CS200540B2 - Method of producing novel optically active derivatives of prostaglandin f 2 alpha or racemates thereof - Google Patents

Description

The present invention relates to a process for the preparation of novel optically active prostaglandin fetuses and their racemates, as well as their pharmaceutically acceptable non-toxic salts.

The compounds produced by the process of the invention, as described hereinafter, with the exception of their optically active antipodes, possess valuable pharmaceutical properties and are therefore suitable as active ingredients of the pharmaceutical compositions also described hereinafter.

Natural prostaglandins are derivatives of prostanoic acid, which is a C 20 fatty acid containing a cyclopentane ring. These compounds are known to be very potent, elicit various biological responses and are therefore suitable for pharmacological purposes (Pharmacol. Rev. 20, p. 1 (1968).) Prostaglandin Faa can be used in gynecology with excellent results (Belgian No. 738,177).

Compounds having a structure similar to that of prostaglandin, for example, prostandin analogs, are described in numerous publications. For example, prostaglandin analogues Faa and E2 containing an oxygen, sulfinyl or alkylimino group at the 17-position and an optionally substituted aryl, benzyl or furfuryl group at the end of the shorter chain, as well as their contraceptive and hypotensive spasmolytic effects, are described in Dutch Patent No. 7,206,361. Dutch Patent No. 7,313,322 relates to prostaglandin analogues of similar structure containing, at the end of the shorter side chain, prostaglandin monovalent heterocyclic groups.

The present invention therefore provides a process for the preparation of novel optically active prostaglandin Faai derivatives or racemates thereof having the general formula (XII):

where it means

R 1 is hydrogen, C 1 -C 4 alkanoyl, C 1 -C 4 trihaloalkanoyl, benzoyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 trihalkoxyalkoxycarbonyl or phenoxycarbonyl; or benzyloxycarbonyl optionally substituted with 1 to 4 carbon alkoxy, nitro or halogen,

R 2 is hydrogen or C 1 -C 4 alkyl,

Rd is hydrogen or a protecting group; and

Q is hydrogen, C 1 -C 4 alkyl or a pharmaceutically acceptable non-toxic cation.

The invention relates not only to optically active isomers of these compounds, but also to racemates consisting of one of the optically active isomers and its mirror image.

As used herein, the term "alkanoyl" means a straight or branched chain aliphatic acid radical having 1 to 4 carbon atoms, for example an acetyl, propionyl, n-butyryl radical, etc. The term "trihaloalkanoyl of 1 to 4 carbon atoms" is preferably herein means trifluoroacetyl. The term "optionally substituted benzyloxycarbonyl" as used herein refers to a benzyloxycarbonyl group, optionally substituted with at least one substituent selected from the group consisting of C 1 -C 4 haloalkoxy and nitro groups. As used herein, the term "C 1 -C 4 alkoxycarbonyl" represents, for example, a methoxycarbonyl, ethoxycarbonyl or butoxycarbonyl group.

The term "haloalkoxycarbonyl" is preferably trichloroethoxycarbonyl.

As for R 2 and Q, examples are C 1 -C 4 alkyl, preferably a straight or branched chain C 1 -C 4 saturated hydrocarbon group, such as methyl, ethyl, petroleum, , isopropyl or n-butyl.

Examples of suitable pharmaceutical non-toxic salts of the compounds of formula (XII) are sodium, potassium, calcium, ammonium, and the like. ...

The process according to the invention for the preparation of said compounds consists of:

the phenyl (4-carboxybutyl) phosphonium salt, and optionally the protecting group Rd is cleaved from the compound of formula (XII), and optionally, the compound of formula XII, wherein Q is hydrogen, is converted to an alkyl ester of 1 to 4 carbon atoms or a pharmaceutically acceptable salt.

The compound of formula XII, wherein R 1 is optionally substituted phenoxycarbonyl, benzyloxycarbonyl, alkoxycarbonyl, or trihalkoxycarbonyl, can be converted to the corresponding compound of formula XII wherein R 1 is hydrogen by hydrolysis in an acidic medium.

Further, the compound of formula XII wherein R 1 is hydrogen can be converted to the corresponding compound of formula XII wherein R 1 is alkanoyl or optionally substituted benzoyl by reaction with a reagent suitable for introducing an alkanoyl or optionally substituted benzoyl group into the molecule.

The novel compounds prepared by the process of the invention are much more potent than natural prostaglandin F 2 and combine the typical effects of prostaglandins with an α-adrenergic stimulating effect. _

A compound of formula XI wherein R 1, R 2 and Rd are as defined above and is a starting material for the preparation of compounds of formula XII is prepared by reacting a compound of formula X,

wherein R1, R2 and Rd are as defined above, reduced with a complex metal hydride.

Also a compound of formula X wherein R 1, R 2 and R d have. as defined above, may be prepared by reducing the compound of formula (VIII), ......

wherein R 1, R 2. and Rd are as defined above, with a complex borohydride followed by introduction of the protecting group Rd.

It is also possible for compounds of the general samples

R1 and R2 are as defined above and

Rd is hydrogen or a protecting group customary in prostaglandin chemistry is reacted with a hypophosphite prepared from X or XI to introduce a R 6 protecting group or a R 6 protecting group from the compounds of formulas VIII, IX, X or XI.

According to a preferred embodiment of the process of the invention, compounds of formula XII are prepared wherein R 1 is acetyl, R 2 is n-propyl, and Q is hydrogen.

In the starting compounds of formulas VIII, X or XI, R 6 is hydrogen or a protecting group. Protecting groups commonly used in prostaglandin chemistry may be used. Thus, R a can be a protective group that is stable to alkaline processing and readily removable in an acidic environment. Examples of suitable protecting groups are tetrahydropyranyl or trialkylsilyl, for example trimethylsilyl or triethylsilyl. R a can also be a p-phenylbenzoyl group.

The protecting groups are introduced into the molecule by known methods.

For example, a tetrahydropyranyl group can be introduced into the molecule by reacting a compound containing a free hydroxyl group with 3,4-dihydro-2H-pyran. The reaction is carried out in or without solvent in the presence of traces of the acid catalyst. Suitable solvents for this reaction are chlorinated hydrocarbons, for example dichloromethane; as acid catalyst, traces of phosphorus oxychloride or p-toluenesulfochloride may be used.

The trialkylsilyl protecting group may be introduced into the molecule using trialkylsilyl chloride. The reaction is preferably carried out in the presence of an acid binding agent, for example pyridine;

The p-phenylbenzoyl protecting group may be derived from p-phenylbenzoyl chloride. This protecting group can be introduced into compounds of formulas X and XI.

Tetrahydropyranyl and trialkylsilyl protecting groups can be cleaved by the action of an acidic reagent after completion of the reaction. An aqueous acetic acid solution is preferably used for this purpose;

The p-phenylbenzoyl group, as R a, is automatically cleaved under Wittig reaction conditions. If the p-phenylbenzoyl group is to be removed at an earlier stage of the process, for example from compounds of formula IX,

wherein R 1, R 2 and R 6 are as defined above, it may be removed with potassium carbonate in a methanolic medium.

Compounds of formula XI can be converted to the corresponding compounds of formula XII by a Wittig reaction in a manner known per se. As reagents in the Wittig reaction, a phosphorane prepared from the triphenyl (4-carboxybutyl) phosphonium salt can be used. In a preferred embodiment, a dimethylsulfoxide solution of dimethylsulphurium is prepared by reacting dimethylsulfoxide with sodium hydride, and to the dimethylsulphurium obtained is then added triphenyl (4-carboxybutyl) phosphonium bromide followed by addition of a compound of the formula XI can be isolated by one of known methods, preferably by chromatography column (e.g., silica gel).

Compounds of formula (XI) may be prepared by reduction of compounds of formula (X). Reductions are carried out by procedures conventional in prostaglandin chemistry. Preferably, the reduction is performed using diisobutylaluminum hydride in an aprotic solvent such as toluene at temperatures in the range of 0 to 100 ° C, preferably in the range of -70 to -80 degrees Celsius.

Alternatively, both hydroxyl groups of compounds of formula (X) wherein R a is hydrogen may be blocked by suitable protecting groups such as tetrahydropyranyl. The reaction is carried out as described above.

Compounds of formula X are prepared by reduction of the corresponding compounds of formula VIII. Complex borohydrides are used as reducing agents. For example, zinc borohydrides or sodium borohydrides in an etheric medium may be used for this purpose. This reduction yields the (SJ-a (Rj-isomers, depending on the configuration of the hydroxyl group at position 15.) When the reduction is performed with zinc borohydride, the (SJ-isomer, corresponding to the structure of natural prostaglandin, and the RJ-isomer in 1: 1.

According to a preferred embodiment, the reduction is carried out with lithium tri (sec. Butyl 1J boron hydride), about 80% of the product being the desired (SJ-isomer, while the (RJ-isomer is obtained in an amount of only about 20%). in an ether medium, preferably in a mixture of tetrahydrofuran and ether, preferably at a temperature below -100 [deg.] C. A temperature of about -130 [deg.] C. is generally preferred, which can be achieved using a cooling bath consisting of a mixture of methylcyclohexane and nitrogen.

