HU186368B - Process for prdicing bracket-3-alpha-4-beta-5-alpha-6a alpha-bracket closed-hexahydro-5-hydroxy-4-hydroymethyl-2h-cyclopenta-square bracket-b-square bracket closed-furan-2-one derivatives - Google Patents

Abstract

The present invention relates to a (3aa, 4β, 5?, 6aa) -hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta [b] furan-2-one derivative of formula (I) wherein Z is hydro- 5 genes optionally substituted with methoxy group triphenylmethyl or alkoxyalkyl of formula Ia, wherein R is optionally substituted with trihalomethyl, alkoxy / or dialkylamino, R1 and R2 are hydrogen; or optionally substituted alkyl, or R 1 and R 2 taken together to form an optionally substituted or unsubstituted alkylene group, and Y represents a hydrogen atom or an acyl group, or a phenyl or biphenylamino group, wherein the alkyl ester of formula (II) is: where R 4 is alkyl and A represents chloro or bromo - is converted to the corresponding ketone by a single or divalent alcohol to reduce complex hydride and the ketal group is removed, the primary hydroxyl group in the resulting product is temporarily protected and the protected derivative is oxidized with organic peracid and finally the δ-lactone of formula (VI), where Z represents the hydroxyl protecting group, is lithium hydroxide and \ t by reacting with hydrogen peroxide to form a compound of formula (I) wherein Y is hydrogen, and is optionally acylated on the hydroxy group or reacted with a substituted phenyl isocyanate. (ii (II) 186368-1-

Description

The present invention relates to a novel process for the preparation of (3aa, 4 [3,5a, 6aa) -hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta [b] furan-2-one derivatives of the formula I - in this formula

Z is hydrogen, triphenylmethyl, tetrahydropyranyl, tetrahydrofuranyl, C 1-4 alkoxy (C 1-4) alkyl, C 1-4 alkoxy (C 1-4) alkoxy (1-4); C4-alkyl) or t-butyldimethylsilyl,

Y is hydrogen or a radical of formula CO-R ^3, wherein

R ³ is C 1-4 alkyl or a C ₆ H ₅ C ₆ H ₄ - group.

The process of the present invention is carried out by reacting a 5-halo-2-oxo-bicyclo [2.2.1] heptane-7-carboxylic acid alkyl ester of the formula (II) wherein R ⁴ is a C 1-6 alkyl group,

A is chlorine or bromine - a monovalent or divalent C 1-4 alcohol acidic catalyst, preferably in the presence of benzenesulfonic acid, p-toluenesulfonic acid or H ⁺ ring ion exchange solvent, preferably benzene, toluene, 1,2-dichloroethane or tetrachloride and azeotropic distillation to remove the resulting water and then reduce the resulting ketal with a complex hydride, preferably lithium aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride, at 0 ± 30 ° C. the resulting hydroxy ketal is decontaminated with an aqueous organic solvent solution of a hydrohalic acid or recrystallized with a C 2 -C 6 ketone to give the primary hydroxyl group of the resulting 7-hydroxymethyl-5-chloro-bromo-bicyclo [a, a, l] heptan-2-one protected in the form of a Z derivative wherein Z has the same meaning as above and the resulting δ-lactone is obtained with peracetic acid or mk oxidation with chlorobenzoic acid in the presence of sodium or potassium bicarbonate, preferably lithium hydroxide and hydrogen peroxide, and the resulting S-lactone of formula I, wherein Y is hydrogen, A and Z are as defined above, optionally acyl halide, preferably acetyl chloride, propionyl chloride or phenylbenzoyl chloride, in the presence of a tertiary amine, preferably pyridine, triethylamine or diisopropylethylamine, to form a compound of formula I wherein Y is other than hydrogen.

Synthetic prostadienoic acid derivatives, so-called. There is particular flexibility in the synthesis of prostaglandins from bicyclo [2,2,1] heptane derivatives.

