CZ17295A3 - Process for preparing misoprostol - Google Patents

Abstract

A process for the preparation of misoprostol-prostaglandin of formula (I), which consists in the direct reaction of a readily available aldehyde of formula (II) wherein R is tetrahydropyranyl or a target. butyldimethylsilyl, with the formula III, in a molar ratio of 1; 1.2-2.0 at a low temperature of -50 ° C to 20 ° C.

Description

Process for producing misoprostol

Technical field

The invention relates to formula I.

misoprostol - prostaglandin production method

These prostaglandins are a group of twenty carbon unsaturated polyhydroxylated fatty acids regulating various functions in the human body. Their effects are described in the cardiovascular, respiratory, reproductive, gastrointestinal and other systems (W. D. Watkins, M. B. Peterson, J. R. Fletcher, Eds. In Prostaglandins in Clinical Practice, Raven Press, New York, 1989).

BACKGROUND OF THE INVENTION

Disorders of the formation of prostaglandin in the human body from essential fatty acids caused by stress, certain medicaments, etc. cause disorders of a number of vital functions, often leading to serious ‘diseases. For example, gastric juice secretion disorders are the cause of gastrointestinal ulcer disease, which may occur after long-term administration of non-steroidal anti-inflammatory drugs (aspirin, ibuprofen, indomethacin and others). Although it has been shown that these disorders can be treated with natural prostaglandins of the E-series, they have not been proven in clinical practice with oral administration. This was due to their rapid metabolic inactivation, chemical instability and the occurrence of side effects. Extensive research has shown that modifying the lower chain of prostaglandin E-series, for example by transposing a hydroxyl group from position C-15 (prostaglandin numbering) to a quaternary carbon atom at position c-16, provides analogs meeting the requirements of clinical practice in terms of stability and efficacy oral administration including substantial suppression of adverse reactions. Among a number of synthetic derivatives, (±) -4,5-dehydro-15-deoxy-16-hydroxy-16-methylprostaglandin methyl ester, known under the INN name Enisoprost (Clin.Sci.71 (S15), 75 (1986),

U.S. Pat. pat.spis.4,536,592, Aug. 20, 1985), methyl ester

16-methoxy-16-methylprostaglandin, Ε _χ , ΙΝΝ Mexiprostil (J. Med. Chem. 29, 1826 (1986), Hepatogastroenterol 34, 117 (1987)),

Prostaglandins 35, 639 (1988), US Pat. No. 4,547,521, Oct.15, 1985) indicating the regulation of gastric juice secretion and treatment of gastrointestinal ulcer disease. Another, (16R, S) - (±) -15-deoxy-16-vinylprostaglandin E ₌ , INN Viprostol derivative has been shown to have active hypotensive effects upon oral and transdermal administration (J. Med. Chem. 25, 492). (1982) Federation.

Proceedings 42, 157 (1983) EuroPat.Appl. 0 249 194 A2, currently found in clinical practice (±) -15-deoxy-16-hydroxy-16-methylprostaglandin E,

INN Misoprostostol, with strong antisectretoric and cytoprotective properties. The main indication area of this preparation is the prevention of non-steroidal anti-inflammatory ulcers and the treatment of duodenal and stomach ulcer (Digestive Diseases and Sciences 30, 148 (1985), DICP The Annals of Pharmacotherapy 276, 282 (1989), Exp. Physiol. 76). , 561 (1991), Medical Research Reviews 10,149 (1990)).

Among the known processes for the preparation of misoprostol, the so-called two-component coupling (Scheme 1) occupies an important position, based on the reaction of cyclopentene precursor A with the corresponding metal-complex lower chain compound (path a) and three-compound coupled coupling (path b). side chains R and R attached to _the 4-substituted cyklopentenovému skeleton in one step. Z is a suitable protecting group.

09.06.87) In methyl ester

related derivatives are well documented in the literature to perform precursors of a very complex synthesis of sophisticated techniques (see _: J. Med. Chem., 32, 1001 (1989), H. Med. Chem. 26, 786 (1983), J. Org.

Chem. 56.2549 (1991), (J. Med. Chem. 56.2549 (1991), J. Med. Chem. 35,

-6 9 4— (1-9 9 2jyTe t r ahedron “4 8T6 3 9 3- (19 9 2jy“ UTS ”pa t — Spř-475-4 775 217“

15, (1985), U.S. Pat. U.S. Pat. No. 4,536,592, Aug.20, (1985), PCT Int. Appl. WO 86 04,330, Jul. 31 (1986) Ger. Offen. DE 3,207,470 to Oct. 07 (1982), Euro, Pat. 0 173 753 Al 29.02.84, Organic Reactions Vol. 41, p. 135, J. Willy and Sons, Inc., New York, 1992). Although at first glance these methods seem highly elegant; simple and therefore lucrative, they have some practical disadvantages. In particular, the preparation of the required R chains and especially R represents a multi-stage process and in many cases requires use in an inert atmosphere at very low temperatures, an absolutely anhydrous environment, etc.) and unusual, often expensive reagents. On an industrial scale, these processes are rarely used and production capacity is likely to be relatively limited for technological reasons. An interesting approach to the synthesis of misoprostol is protected by Spanish Patent Specification No. 545,634, May 16, (1986). It utilizes the Wittig reaction of the corresponding methyl (7- (2-formyl-3-hydroxy-5-oxocyclopentyl) heptanoate C derivative) in which the hydroxyl function is protected by the corresponding tetrahydropyranyl or triethylsilyl ether (X = THP or Et Si) and

The 5-oxo group is free or protected in the form of ethylene acetal, with the corresponding ylide D, in which the tertiary hydroxyl group is also protected in the form of tetrahydropyranyl or triethylsilyl ether (Y = THP or Et Si) (Scheme 2).

Scheme 2

> ^CH3 <1

According to this specification, the desired product is obtained in a relatively low yield of 35-40%, and the process for its isolation is very difficult and expensive. Moreover, based on theoretical knowledge, very low yields can be expected when carrying out the reaction with an unprotected oxo group at the 5-position of the cyclopentane ring.

It is also known that blocking of the hydroxyl function with a protecting group can lead to a reduction in the stereoselectivity of the olefinic reaction, which is undesirable because the high biological activity of this compound is conditioned by the trans configuration of the resulting double bond (Chem. Rev. 89, 836 (1989); 86, 662 (1992)).

Another approach to the synthesis of misoprostol based on the so-called Coréy lactone has only been theoretically indicated, but has not yet been experimentally verified (Tetrahedron Lett. 23, 1067 (1982)). These known processes are followed in a positive manner by the process of the invention, which simplifies the entire process of preparing misoprostol and provides the product with the desired isomeric composition in good yield.

SUMMARY OF THE INVENTION

The essence of the process according to the invention rests easily on the direct reaction

I of the available aldehyde of the general formula. II, wherein R is a tetrahydropyranyl or t-butyldimethylsilyl protecting group

CH, .G00 J € 5

GOOGH.

RQ

Gf = O and the ylide of formula III h ₅ P

CI ₅ ch-ch-c- (ch ₂ ) ₃ ch ₅

OH

nolárním the ratio of aldehyde and the ylide of 1: 1,2 to 2.0 at low t ^ ^_ summer -50'-C ^ * ^ 20''cTReaRčě of přová'ďí ~ '* ~ tock' 7 ^ žense'- In an inert atmosphere to a suspension of the corresponding phosphonium salt in a suitable aprotic oxygen solvent, preferably in tetrahydrofuran, dimethoxyethane or dioxane, a strong base solution is added, with vigorous stirring, at a temperature of from -65 ° C to -20 ° C, preferably The solvent was hex-hex-or di-methyl-na-tr-i-imidimethyl sulfoxide for 10 to 30 minutes. The reaction mixture is allowed to warm to room temperature, the resulting deep-dark red ylide III solution is cooled again to -50 ° C to -20 ° C and then the aldehyde II dissolved in the appropriate solvent is added. Stirring is continued at this temperature for 5 to 30 minutes. Progress of the reaction was monitored by tlc or HPLC analysis. After completion of the reaction, the mixture was diluted with an organic solvent. (e.g. ethyl acetate, tetrahydrofuran or dimethoxyethane), the remainder of the reagent is quenched by addition of saturated ammonium chloride solution, the organic phase is separated and the aqueous layer is extracted with the above solvent. Following a conventional processing method, the isolated product of formula (IV),

where R has the aforementioned R = TH 3, t-BuKe 4 Si R 4 = CH 4 GO, H is the meaning of acetyl, it is purified by filtration on a silica gel column. Removal of the acetyl protecting group is accomplished by treatment with a base in an excess of alkanol, preferably methanol, ethanol or propanol, with stirring at 30 ° C to 70 ° C. Preferably, anhydrous potassium carbonate, potassium acetate or alcoholates may be used as the basic agent

5 »» _r r

alkali metals. Upon completion of deprotection, which can be monitored by body or gle analysis, the reaction mixture, if it contains a solid phase, is filtered and the filtrate is neutralized with acetic acid, oxalic acid or sodium hydrogen sulphate, it being preferred to control the progress of neutralization with a pH meter. After the usual working up of the reaction mixture, a hydroxy derivative of the general formula IV is obtained (R is as defined above and R _x is hydrogen) in which the free hydroxyl group at the 9-position is further oxidized in a halogenated hydrocarbon environment, preferably dichloromethane or 1,2-dichloroethane at 20 DEG C. to 50 DEG C. pyridine / chromium trioxide complex with a molar ratio of hydroxy derivative and reagent of 1: 5 to 15. After completion of the oxidation monitored by tlc analysis, the reaction mixture was filtered, washed with the chlorinated solvent and the combined filtrates. evaporation of the solvent in vacuo yields a crude product from which the oxoderivative of formula V, wherein R is as defined above, is isolated by column chromatography.

• A -. · »Λ '

The oxidation described can also be carried out by Jones reagent. Deprotection of the hydroxyl group on carbon C-11 is accomplished by treatment with acidic reagents. In this case, it is preferred to use hydrochloric, hydrobromic, benzenesulfonic, p-toluenesulfonic or H * cycle ion exchangers in tetrahydrofuran, acetone, methyl ethyl ketone, acetic acid or mixtures thereof with water at a temperature of -15 ° C to +50 ° C. The course of the reaction can be monitored by body analysis. After completion of the reaction, the mixture is diluted with a suitable solvent such as ethyl acetate or tetrahydrofuran, the aqueous phase is separated, extracted with said solvent, and the combined extracts are worked up by conventional techniques. A practically pure substance of formula I is isolated from the crude product by preparative chromatography.

The advantage of the process according to the invention is the simple and time-saving execution of the individual reaction steps, easy isolation

-. - intermediate and end product in relatively high yields.

Another advantage is that the process uses inexpensive and easily recoverable solvents with minimal waste,

». so it is also advantageous from an environmental point of view. The invention and its effects are illustrated in more detail in the following

... ------- _----- when-to-ice — execute, which — are — only — illustrative_and_none ____.

* they do not limit the scope of the invention.

Examples *

6.25 g ĚTsuspenzi _{^'r_;} -

To a suspension of 6.25 g of (3-hydroxy-3-methylheptyl) triphenylphosphonium iodide in 40 ml of dry tetrahydrofuran was added dropwise 10 ml of a 2.4 M solution of n-butyllithium in hexane under stirring after cooling to -70 ° C under nitrogen. The cooling bath was then removed and the mixture was further stirred for 2 hours while spontaneously warming to room temperature. The resulting deep red solution of ylide m was cooled to -35 ° C and then treated with a solution of 2.4 g of the aldehyde of formula II (R = THP group) in 20 mL of dry tetrahydrofuran. The temperature of the reaction mixture was maintained at -10 ° C for 2 hours and 0-5 ° C for 1 hour.

To the orange reaction mixture, after stirring for an additional 30 minutes, no longer starting aldehyde according to the analysis (silica gel, benzene-ethyl acetate 10: 1), 50 ml of ethyl acetate and 50 ml of saturated aqueous ammonium chloride solution were added slowly. The aqueous phase was separated, extracted twice with 40 ml of ethyl acetate and the combined organics were washed with 50 ml of water and washed with ethyl acetate. 50 ml saturated brine dried over magnesium sulfate. After evaporation of the solvent in vacuo, the oily residue was subjected to column chromatography (220 g silica gel, benzene-ethyl acetate 3: 1). Evaporation of the product fractions yielded 1.52 g (50% yield) practically pure acetate IV (R = THP, R ^ CH ^ CO group) whose identity was proven by elementary analysis, IR, ^{Χ Η} and ¹³ C-NMR spectra.

Example 2

To 3.8 g of the phosphonium salt (see Example 1) suspended in 15 ml of dry tetrahydrofuran was added 6.2 ml of a 2.35 M solution of n-butyllithium in hexane under nitrogen at -65 ° C. The reaction mixture was stirred for 25 minutes without cooling. To the red-orange solution of ylide III, after cooling to -40 ° C, 1.8 g of an aldehyde of formula II (R = t-butyldimethylsilyl) dissolved in 15 ml of dry tetrahydrofuran was added. The mixture was then stirred at -10 ° C for 2 hours and at 0 ° C for 1 hour when the reaction mixture no longer contained the starting aldehyde according to the above analysis. The reaction was quenched with 30 mL of saturated ammonium chloride solution, the aqueous phase was separated and extracted twice with 10 mL of ethyl acetate. The combined organics were washed with 20 mL of water, 20 mL of saturated brine, and dried over magnesium sulfate. After filtering off the desiccant and evaporating the solvents under vacuum, 4.53 g of a viscous oil was obtained, which after column chromatography (silica gel, eluent dichloromethane-ethyl acetate 97: 3) gave 0.42 g (22% of theory) of practically pure acetate IV (R = t-BuMe _and Si groups and R ₁ = CH 2 ₍ CO group). The structure of the product was shown by IR, MS, ¹ H and ¹³ C-NMR spectra.

Γ

Example 3 r

*

To a solution of 8.0 g of acetate IV (from Example 1) in 100 ml of dry methanol was added 3 g of calcined potassium carbonate and the mixture was stirred at 50 ° C for 1 hour. After this time, tlc analysis (silica gel, ethyl acetate-hexane) was performed

1: 1) and the mixture which was practically free of starting material was acidified by addition of 2.8 ml of acetic acid. Most of the methanol was evaporated in vacuo, the residual thin oil was diluted with 200 mL of ethyl acetate, the solution was washed successively with three times 20 mL of saturated sodium bicarbonate solution, twice with 50 mL of saturated brine and dried over magnesium sulfate. After filtering off the desiccant and evaporating the solvent under vacuum, 6.6 g of hydroxy derivative IV (R = THP group, R ^-H) were obtained, which according to the above analysis was uniform (R = 0.55) and whose identity was proved Elemental analysis, IR and 1H-NMR spectra.

Example 4

To a solution of 0.37 g of acetate IV (from Example 2) in 3 ml of dry methanol was added 0.41 ml of a 1.12 M solution of sodium methoxide in methanol .______ The reaction mixture was left at room temperature overnight, but according to tlc analysis When the reaction was complete, the mixture was heated to boiling for 8 hours when it was no longer containing the starting urea. The base was removed by addition of solid carbon dioxide and the solvent was evaporated in vacuo. The residue was dissolved in 10 ml of ethyl acetate, washed four times with 2 ml of water, and the organic phase was dried over magnesium sulfate. After filtering off the drying agent and evaporating the solvent under vacuum, 0.33 g of the hydroxy-N - (- (R = tert-butyldimethyl) -silyl-group, - R - = H -) - was obtained, which was Analysis (silica gel, 90: 7: 3 benzene dioxane-ethyl acetate system) was further purified by chromatography (hexane-ethyl acetate (5-20% gradient)) and finally 0.163 g of pure IV was obtained, whose identity was proved by IR, MS , ^{X is} H and ¹³ C NMR spectra.

Example 5

To a solution of 6.0 g of the hydroxy derivative IV (from Example 3) in 100 ml of dry dimethylformamide was added with stirring at room temperature 6 g of pyridinium dichromate and 0.5 g of pyridinium trifluoroacetate. The reaction mixture was stirred at the indicated temperature for 10 hours, according to tlc analysis, practically free of starting material. The reaction mixture was diluted with 100 mL of water and the product was extracted five times with 50 mL of ether. The combined ether portions were washed twice with 50 mL saturated brine and dried over magnesium network. After filtering off the desiccant, the solvent was evaporated in vacuo and the oily residue was purified by silica gel column chromatography using ethyl acetate-benzene 1: 2 as eluent. Obtained were 4.9 g oxo derivative of formula V (R = THP), which was indicated by tlc analysis, a single (silica, and a hexane - ethyl acetate 1: 1 _Rf = 0.7), whose identity was confirmed by elemental analysis, IR and ^X-H NMR spectrum.

Example 6

To a solution of 0.12 3 g of hydroxy derivative IV (from Example 4) in 3 ml of dry dichloromethane was added with stirring at room temperature 0.139 g of pyridinium dichloride and 44 mg of molecular sieve Potassit 3A. The mixture was cooled to 0 ° C and 24 mL of acetic acid was added. The mixture was stirred at 5 to 8 ° C for 3 hours. The contents were diluted by the addition of 12 ml of tert-butyl methyl ether, after an additional hour of stirring, the mixture was filtered through a silica gel column which was washed with 10 ml of t MTBÉ. Evaporation of the filtrate in vacuo gave 0.14 g of an oil which, after chromatography (silica gel, hexane)

10% ethyl acetate) afforded 108 mg of the oxo product of formula V (R = t-butyldimethylsilyl) whose identity was confirmed by IR, MS, ¹ H and ¹³ C-NMR spectra.

. iíÝ

Example 7

To a solution of 0.3 g of the oxo derivative of formula V (from Example 5) in 8.6 ml of tetrahydrofuran was added stirring at room temperature.

8.6 ml of 1 M aqueous hydrochloric acid over 2 minutes. The progress of the reaction was monitored by tlc analysis (silica gel, chloroform)

- 3% methanol). After 10 minutes of practically free of starting material, the mixture was diluted with 30 ml of ethyl acetate, the aqueous phase was separated, extracted with 10 ml of ethyl acetate, the combined organics were washed successively with 4 ml of water, 4 ml of saturated sodium bicarbonate solution and dried with sulfate. feverish. After filtering off the desiccant and evaporating the solvent under vacuum, 293 mg of crude product was obtained, which after chromatographic purification (silica gel, cyclohexane-ethyl acetate 1: 3) yielded 208 mg of the final product of formula I (Misoprostol) uniform according to tle analysis (silica gel, chloroform). acetonitrile-methanol

80: 15: 5 _Rf = 0.5.>. The chemical structure of the product was confirmed by elemental analysis (calculated for C a _and H _{3 e} O _s (382.5): 69.08% C,

- 10.01% H? Found: 68.72% C, 10.43% H), IR (1740s,

2810 m, 2920s, 3400bs / cm ~ ^L /) and spectra (CDCl _3: 0.90 t, 3H;

1.15 S, 3H; 1.20-1.70 m, 16H; 1.95 m, 2H, 2.10-2.45 m, 6H; 2.72dd, 1H;

3.22 bs, 1H; 3.65 s, 3H; 4.05 m, 1H; 5.30-5.80 dm, 2H; (ppm).

Example 8,

To a solution of 6.0 g of the oxo derivative of formula V (from Example 5) in 100 mL of 75% aqueous methanol was added 15 g of Amberlyst 15 in an H * cycle and the mixture was stirred at 40 to 50 ° C for 3 hours raw material. The ion exchanger was filtered off, washed well three times with 20 ml of methanol and the combined filtrates were evaporated in vacuo. 3.4 g of pure product of formula (I), isolated by HPLC analysis (silica gel, hexane-ethyl acetate 1: 1), were identical to the authentic sample of Misoprostoles of Example 7 by HPLC analysis. .. gpQlí ^ NA ^ “ ^S · -

Claims (5)

Claims ff / 4? - 7 / Ϊ ó t!> 1. A process for the production of misoprostol of formula (I) starting from an easily available aldehyde of formula (II) wherein R is a tetrahydropyranyl (THP) or tert-butylsilyl group, characterized in that after reaction of the aldehyde of formula (II) with an ylide of formula (III) prepared from the corresponding phosphonium salts of ca, i X -, - GH - CiLc - G. i OH in an organic solvent medium by treatment with a strong base, in a molar ratio of aldehyde to ylide of 1: 1.2 to 2.0 at a low temperature of -50 ° C to -20 ° c, from the obtained olefin of formula IV wherein R is as defined above; R _x denotes an acetyl group (CH _and CO) is first removed by treatment with an acetyl protecting group in an anhydrous methanol medium and oxidation of the free secondary hydroxyl function on carbon C-9 results in a protected oxoderivative of formula V wherein R is as defined above, after removal of the protecting group from the hydroxyl function at the C-11 position by treatment Vvealo raami 4 Yr> Y nh pinidyl y-f clear ir rol and + -i carcinoma target product of formula I. according to item 1 marked Oxygen process of formula III by generating the ylide of the general phosphate salt from an appropriate phosphonium salt in an aprotic solvent such as tetrahydrofuran, dimethoxyethane or dioxane by treating a solution of butyllithium in hexane or dimethylsodium in dimethylsulfoxide at temperatures from -70 ° C to +25 ° C. / 3. A process according to claim 1, wherein the removal of the acetyl protecting group from the intermediate of formula (IV) is carried out by treatment with basic reagents such as potassium carbonate or sodium methoxide in excess of anhydrous methanol. 4. A process according to claim 1, wherein the oxidation of the secondary hydroxyl function at the C-9 position is carried out by means of a complex of pyridine with a chromium oxide or Jones reagent in a halogenated hydrocarbon environment such as dichloromethane; 1,2-dichloroethane, optionally in dimethylformamide or acetone using Jones reagent at temperatures from -20 ° C to + 50 ° C. 5. A process according to claim 1, wherein the deprotection of the secondary hydroxyl function at the C-11 position of the intermediate of formula (V) is carried out using acidic reagents such as hydrochloric, hydrobromic, benzenesulfonic, p-toluenesulfonic acid or ion exchange in an H * cycle tetrahydrofuran, acetone, ethyl methyl ketone, acetic acid and water at -15 ° C to + 50 ° C. after their case NA a.s.