The (S- and (RJ) -isomers of the compounds of formula (IX) may, if desired, be separated by conventional means, generally by column chromatography. However, this step may be avoided, especially when the lithium-trisphosphate reduction is carried out. butyl borohydride, since the resulting product is still isolated by column chromatography, which allows separation of the undesired isomers present in small amounts.

From the compounds of formulas IX and X, where Rd is p-phenylbenzoyl, the p-phenylbenzoyl protecting group may be removed by treatment with alkali, preferably potassium carbonate.

Compounds of formula XII wherein R 1 is aryloxycarbonyl, alkoxycarbonyl or trihaloalkoxycarbonyl may be converted to the corresponding compounds of formula XII wherein R 1 is hydrogen. This conversion is preferably carried out in a mixture of hydrogen bromide and glacial acetic acid.

The compounds of formula (XII) in which R @ 1 is hydrogen may be alkanoylated or benzylated with reagents suitable for introducing a lower alkanoyl or optionally substituted benzoyl group into the molecule. Examples of suitable reagents are acetyl chloride, acetic anhydride or benzoyl chloride.

The resulting compounds of formula (XII) wherein Q is hydrogen can be converted to the corresponding esters wherein Q is lower alkyl. The esterification is carried out in a known manner, for example using diazomethane.

The compounds prepared by the process of the invention are converted into their respective salts by conventional methods, for example by reacting the acid with the appropriate base.

The starting compounds of formula (VIII) are novel and can be prepared as described below. The amine of formula I,

Ra-NH2 (I), wherein Ra is as defined above, is acylated with an acid chloride of formula II,

R’i — Cl (Π), where R’i represents an alkanoyl, trihaloalkanoyl or optionally substituted benzoyl group, in the presence of an acid binding agent, in a known manner. If compounds of formula III are to be prepared,

HN — Ra I

R1 (ΠΙ), where R1 is an alkoxycarbonyl, trihalkoxycarbonyl or aralkoxycarbonyl group, is reacted with an alkyl or aryl chloroformate ester of the formula I.

For the preparation of compounds of formula IV, ( ⁺ ) (Γ)

MeN — R2

AND

R1 (IV), where

Me means an alkali metal and

R 1 and R a are as defined above, the acidic proton in the compound of formula III is replaced by an alkali metal atom with a strong base such as alkyl lithium, preferably butyl lithium or an alkali metal hydride. The resulting compound of formula (IV) is then reacted with a hypophosphite of formula (IV).

X - CH a - C - CH = P (C 6 H 5) s

II .i o

(V) wherein X is halogen.

The reaction is carried out in a manner known per se. The compound of formula VI thus prepared, (C6H5) 3P = CH-C-CHa-N-R2 (VI),

II I

R 1 wherein R 1 and R a are as defined above, are reacted in a known manner with the Corey aldehyde of formula VII,

wherein R 4 is as defined above.

The Corey aldehyde VII is preferably prepared - due to its volatile nature - in situ by oxidation of the corresponding alcohol VIIa,

wherein R 1 is as defined above.

The compound of formula (VIII) obtained is separated from the triphenylphosphine oxide as described in connection with the Wittig reaction (column chromatography).

The compounds of formula (XII) possess valuable pharmaceutical properties. Biochemical tests performed on uteri of rats bred in Krebs-Ringer's bicarbonate solution showed that the compounds of the invention showed approximately the same potency as prostaglandin Fza. They induce stronger contractions in the presence of adrenergic blocking agents. Increase lipolysis of epidermal adipose tissue of rats. In this respect, they have a stronger effect than natural catecholamines.

In view of the above results, the compounds of the invention have a dual effect. They can act as catecholamine or prostaglandin, depending on the organs they act on and the environment used in the application. When catecholamine inhibitors are used, the prostaglandin character is predominant. The effect on adipose tissue and smooth muscle, especially on the uterus, is particularly important therapeutically.

The compounds of the present invention are effective for regulating gastric secretion and for dispersing thrombosis-causing platelets.

The compounds of the invention are preferably administered in doses ranging from 0.1 to 5 µg / kg / min as an infusion. The same doses can also be used to regulate fatty acid metabolism.