These appear to be among the most preferred methods of producing said important and biologically active prostaglandins. Intermediates of crucial importance in these processes are the (3aa, 4Ji, 5a, 6aa) -hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta [b] furan-2-one derivatives of the general formula (I) all six primary prostaglandins, the Α-, B-, C-, D-, E-, and F-series prostaglandins can be produced with high stereoselectivity. Prostaglandins play a significant role as tissue hormones. These compounds are used in gynecology (to facilitate childbirth), to treat circulatory disorders, etc. They applied. They are also gaining widespread use in veterinary medicine.

Some methods for the synthesis of these compounds have been described in the literature, in particular in J. S. Bindra, A. Grodski, T. K. Schaaf, E. J. Corey;

J. Amer. Chem. Soc. 95, 7522 (1973); K. Inone, Sakai: Tetrahedron Lett. 1977, 4063: Ε. I. Corey, N. M. Weinshenker, T. K. Schaaf, W. Hubert; J. Amer. Chem. Soc. 91, 5675 (1969); K. G. Paul, F. Johnson, D. Favara: J. Amer. Chem. Soc. 98, 1285 (1976); A. Fisch'i, M. Klaus, H. Mayer, P. Schönholzer, R. Rüzgg: Helv. Chim. Acta 58, (1975).

The aforementioned second literature is close to the subject matter of the invention, but the reduction step is carried out in a much less favorable manner. In addition, isolating the resulting product is cumbersome and costly. Likewise, the reaction components used are expensive.

In most of the processes described, the intermediates need to be isolated from their production reaction mixtures and require purification by chromatography. The object of the process of the invention is to overcome these drawbacks of the known processes and to prepare the said compounds in a simple manner and in good yield.

A particular advantage of the process according to the invention is that it is not necessary to use chromatographic methods to isolate and purify each of the intermediates. Each intermediate can be purified by simple crystallization as needed. Another important advantage is the use of readily available and inexpensive starting materials; moreover, the process of the present invention can be easily magnified to large industrial sizes.

The process according to the invention is characterized in that an alkyl ester of 5-halo-2-oxo-bicyclo [2,2,1] heptane-7-carboxylic acid of formula II - wherein

R ^{4 represents a C} 1-6 alkyl group and A represents a chlorine or bromine atom - in the presence of an acid and an organic solvent such as benzene, toluene or a chlorinated alkane, reacts with a monovalent or divalent C 1-6 alcohol and azeotropically forms the water formed during the reaction. using an inorganic desiccant. After completion of the reaction, the acid is removed from the reaction mixture, preferably with sodium bicarbonate, and the solvent is distilled off to give the ketal of formula II1, wherein R ^{5 is C} 1-3 alkyl, or the two R ⁵ - represents (CH ₂ ) _n (where n = 2 or 3) -

1: 0.5 to 2 molar proportions of a complex hydride at 0 ± 30 ° C and the resultant alcohol of formula (IV) - wherein ^R5 and A are as defined above and - R ⁵ is deprotected under acid catalysis. This operation can be carried out either by mixing with water and a water-miscible organic solvent in the presence of an inorganic acid, or with a ketone containing 3 to 6 carbon atoms in the presence of an organic acid such as benzenesulfonic acid or toluenesulfonic acid or an ion exchanger at 15-90 ° C. juice. In this way, the 5-halo-7-hydroxymethylbicyclo [2.2.1] heptan-2-one of the formula (V), wherein A is as defined above, is obtained in crystalline form; the hydroxyl group of this compound is protected before further operations with a substituent Z as defined above. The protected ketone derivative lg) is oxidized according to Beyer-Villiger with an organic peracid such as peracetic acid or m-chloroperbenzoic acid to a weak base reagent such as sodium bicarbonate.

-2186368 in the presence of sodium or sodium acetate followed by reaction of the crystalline δ-lactone of the formula (VI), wherein A and Z are as defined above, with a mixture of an alkali metal hydroxide and hydrogen peroxide to give the desired compound of formula (I). of formula (Y) wherein Y is hydrogen. From this product, the corresponding acyl chloride can be reacted with a tertiary amine or with a substituted phenyl isocyanate to give a further compound of formula (I) wherein Y is as defined above (Y). where Z is as defined above).

Practical embodiments of the process of the invention are illustrated by the following examples; it should be noted, however, that the scope of the invention is in no way limited to the reaction conditions set forth in the Examples or to the use of the reagents mentioned therein.

