. 24.7 trifeep / fries in 125 µl of dry water was added, and the reaction mixture was heated to boiling for 10 hours, after which the glassy mass was obtained after evaporation of the solvents. chloroform-ethanol-ether mixture yielded 46 g (70%) of solid phosphonium salt The structure was confirmed by 1 H NMR spectra.

Example 9

To a mixture of 15 g of 20oadamaaeanol. 40 µm of dry pyridine was treated with 22 g of 5oboomvaleoic acid chloride as well. as indicated in Example 8. The crude product (30 g) was converted martial manner (in terms mnnožsví chemikkllí and procedure) with the previous example and 45.5 g ^{of n-orippo} Daiichi ^{diphenylphosphine} he ^{f i} b ^s salt ^{(8 2} 0) . in accordance ^with the Tate ^^ Some people ^{with 1} H-NMR pektra

Example 10

A mixture of 13.5 g of 2- (ё, ёabablycorkorker) and 40 ml of anhydrous opium was treated with 22 g of 5-chloroboronic acid chloride as described in Example 7. The crude product (29.2 g) was dissolved in 75 ml of acetone. and, as described in Example 7, was left with 26.4 g of trifeep / frsfiesin 130 ml of βΙο ^ΗΗ, which was isolated by isolation to give 44 g (79%) of ^ t t, whose structure was confirmed by @ 1 ^H NMR spectrum.

Example 11

22 g of 5-oovaleric acid chloride were added dropwise at -78 ° C to a mixture of 13 g of 1,200 isporporppliedeglpcerieu and 30 ml of anhydrous pyridine. The mixture was left at -17 ° C for 6 hours. at 12 hours and quenched with water. The product was shaken into chloroform (3 x 100 mL). the combined chloroform solutions were extracted with water. dilute hydrochloric acid. saturated sodium bicarbonate solution. water and dried with magnesium sulfate. After filtration and evaporation of the solvent, 30 g of crude 1-O- (50% ^and 10% -OrrPr) 1,2,3-isopropylpyrrolidine was obtained, which was converted to the phosphonium salt by treatment with triphenylpentilone in 200 ml of acetonitrile. as described in Example 8. Yield: 51 g (85 Kllu rysaHcké-phosphonium salt. raktafa whose ^j ^ ev accordance with the ^{1 H NMR} spectra interpretation

Claims (4)

SUBJECT OF THE INVENTION A process for the preparation of prostaglandin analogs of formula (I) of the general formula I wherein X is hydroxyl or OR ¹ * wherein R ¹ denotes alkyl or altanyl and 1 to 8 carbon atoms; or cycloalkyl-, tricycloalkyl having 5 to 10 carbon atoms, which optionally contain 1 to 6 hydroxyl groups free or partially or completely protected in the form of esters * ethers or acetates and (or substituents from the group of halogens * trihao-methylmethyl * nitro-, mercapto-, alkoxy groups having 1 to 2 carbon atoms in the alkyl chain * n is 0 to 6, Y is a hydrogen atom or an alkyl or alkenyl group having 1 to 6 carbon atoms or a cycloalkyl group having 5 to 10 carbon atoms optionally substituted by 1 to 3 halogen atoms * trihaoogenomethyl- * nitroτ * Uydroxydy-, mercapto-, alkoxy groups having 1 to 2 atoms C 1 -C 3 dialkylamines and 1 to 3 carbon atoms in the aliphatic chain; or OR * group * where; O R is a (C 6 -C 10) aryl group which is optionally substituted with 1 to 3 halogen atoms or a hydroxyl nitro group; alkyl * alkoxy or dimethylamino groups having 1 to 3 carbon atoms in the Pl2 chain * or r2 is an alkyl or plknya group having 3 to β carbon atoms * optionally substituted with 1 to 3 carbon atoms; 3 halogen atoms * hydroxyl * mercapto groups or alkoxy groups and 1 to 3 carbon atoms * A is hydroxyl or hydrogen * B is hydrogen or hydroxyl, * and, when A * is hydroxyl, B is hydrogen or * When A is hydrogen, B * * hydnoxyy. ^▼ _У_2_ п _р_ _г_п ^ £ t 1 m * in that a compound of formula II 1Л 204 595 who, Y are as defined above, A is OZ or hydrogen, V is hydrogen or a group OZ, if any A is O, is hydrogen or, when A is hydrogen, is В group OZ, Z is a triphenylmethyl radical, optionally substituted with a methoxy group or an alkoxyalkyl group of the type wherein R ³ represents an alkyl of 1 to 5 carbon atoms, optionally bearing substituents from the group of halogen, alkoxy of 1 to 4 carbon atoms in the aliphatic chain, R ⁴ , R ⁵ denote hydrogen or alkyl radicals, preferably the same, in the range from 1 to 5; 10 carbon atoms optionally carrying a substituent from the group of halogen or alkoxy groups containing 1 to 5 carbon atoms Or R together with R forms an alkenyl radical having 4 to β carbon atoms, optionally containing an oxygen atom, optionally bearing substituents from halogen groups, alkoxy groups having 1 to 3 carbon atoms in the aliphatic chain. after reduction of its lactone moiety to lactol, it is treated with an ylide of formula ⁸ CH (CH ₂ ) ₃ COX, where X is as defined above, then deprotecting Z, preferably in an aqueous organic medium, under acid crystallization, or optionally recovering the product of formula I wherein X, A, Β, Y and n are as defined above, to be converted to an ester. 14. 204 595 2. A method according to claim 1, characterized in that for the preparation of said esters by treating a compound of formula I where X = _F b Chao, Yan are as defined above, with a diazoalkane of 1 to 4 carbon atoms or an oxirane derivative, containing 1 to β carbon atoms, in an aprotic organic solvent. 3. Process according to claim 1, characterized in that for the preparation of the esters of converting a compound of formula I wherein X ⁸ CH, and A, Β, Y, and n are as defined above, to a silver salt »which is treated with an appropriate alkylating agent 8 to 13 carbon atoms optionally containing 1 to 6 hydroxyl groups in the chain in the form of an ether, acetal or ester, or substituents such as halogen. 4. The process according to claim 1, wherein the reduction of the lactone moiety to lactol is carried out at a temperature of 0 to 80 ° C with a complex hydride, preferably di-butylaluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride.