CS230650B1 - Production method of prostanoid acetale - Google Patents

Description

The invention relates to a process for the preparation of prostanoid acetals of the formula I wherein R is hydrogen or alkyl having 1 to 3 carbon atoms, r 'is hydrogen or methyl, X is O or S and n = 0 or 1.

Prostanoids are derivatives of prostadienoic acid with high physiological efficacy.

They act as tissue hormones and affect a number of important systems, such as the cardiovascular system, regulate gastric glory secretion, reproductive cycle, nervous system, respiratory system. Natural prostaglapdins, when applied in human medicine, have some disadvantageous properties, in addition to the desired effect adversely affects pressure increase, temperature rise, cause diarrhea and headaches. In many cases they metabolize relatively quickly in the body (metabolisae usually begins with oxidation of the liydroxyl group on carbon at the 15-position - prostaglandin numbering) and thereby loses its efficacy. For these reasons, synthetic analogs are sought that act specifically without the side effects of protracted action. For these analogs to be physiologically effective, the alpha orientation of the hydroxyl group on the 15-position carbon is almost a necessary condition. On an industrial scale, these isomers are obtained by relatively difficult separation of the correct (alpha-isomer) and undesired epi- (beta-isomer) mixture. obtained after reduction of the carbonyl group (see, e.g., JS Bindra, R. Bindra, Prostaglandin Synthesis, Academic Press, Inc, New York 1977; SM Roberts, RF Newtom, Prostaglandins and Thromboxanes, Butterworth Scientific, London 1982). This process is considerably disadvantageous from a technological and economic point of view.

More recently, prostanoids having acetal-bound oxygen in place of the hydroxyl group have been shown to be effective (see DOS No. 2,654,113; J. Med. Chem. 21, 443 (1978)). In this way, physiologically active prostanoid derivatives can be prepared in a substantially simpler manner. These known facts are followed in a positive sense by the method according to the invention. The process according to the invention protects a novel process for the production of prostenoid chelates of the general formula I, which have a significant activity in the synchronization of cattle heat, childbirth and are further used in their treatment. '

The essence of the process according to the invention consists in the readily available enone of the general formula

3 of formula II wherein R is C 1 -C 3 alkyl or R -C 8 H 4 - the radical where R ^J is hydrogen or phenyl is converted by reaction with an alkanediol or an alkanedithiol having a carbon number of 2 to 5 in an inert organic solvent, such as benzene, toluene, in the presence of an acidic reagent, preferably p-toluenesulfonic acid or ion exchangers in the acetal cycle of formula III, wherein R, r ', R ² , X, n are as defined above.

This azetal is removed in a further reaction step by treatment with a C 1 -C 4 alcohol in the presence of basic reagents, preferably potash, soda or ion exchangers in the OH 4 -cycle, protecting the acyl group at the 11-position (prostaglandin numbering), and the hydroxyacetal of formula IV is obtained. The compound of formula (IV) is converted to a lactol by treatment with a complex hydride, which is converted to a compound of formula I by treatment with a ylidera (CgH4) 3? = 0Η (0 ^2 ^ COc / ^- ). of the formula IV in the 11-position in the form of an ether of the formula V wherein R, R ¹ , X, n are as defined above and Z is tetrahydrofuryl or 1-methoxybenzyl. This reaction is carried out by adding 2,3-dihydrofuran in the presence of an acidic reagent in a molar ratio of 1: 1.0 to 1.5 or 1-methoxybenzyl chloride to a compound of formula IV dissolved in an inert solvent such as dichloromethane or carbon tetrachloride. in the presence of a tertiary amine such as triethylamine, diisopropylethylamine and the like. It monitors the progress of the reaction by thin layer chromatography.

Thereafter, the compound of formula (V) is complexed with a complex hydride, preferably diiaobutylaluminum hydride or sodium bis-2-methoxyethoxyaluminium hydride at -80 to -40 ° C to the lactol of formula VI, wherein R, R ¹ , X, n, Z have the above said significance, which is reacted with an excess of the ylide at a temperature of 10 to 30 ° C prepared from 4-carboboxybutyltriphenylphosphonium bromide in a polar aprotic solvent such as dimethylsulfoxide, sulfolane with a strong base, preferably sodium hydride, potassium tert-butylate, butyllithium, dimethylsulfoxyidium to give a compound of formula VII wherein R, R ¹ , X, n, Z are as defined above. ¹ In this reaction, it is preferred to use 2 to 4-fold molar excess ylide.