Example 1

5-Bromo-2-oxo-bicyclo [2,2, l] heptane-7-carboxylic acid iso-propyl ester diethyl ketone (formula III), R ⁴ = (CH 3) 2 CH-, R ⁵ = C 2 H ₅ -, A = Br

To a solution of 44.5 g of the bromo ketoester II in R (CH ₃ ) ₂ CH and A in bromine and 40 mL of ethanol in 300 mL of benzene is added 0.3 g of p-toluenesulfonic acid for 8 hours. it is refluxed and the calculated amount of water formed during the reaction is separated off using an apparatus for azeotropic distillation. The reaction mixture is cooled, the acid is neutralized by addition of solid sodium bicarbonate, the solids are filtered off with suction, the benzene layer is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After distilling off the solvent, 56.3 g of crystalline product are obtained, which is recrystallized from a mixture of isopropanol and water to give the title compound (III) in pure form.

m / z = 348/350; 333/335; 289/291, 268 and 209.

Infrared spectrum: 17-26 cm- ¹ (ester group) 1365 and 1385 cm- ¹ (CH-deformation) (CH ₃ ) ₂ -CH.

Example 2

5-Chloro-2-oxo-bicyclo [2,2, l] heptane-7-carboxylic acid methyl ester-ethylene ketal (formula III), R = CH _3, R ^s + R ⁵ = - (CH _{2) 2} -,

A = Cl

88.5 g of a chloro-keto ester of the formula II containing R ^{4 -} CH ₃ and A - are chlorinated using azeotropic distillation from a mixture of 27 ml of ethylene glycol, 700 ml of benzene and 0.58 g of p-toluenesulphonic acid 8 ml of water formed during the reaction are separated off. After cooling, the reaction mixture was rinsed with aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and the separated organic solvent layer was dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue solidified crystalline. Recrystallization from water / methanol gave 98.6 g (91.5% of theory) of the title compound, m.p. 64-66 ° C.

Analysis for C _n H ₍₅ C10 ₄ (246.7):

Calculated: C, 53.56; H, 6.13; Cl, 14.37; Found: C, 53.42; H; 6.31%, Cl: 14.25%.

Infrared spectrum: 1717 cm -1 (ester group).

Example 3

-Bromo-7-hydroxymethyl-bicyclo [2,2,1] heptan-2-one-diethyl ketal Compound IV, R ³ = -C ₂ H _S , A = Br

A solution of 34.9 g of a compound of the formula (III) in which R ⁴ is (CH 3) 2 CH, R ⁵ is -C ₂ H ₅ and A is bromine is prepared in 600 ml of absolute ether at -30 ° C to -10 ° C. of lithium aluminum hydride in ether (0.36 M) was added at a rate such that the addition was complete in 20 minutes. After stirring at the same temperature for 2 hours, the mixture was quenched by addition of 120 ml of ethanol followed by 200 ml of about 2N hydrobromic acid. The ether layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off; the resulting 28.6 g of an oily residue was found to contain 97.8% of the title compound by gas-liquid chromatography. The product's spectral data correspond to the assumed chemical structure.

Analysis (293.2) calculated for C ₂ H ₂₁ BrO ₃ Calculated compound: Br: 27.26%;

Found: Br, 26.94%.

IR: 3610, 3440-3530 cm ^-1 (hydroxy); 1078 cm (ether group).

Example 4

7-Hydroxymethyl-5-chloro-bicyclo [2.2.1] heptan-2-one-ethylene ketal, Formula IV, R ⁵ + R ⁵ = - (CH ₂ ) ₂ -, A = Cl g of general formula III To a solution of the chloro ketoester of formula (1400 ml) in absolute ether is added dropwise at -15 ° C to + 5 ° C 456 ml of a solution of lithium aluminum hydride in ether containing a total of 0.34 moles of lithium aluminum hydride.

After 3-5 hours, ethanol (37 mL) was added followed by 2N hydrochloric acid. Workup as described in Example 3 gave 70.8 an oily product which then solidified crystalline. The product contained 99.5% of the title compound by gas-liquid chromatography.

Analysis for C ₁₀ H ₁₅ ClO ₃ (218.7):

Calcd. Cl: 16.12;

Found: Cl, 16.31%.

IR: 3610, 3440-3540 cm ^-1 (hydroxy).

Example 5

5-Bromo-7-hydroxymethyl-bicyclo [2.2.1] heptan-2-one Formula V, A = Br

A mixture of 2.93 g of bromo ketal alcohol of formula IV wherein A is bromo, R ⁵ is ethyl, 50 ml of azeotropic hydrobromic acid and 20 ml of water

Reflux for 4-6 hours. The hydrobromic acid is then distilled off under reduced pressure, the residue is extracted twice with 30 ml each of chloroform, and the combined chloroform solution is washed with 3 ml of 2% aqueous sodium bicarbonate solution and then with 5 ml of a saturated aqueous sodium chloride solution. and then dried over anhydrous magnesium sulfate. The solvent is then evaporated; the resulting oily residue solidifies crystalline upon standing. The product thus obtained was recrystallized from a mixture of benzene and cyclohexane to give 1.79 g of the title compound in crystalline form; the product's characteristic spectral data correspond to the presumed chemical structure. M.p. 87-89 ° C.

Example 6

7-Hydroxymethyl-5-chloro-bicyclo [2,2, l] heptane-2-one (V) A = C1 g is chlorine and R ⁱ + R ^I site - containing _{(CH2) 2} groups ( A mixture of chloro-keto alcohol (IV), acetone (16 mL) and p-toluenesulfonic acid (30 mg) was heated to reflux for 20 hours, after which the acid was neutralized by addition of solid sodium bicarbonate. The solids were filtered off with suction, the solid remaining on the filter was washed with acetone and the solvent was removed from the filtrate combined with the washings. The residue was recrystallized from benzene; 0.66 g of the title compound is obtained, m.p. 81-82 ° C. The infrared, nuclear magnetic resonance and mass spectra of the product are consistent with the assumed chemical structure. IR: 3600, 3440-3540 cm ^-1 (hydroxy); 1738 cm ^-1 (ketone).

Example 7 3-Hydroxy-5-chloro-2- (tetrahydro-2H-pyran-2-yloxymethyl) -cyclopentyl] -acetic acid (1α, 3α, 5β) -S-lactone (VI) , A = C1, Z = tetrahydropyranyl g A solution of chloro-keto alcohol (V) wherein A is chlorine and 130 mg of anhydrous p-toluenesulfonic acid in 1000 ml of dichloromethane while stirring and cooling with ice and water 31 4 ml of dihydropyran are added dropwise. After 45 minutes, the reaction was quenched by the addition of a saturated aqueous sodium bicarbonate solution, the aqueous phase was separated, the organic solvent phase was dried over magnesium sulfate and the solvent was evaporated. The residual oil (48.2 g) was dissolved in dichloromethane (680 ml), and m-chloroperbenzoic acid (48 g) and sodium bicarbonate (36 g) were added portionwise under external cooling with water and ice. After standing for 12 hours, the reaction mixture was quenched by addition of excess sodium bicarbonate, the organic solvent layer was separated and washed with saturated aqueous sodium sulfite until a negative reaction with iodine starch paper. The organic solvent layer was then separated, dried over anhydrous magnesium sulfate, the solvent was distilled off and the resulting residue was recrystallized from benzene / cyclohexane. 39 g of the title compound are obtained in crystalline form; the spectral data of the product correspond to the presumed chemical structure.

Infrared spectrum: 1745 cm ^-1 (lactone)

Analysis for C ₁₃ H ₁₉ ClO ₄ (274.8):

Calculated: Cl, 12.91%. Found: Cl, 13.07%.

Example 8 [5-Bromo-3-hydroxy- (2-methoxy-prop-2-yloxymethyl) -cyclopent-1-yl] -acetic acid (1α, 2β, 3α, 5 (i) -S-lactone Formula VI, A = Br, Z = MPO

To a solution of 2.19 g of bromo-keto alcohol (V) where A is bromo and 10 mg of p-toluenesulfonic acid in 50 ml of dichloromethane are added 1.1 g of isopropenylmethyl methyl alcohol with stirring for 5 minutes. ether. The reaction mixture was worked up as described in Example 7 to give 3.05 g of an oily product; this was dissolved in dichloromethane (50 mL) and m-chloroperbenzoic acid (2.8 g) and sodium bicarbonate (2.3 g) were added gradually to the solution under external cooling with taste. The mixture was then stirred at room temperature for 10 hours and worked up as described in Example 7. In this way, 1.95 g of the title compound are obtained having infrared nuclear magnetic resonance and mass spectral data consistent with the assumed chemical structure.