The product of formula (I) is released from the compound of formula (VII) by treatment with acidic reagents such as dilute acetic acid, oxalic acid or ion exchangers in a cycle.

In reaction sequence IV to I carried out without protecting the hydroxyl group at position 11 (prostaglandin numbering), two reaction steps, i.e. protecting the hydroxyl group and then removing it, are omitted. In this embodiment of the reaction sequence, the amount of reagents must be substantially increased in the reduction of the lactone moiety to the lactol moiety and in the reaction of the lactol and the ylide. Another disadvantage of this process is the more difficult isolation of the product of formula I.

The process according to the invention favors the preparation of the substances, the technical implementation of all reaction steps is very simple and the yields at all stages are very good.

The invention is illustrated by the following non-limiting examples.

Example

To a solution of 4.2 g of an enone of formula II (where R = C 8 H 8 C 8 H 4) in 130 ml of benzene was added 2.5 ml of ethylene glycol and 100 mg of p-toluenaulfonic acid. The mixture was heated with an azeotropic tube for a total of 6 hours, then the reaction mixture was washed with saturated sodium bicarbonate solution and finally with common salt. The organic phase was dried over magnesium sulfate, the solvents were removed by rotary evaporation, and the product of formula III (R R = CgH ^C CH ^, X = oxygen, n = O, R = H) was purified in a total amount of 4.1 g. column chromatography (eluted with chloroform-ethanol). In the infrared spectrum there are no bands of CO group corresponding to carbonyl in the ketone at position 15, the band 1 735 om ^- corresponds to the valence vibration of CO in the ester, 1 785 cm ^{- to the} valence vibration of the gamma-lactone moiety. Ion species were found in the mass spectrum at m / z: 560 (lithium), 433,

419, 362, 181.

Example

4.2 g of enone of the formula II (where R = ^ CGH-CGH) rozpuatí e in 130 ml of benzene, 2.5 ml of ethylene glycol and 0.5 g of ion exchange resin in ¹ * Η 'cycle (Domex 50, grain size 200 mesh ).

After treatment of the reaction mixture in analogy to Example 1, 4.4 g (96%) of product XII were obtained, where R &^lt; 1 ^> X = oxygen, n = 0, R = H), whose spectral characteristics are the same and are standard.

Example 3

3.5 g of acetal of the formula III (where R = C8H4CgH4, R = Η, η = 0, X = oxygen) are dissolved in 75 ml of dichloromethane, 75 ml of methanol and 2.5 g of anhydrous potash are added. The reaction mixture was stirred at room temperature for 2 hours while the progress of the reaction was checked by thin layer chromatography. After filtering the potash, the reaction mixture was neutralized with 3 K hydrochloric acid to pH 5.5-6 and evaporated to dryness in vacuo. The residue is extracted with 120 ml of chloroform, the extract is dried over magnesium sulphate and, after evaporation of the solvent, the product is purified by chromatography on a silica gel column, eluting with chloroform-methanol. Yield 2.55 g (95 96) of the product of formula IV (wherein R - Η, η = O, X = oxygen) whose infrared spectrum comprising bands at 3590, 3320 until 3400 cm ^- 'and 1105 cm ^- 'which confirm the presence of OH groups in the dog 1 783 om ^-' corresponds to the valence 'vibration of CO groups in the gamma-lactone. The mass spectrum contains ionic species m / z 380, 253, 239, 235, 221, 179.

Example 1 a and 4 o

To a solution of the enone of formula II (where R = CgH4) in 40 ml of toluene was added 0.8 g of 2,2-dimethyl-1,3-propanediol, 50 mg of p-toluenesulfonic acid, and the resulting reaction mixture was heated on an azeotropic adapter. 4 hours (after separation of the calculated amount of water).

After. cooling was washed with 10 ml of sodium bicarbonate, 5 ml of saturated sodium chloride solution, the organic phase was dried over magnesium sulphate and after evaporation of the solvents, 2.15 g of an oily product of the formula III (where R = C8H4, R =,, X = oxygen, η = 1, r 'p CH,), whose spectral characteristics are in accordance with the proposed structure. In the infrared spectrum, the bands of 1735 cm valence vibration of the CO group in the ester, 1780 cm valence vibration of the CO group in gamma-lactone, 1380 cm ^- 1 deformation vibration CH in the cluster (CHjJgCj in the mass spectrum were found the following ionic species m / of: 526, 404, 399,

385, 421,280.

Example 5 *

To a solution of 3.8 g of an enone of formula (II) wherein R R = CHj and 1.1 g of 1,2-ethanedithiol in 5 ml of dichloromethane was added 0.5 ml of BF ^ etherate and the reaction mixture was left at room temperature for 10 hours. Then, 20 ml of 5% sodium hydroxide solution was added, the organic phase separated, washed with water and dried over magnesium sulfate. After evaporation of the solvents, 4.15 g of an oily product of the formula III were obtained, wherein RH, R = CH3, n0, X = S, the structure of which is in accordance with the interpretation of the spectra. The infrared spectrum bands were present 1725 cm '', corresponds to the CO group in acetate, 1238 cm ^- 'C stretching vibration in θ-acetate

I 785 cm ^- 'CO y-lactone and 970 cm ^-' CH deformation vibration of the trans double bond. The mass spectrum contains ionic species m / z 454, 313, 327, 394, 253 · t

Example 6

To a solution of 2 g of hydroxyacetal of formula IV (where R = Η, X = oxygen, n = 0) in 50 ml of benzene was added 0.25 g of triethylemine, and 0.9 g of 1 g were added dropwise to the resulting solution under stirring at room temperature. -methoxybenzyl chloride in the form of a 20% benzene solution. After 2 hours, the reaction mixture was washed with saturated brine, the organic phase separated and dried over magnesium sulfate and the solvents evaporated in a rotary evaporator. 2.5 g (96%) of an oily product of the formula V, where R H,

X = oxygen, n = 0, Z = C 8 H 9 CHOCH 4, whose spectral characteristics are in accordance with the proposed structure. IR spectrum comprising a band at 1782 cm ^- 'příslužející stretching vibration of the carbonyl group in the gamma-lactone, 965 cm ^-' CH trans-double bond, MS comprises ion species m / z: 500, 362, 221, 359, 373, 379.

Example 7

To a mixture of 1.4 g of a compound of formula III (R ² = CH 2, X 1 S, R = Η, n = 0) 20 µl of dichloromethane and 20 ml of methanol was added 1.6 g of anhydrous skin. After stirring at room temperature for 3 hours (reaction progress was monitored by thin layer chromatography) the potash was filtered off, the mixture was neutralized with dilute hydrochloric acid to pH 5.5-6 and evaporated to dryness. The residue was then extracted with chloroform, the chloroform solution was dried over magnesium sulfate and the distillation residue was chromatographed on a silica gel column (eluent: chloroform-ethanol). 1.1 g of an oily product of formula IV (wherein R = Η X = S, n = 0) which has the infrared spectrum bands at 3600 cm ^- ', 3320 cm ^-' EŽ 3450 cm ^- 'hydroxyl group, and associated band at 1785 cm ^-' corresponds to the presence of gamma-lactone. In the mass spectrum there are significant ionic species with m / z values: 412, 352, 211, 285, 271.

Example 8

To a solution of 2.25 g of a compound of formula V, (where R = Η, X = oxygen, n = 0,

Z = (CH 2 CH 3 CH 3) in 120 ml of toluene and 15 ml of tetrahydrofuran (nitrogen atmosphere) was added gradually over 20 minutes 12 ml of dibal (1.2 M diisobutylaluminum hydride in toluene) with stirring at -78 to -70 ° C. then stirred for 45 minutes. After addition of 20 ml of methanol, the reaction temperature was raised to 0-5 ° C and the reaction mixture was poured into 250 ml of 10% common salt solution, the organic phase separated and aqueous extracted with ethyl acetate (total 250 ml), the combined organics were washed with brine. , dried over magnesium sulphate and the solvents evaporated in vacuo. 2.2 g (97%) of the product of formula VI (where R = Η, X = oxygen, n = 0, Z = C =H ^CHOCH ^) were obtained, the mass spectrum of which was in accordance with the proposed structure. Mass spectrum m / z: 502, 364, 484, 346, 223, 361, 375, 381.

Example 9

To 2.5 g of the lactone of formula V (where R = H, R ¹ = CH 2, n = 1, X = oxygen, Z = tetrahydrofuryl) in 130 ml of toluene and 75 ml of tetrahydrofuran was added 15 ml of a 1,211 toluene solution of diisobutylaluminium hydride. (DIBAL) over 5 minutes at -75 to -70 ° C. After 20 minutes, the reaction was quenched with 2 mL of methanol, and after slowly warming to 5-10 ° C, 2 mL of saturated sodium chloride solution was added. The organic layer was separated, the aqueous phases extracted 3 x 10 mL ethyl acetate, the combined organics washed with saturated brine, dried over magnesium sulfate, and the solvents evaporated on a rotary evaporator (bath temperature 30-40 ° C, 30 psi). Was obtained 2.45 g of product of formula VI (where R = H, ^R1 = CH ^, n = 1, Z = tetrahydrofuryl), whose structure is consistent with the interpretation of the spectra.

Example, 0

To a solution of 10.45 g of 4-carboxybutyltriphenylphosphonium bromide in 40 mL of domethylsulfoxide was added 41.6 mL of 1.38 M dimethylsulfoxidnatrium solution in an inert atmosphere and the reaction mixture was stirred at room temperature for 15 minutes and then added to the dark red ylide. 2.2 g of lactol of formula VI (where R = Η, X = oxygen, n = 0, Z = C CHHCHOCH ^) dissolved in 50 ml of dimethylsulfoxide. After stirring for 3 hours, 95 mL of saturated sodium chloride solution was added to the reaction mixture, then the solution was acidified to pH 3.5 with saturated oxalic acid solution and shaken 4x with 50 mL of benzene. The combined benzene extracts are concentrated to about 1/4 of the original volume, washed with saturated brine and the organic phase is evaporated to dryness. 7 g of a residue are obtained, from which, by column chromatography on silica gel (eluent of chloroform-tert-butyl alcohol), 1.7 g of product are obtained, which is 83% of the general formula I (where R = Η, X = oxygen, n). = 0) whose mass spectrum is in accordance with the proposed m / z structure: 466, 325, 448, 321, 307, 328.

They did

To 4.2 g of an enone of formula XI (where R '- C 8 H 8 C 9 H 4) in 110 mL of toluene was added 2.7 mL of 1,2-propanediol and 70 mg of p-toluenesulfonic acid and then heated to boiling using an azeotrope adapter. for water separation. After separation of the calculated amount of water, the reaction mixture was cooled, washed successively with 10 ml of saturated sodium bicarbonate solution, 10 ml of brine, dried over magnesium sulfate and the solvents were evaporated. The obtained product 4.21 g of the general formula III (where R ² = ^C 6 ^H 5-6 ^H 4 'X = oxygen, R = CH 3, n = 0) was purified on a silica gel column. The structure was confirmed by IR spectrum - absence of band corresponding to CH = CHCO grouping, and presence of band 1,785 cm @ -1 CO valence vibration in gamma-lactone, 1,730 cm @ -1 CO valence v ester (position 11 PG numbering) and 3,010 to 3,085 cm -1 aromatic protons. A molecular ion of m / z 574 rel. intensity of 1.2%.

Example 12

To a solution of 3.9 g of the compound of formula III (where R ² = C 4 H 4 C 6 H 4, X = O, R = CH 4 in = 0) in 80 mL of dichloromethane was added 80 mL of methanol and 2.7 g of anhydrous potash . After the reaction mixture was worked up analogously to Example 3, 2.73 g of the product of the general formula IV (where R = CH, X == oxygen, n = 0) were obtained in the infrared spectrum of which the characteristic " _M " at: 3592, 3, 340-3, 405 and 1100 cm corresponding to an OH group band 1785 cm ^- 'CO stretching vibration in a gamma lactone group.

Example, 3

To a dark red-orange solution of ylide (prepared from 14.1 g of 4-carboxybutyltriphenylphosphonium bromide and dimethylsulphoxide-sodium in dimethylsulphoxide by standard procedure) was added 3.15g of lactol of formula IV (where R = CH3, X = oxygen, n = 0, Z). Dissolved in 70 ml of dimethyl sulfoxide and 5 ml of benzene After stirring at room temperature for 1 hour at 50-60 ° C (bath temperature), the mixture was cooled, quenched with 110 ml of dilute sodium chloride solution, and The crude product was chromatographed on a silica gel column to give 2.35 g of a compound of formula I (R = CH, X = oxygen, n = 0) as a viscous oil. In the in-5 ' 1 ' infrared spectrum, the bands at 3,345-3,410, 3,580 and 1,110 cm confirm the presence of the sec-hydroxyl group, a broad band of low intensity at 2,500-3,200 cm @ -1 and 1,713 cm @ -1. confirms the presence of COOH groups y, bands at 785, 1,540, 1,597 and 3,030 cm '' of the presence of the aro230650 mat core. Ionic species with m / z values were found in the mass spectrum: 480/482, 462/464, 422/424, 404/406, 339, 335, 298, 278 confirming the proposed structure.

Claims (7)

SUBJECT OF THE INVENTION AND A process for the preparation of acetals of prostanoids of formula I wherein R is hydrogen or C 1 -C 3 alkyl, R ¹ is hydrogen or methyl, X is oxygen or sulfur, n = 0 or 1, characterized in that the lactone of the formula II, where R is C1 -C3 alkyl or R @ 5 C8 H @ - - the radical R @ 5 is hydrogen or phenyl, is converted by conversion of an alkanediol or alkanedithiol of 2 to 5 in the presence of a catalytic amount of an acidic reagent into an acetal of formula III wherein R, R, R, X, n are as defined above, which upon reaction with a C 1 -C 4 alcohol in the presence of bases provides the hydroxyecetal of formula IV wherein R, r ', X , n are as defined above, which are treated with a complex hydride, optionally after preliminary protection of the hydroxyl group at the 11-position of the compound of formula IV, to give the corresponding lactol, which is reacted with an ylide (CGH ^ i ^ = P ^ CHIC) ^ 000 ^ ^- ^ converted to a compound of formula I. 2. A process according to claim 1, wherein the compound of formula IV is protected from the complex hydride with a hydroxyl group at position 11 by treatment with 2,3-dihydrofuran in the presence of an acidic reagent in a molar ratio of 1: 1.0. to 1,5 or 1-methoxybenzyl chloride in the presence of a tertiary amine, for example triethylamine, diisopropylethylamine, to give a compound of formula V wherein R, R, X, n are as defined above and Z is tetrahydrofuryl or 1-methoxybenzyl which at -80 to -40 ° C, it converts to the lactol of formula VI wherein R, R ¹ , X, n, Z are as defined above, which are reacted with an ylide of formula (C 8 H 4) 4 P = CH (CH ₂ ) 4 C 100 at 10 to 80 ° C at a molar ratio of reactants of 1: 2 to 4 to give compounds of formula VII wherein R, R ¹ , X, n, Z are as defined above, the product of formula I is liberated by treatment with acidic reagents. 3. A process according to claim 1, wherein the alkanediol or alkanedithiol is ethylene glycol, 1,2-propylene glycol, 2,2-dimethyl-1,3-propanediol, ethanedithiol. 4. A process according to any one of claims 1 to 3, wherein the acid reagent is p-toluenesulfonic acid, phosphorus pentoxide, or ion exchange resin ( ^{+ /} - cycle). 5. Process according to claim 1, characterized in that an alkali metal carbonate, for example sodium carbonate, potassium carbonate or an ion exchanger in the OH @ 4 cycle is used as the basic agent. 6. Process according to claim 1, characterized in that diisobutylaluminium hydride is used as the complex hydride, and trisulphite bis-2- (methoxy) ethoxyeluminium hydride is used. 7 * Process according to claim 1-6, characterized in that as acidic reactants to uvolněnl product of formula I is an organic carboxylic acid such as acetic acid, oxalic ion exchanger or VH ⁽⁺ @ cycle.