Analysis for C ₁₂ H ₁₉ BrO ₄ (307.2):

Calculated: Br: 26.01%:

Found: Br, 26.45%.

IR: 1738 ^cm-first

Example 9 (3ax, 4p, 5a, 6aa) -Hexahydro-5-hydroxy-4- (tetrahydro-2H-pyran-2-yl-oxymethyl) -2H-cyclopenta [b] furan-2-one Formula I , Y = H, Z = tetrahydropyranyl

150 ml of δ-lactone containing A as chlorine and Z as tetrahydropyranyl and 5 ml as tetrahydro5

To the furan mixture of -4186368 was added 3.5 mL of concentrated hydrogen peroxide, and after stirring for 20 min, 2.2 mg of lithium hydroxide in water (3.5 mL) was added. After 1 hour, the reaction mixture was poured into ethyl acetate (60 mL), the excess peroxide was completely decomposed by addition of saturated sodium sulfite solution (while maintaining the temperature of the reaction mixture at 15 ± 5 ° C), and the organic solvent layer was separated. dried over sulfate and the solvent was evaporated in a rotary evaporator. The resulting oil (120 mg) was 98.5% of the title compound as an oil residue; the product's infrared, nuclear magnetic resonance, and mass spectral data are consistent with the assumed chemical structure.

IR: 1785 cm ^-1 .

Mass Spectrum: m / z 240, 222.139.137, 121, 101 and

85th

Example 10 (3aa, 4 (1,5a, 6aa) -Hexahydro-5 - [(1,1'-biphenyl-4-ylcarbonyloxy) -4-hydroxymethyl] -2H-cyclopenta [b] furan-2- is formula I, Y = C ₆ H 1 -C ₆ H ₄ -CO-, Z = H

To a solution of 8.1 g of 8-lactone I in which Y is hydrogen and Z is tetrahydropyranyl in 50 ml of absolute pyridine is added 6.85 g of p-phenylbenzoyl chloride and the mixture is stirred for 2 to 6 hours at room temperature, water (1 ml) was added and the mixture was stirred for an additional 30 ± 10 minutes. The pyridine is then evaporated in a rotary evaporator, 100 ml of chloroform are added, the aqueous phase is separated off, the organic phase is washed with a saturated aqueous sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate and the organic solvents are evaporated. The resulting 13.5 g of an oily distillation residue was dissolved in acetone (160 mL), treated with 1M hydrochloric acid (10-15 mL) and allowed to stand at room temperature for 4 to 10 hours. The acid is then neutralized by stirring with solid sodium carbonate, the solids are filtered off with suction, washed with acetone and the acetone from the filtrate combined with the washing liquid is distilled off in a rotary evaporator. The distillation residue is extracted with a total of 300 ml of chloroform, the chloroform extract is washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The resulting residue was 2; Recrystallize from 1: 1 dichloromethane-petroleum ether; This gives 6.79 g (61% of theory) of the title compound (I). the infrared, nuclear magnetic and mass spectral data of the product are consistent with the assumed chemical structure. 124-125 ° C.

Analysis for C ₂₁ H ₂₀ O ₅ (352.4):

Calculated: C, 71.58; H, 5.72;

Found: C, 71.34; H, 5.82.

Infrared spectrum: 1785 cm ^-1 (CO in γ-lactone); 3595, 3420-3550 and 1055 cm ^-1 (hydroxy).

Example 11 [gamma] - [beta] of [5-Chloro-3-hydroxy-2- (methoxyethoxymethyloxymethyl) -cyclopent-1-yl] -acetic acid (1α, 2β, 3α, 5β)] In formula VI, A = C1; Z = CH ₃ OCH ₂ CH ₂ OCH ₂ -]

1.75 g of chloro-keto alcohol [V]

A is chlorine] Dissolve in 15 ml of acetonitrile and add a solution of 2.26 g of methoxyethoxymethyltriethylammonium chloride in 15 ml of solvent at 20-25 ° C. After 30 minutes, the precipitated triethylamine hydrochloride is filtered off, the solvent is distilled off under reduced pressure, the bath temperature is 40-50 ° C and the pressure is 5.2 ° C. . The distillation residue was taken up in water (10 mL) and extracted with 1,2-dichloroethane (3 x 10 mL). The combined extracts were dried over magnesium sulfate to give 2.13 g of an oily product after evaporation of the solvent. The oily product was dissolved in dichloroethane (30 ml) and m-chloroperbenzoic acid (2.4 g) and sodium bicarbonate (1.8 g) were added under cooling. After stirring for 10 hours at 20-25 ° C, excess sodium bicarbonate is added, the organic phase is separated, and the mixture is washed 3 times with 3 ml of saturated aqueous sodium sulfite until the iodine is removed. -starch reaction will not be negative. The organic solution was dried over sodium sulfate, the solvent was distilled off and the residue was recrystallized from hexane-benzene. 1.82 g of product are obtained. In formula (VI), A is chlorine, Z is CH ₃ OCH ₂ CH ₂ OCH ₃ .

Analysis A'c _Ig H ₁₂ ClO ₅ (266.7) Calculated compound:

Calculated: Cl: 13.29%;

Found: Cl, 13.03%.

m / z 226/229 IR: 1735 cm ^-1 .

Example 12 γ-Lactone of [5-Bromo-3-hydroxy-2- (tert-butyldimethylsilyloxymethyl) cyclopent-1-yl] -acetic acid (Ia, 2β, 3a, 5β) [A = Br, Z = (CH ₃ ) ₃ C (CH ₃ ) ₂ Si—]

To a mixture of 2.29 g of bromo-keto alcohol (in formula V) is bromine and 1.65 g of tert-butyldimethylsilyl chloride, 1.21 g of triethylamine and 50 mg of 4-dimethyl A solution of aminopyridine in 5 ml of dichloromethane was added dropwise. After stirring for 1 hour under nitrogen, the reaction mixture was washed with water (3 ml) and saturated aqueous ammonium chloride solution (5 ml); the organic phase is dried over magnesium sulfate. The solvent was removed in vacuo; 3.08 g of an oily product are obtained. The product was dissolved in dichloromethane (40 mL) as described in Example 7; oxidizing the solution with p-chloroperbenzoic acid. The reaction mixture was worked up to give 2.34 g of an oily product.

Analysis for C ₁₄ H ₂₅ BrO ₃ Si (MW 394.4):

Calcd for Br-22.88368: Br, 22.87;

Found: Br, 22.12%.

m / z; 348/350, 268, 217/219, 203/205.

Infrared spectrum: 1741 cm ^-1 (lactone group)

CO-).

Example 13 [3aα, 4β, 5β, 6aα] Hexahydro-5-hydroxy-4- [methoxyethoxymethyloxymethyl] -2H-cyclopenta [b] furan-2-one [In the formula I, Y = H; Z = CH ₃ OCH ₂ CH ₂ OCH ₂ -]

1.5 g γ-lactone [(VI): wherein A = C1, Z = CH ₃ OCH ₂ CH ₂ OCH ₂ -] are dissolved in 50 ml of dichloroethane; 35 ml of concentrated hydrogen peroxide are added to the solution, and after stirring for 15-20 minutes, a solution of lithium hydroxide in 35 ml of water is added. Work-up was carried out as in Example 9; 1.05 g of product are obtained.

IR: 1783 cm ^-1 (CO group) 3596,

3450-3500 and 1106 cm ^-1 (OH group) 1063 and 1085 cm ^-1 (C-O-C group)

Example 14 [3aa, 4p, 5a, 6aa] Hexahydro-5-hydroxy-4- (tert-butyldimethylsilyloxymethyl) -2H-cyclopenta [b] furan-2-one [Formula I Y = H; Z = (CH ₃ ) ₃ C (CH ₃ ) ₂ Si -]

To a solution of 500 mg of δ-lactone in [A = Br, Z = (CH ₃ ) ₃ C (CH ₃ ) ₂ Si]] in tetrahydrofuran, add 10 ml of 30% hydrogen peroxide, and after stirring for 15 minutes, 7.1 mg of lithium solution of hydroxide in water (11.5 ml). After working up the reaction mixture (Example 9), 324 mg of product are obtained.

m / z: 286 Infrared Spectrum: 1785 cm- ¹ (lactone group)

CO) 3598 and 1097 cm ^-1 (hydroxy).

Example 15 [3a?, 4 p, 5a, 6aa] hexahydro-5-acetyloxy-4-hydroxymethyl-2H-cyclopenta [b] furan-2-one [in the formula Y = CH ₃ CO- (S); Z = H]

350 mg of compound of formula I [Y = H; Z = (C ₆ H ₅ ) ₃ C - 3 ml pyridine, 210 ml acetyl chloride and 0.1 ml water are added after stirring for 4 hours. The reaction mixture was stirred for an additional 30 minutes. The excess pyridine was removed by distillation in vacuo and the mixture was stirred for 30 minutes and then extracted with 3 ml of chloroform. The combined organic extracts were washed with saturated aqueous sodium bicarbonate or water. The organic solution was dried over magnesium sulfate and the solvent was distilled off. The oily residue was diluted with 2.5 mL of dilute acetic acid (1: 2), and after stirring for 6 minutes (at room temperature), the reaction mixture was neutralized. Extract four times with 5 ml of chloroform each time, dry the combined organic extracts, evaporate the solvent and chromatograph the residue on a silica gel column; 156 mg of product were collected.

Analysis: Calculated for C ₁₀ H ₁₄ O ₅ (MW 214.2): C, 56.07; H, 6.59; Found: C, 56.17; H, 6.72.

Infrared spectrum: 1780 cm ^-1 (10 CO groups of the lactone group).

m / z 214, 155, 154, 139, 60 and 59.

Claims (1)

Patent claims A process for the preparation of (3aa, 4p, 5a, 6aa) -hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta [b] furan-2-one derivatives of the formula I wherein Z is hydrogen, triphenylmethyl, tetra20 hydropyranyl, tetrahydrofuranyl, C 1-4 alkoxy (C 1-4) alkyl, C 1-4 alkoxy (C 1-4) alkoxy (1-4) C 1 -C 4 alkyl or tert-butyldimethylsilyl, Y is hydrogen or a group R ³ CO-, wherein R ³ is a C 1-4 alkyl group or a C ₆ H ₅ C ₆ H ₄ group, characterized in that one of the compounds of formula II 5-halo-2-oxo-bicyclo [2.2.1] heptane-7-carboxylic acid, alpha.30 kilo ester R ⁴ is C 1-6 alkyl, A is a chlorine or bromine atom - an acidic catalyst of a monovalent or divalent C 1-4 alcohol, preferably benzenesulfone, In the presence of 35 p-toluenesulfonic acid or an ion exchanger in the H ⁺ cycle, the reaction is preferably carried out in benzene, toluene, 1,2-dichloroethane or tetrachloromethane to remove the resulting water by azeotropic distillation, followed by hydration of the resulting ketal with or by reduction with sodium bis (2-methoxyethoxy) aluminum hydride at 0 ± 30 ° C, then the resulting hydroacetal is decanted with an aqueous solution of a hydrohalic acid or recrystallized with 2 to 6 carbon atoms of ketone to give The primary hydroxyl group of 7-hydroxymethyl-5-chloro (bromo) -bicyclo [a, a, 1] heptan-2-one is protected in the form of a Z derivative wherein Z is as defined herein and the resulting δ- lactone is oxidized with peracetic acid or m-chloroperbenzoic acid in the presence of sodium or potassium bicarbonate, preferably lithium hydroxide and hydrogen peroxide. oxide, and the resulting S-lactone of formula I, wherein Y is hydrogen, A and Z are as defined above, optionally a tertiary amine, preferably pyridine, triethyl, with acyl halide, preferably acetyl chloride, propionyl chloride or phenylbenzoyl chloride. in the presence of an amine or diisopropylethylamine, to form a compound of formula I wherein Y is other than hydrogen.