The smooth muscle stimulating effect of the compounds of the invention can be used to potentiate the effect of known smooth muscle stimulating agents at doses of from 0.001 to 25 µg / kg. On the other side, these compounds are useful in mammals for inducing miscarriage, labor pain and for regulating menstruation or for cervical enlargement by intravaginal, intrauterine or intravenous administration. For the above purposes, the compounds of the invention are used in unit doses in the range of 1 µ to 20 mg or intravenously in infusion doses in the range of 5 to 50 mg / kg / h. The exact dose depends on the age, condition and weight of the person or animal to whom the compound of the invention is to be administered.

The compounds described by the formula (XII) and their pharmaceutically acceptable non-toxic salts can be formulated into pharmaceutical compositions by methods conventional in the pharmaceutical industry. These compositions may be in solid form, for example capsules or tablets, in semi-solid form, for example an ointment, or in liquid form, for example, solutions, suspensions or emulsions. Preferably, the compositions are administered parenterally or vaginally. The compositions comprise a conventional solid or liquid pharmaceutical carrier or excipient, for example water, aqueous sodium acetate solution, normal saline.

The following examples illustrate the invention in greater detail without limiting its scope.

Example 1

In a four-necked round-bottomed flask equipped with a condenser, stirrer, thermometer and dropping funnel, 12 g of sodium hydride suspension (0.1 mol; 20% suspension in paraffin oil) are weighed in a nitrogen atmosphere, then 358 ml of anhydrous dimethoxyethane are added. A solution of 10.1 g (0.1 mol) of N-propyl acetamide in 50 ml of anhydrous dimethoxymethane was added at room temperature while stirring vigorously, and the mixture was heated under reflux for 2 hours, then cooled to room temperature. 35.3 g (0.1 mol) of triphenylchloroacetonylphosphorane suspended in 50 ml of anhydrous dimethoxyethane are added to the reaction mixture.

The reaction mixture was heated for an additional 2 hours while the amide salt precipitate slowly dissolved. The dimethoxyethane was distilled off and the residue was taken up in ethyl acetate, washed first with water, then with brine, dried over sodium sulfate and evaporated.

44 to 46 g of crude triphenyl- (N-propylacetylamino) acetonylphosphorane are obtained. The melting point after recrystallization from tetrahydrofuran / ether is 147-148 ° C.

Yield: 34.7 g (83% of theory),

IR: 3080, 1640, 750, 720, 695 cm -1,

NMR (CDCl 3) δ = 7.4 - 8.0 (m, 15H, aromatic),

=. 3.65 - 4.25 (complete 3H, PCH + + COCH 2 N), = 3.52 (t, 2H, NHCH, J = 7 Hz), = 2.17 (s, 3H, COCH 3), = 1, 1-2 (m, 2H, CH 2 CH 3) = 0.9 (t, 3H, CH 2 CH 3).

Example 2

In a 2000 ml four-necked round-bottomed flask fitted with a dropping funnel, stirrer, thermometer and drying tube, filled with 2 000 ml calcium chloride, 290 ml of 0,049 g of chlorine solution / ml in carbon tetrachloride (0,2 ml) molu). The solution was cooled to -10 ° C in a chloroform / dry ice bath at which temperature 24.8 g (0.1 mol) of thioanisole in 200 ml of anhydrous dichloromethane was added. After stirring for 30 minutes, the mixture was cooled to -25 ° C and 35.2 g (0.1 mol) of (-) - 3 was added dropwise _; 3a [3,4,5,6,6a] 3-Hexahydro-4/3-hydroxymethyl-5- [(4-phenylbenzoyloxy) -2-oxo-cyclopenta [b] furan. temperature for 2 hours.

40.4 g (0.4 mol) of triethylamine in 200 ml of dichloromethane are then added dropwise and the temperature of the reaction mixture is allowed to rise to room temperature. The reaction mixture was then poured into 1 liter of a 1N aqueous hydrochloric acid solution. The aqueous phase is separated, the organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure.

The solid obtained is suspended cold in ether and the resulting white crystals are filtered off. 26.4 g of (-) - 3,3a0,4,5,6,6a0-Liexahydro-40-formyl-5 '- (4-phenylbenzoyloxy) -2-oxo-2H-cyclopenta [b] furan are obtained. .

In a 250 ml round bottom flask, to a solution of 34.2 g (0.082 mol) of triphenyl (N-propylacetylamino) acetonylphosphonate in 100 ml of dichloromethane is added the resulting compound of formula VII. The resulting solution was allowed to stand overnight, then diluted with 200 ml of dichloromethane and washed first with 200 ml of a 1N hydrochloric acid solution at 0 DEG C., then with 100 ml of water, and the organic phase was dried and evaporated. 63 g of (-) - 3,3a0,4,5,6, amino-1-trans-ibutenyl] -5 '- ((4-phenylbenzoyloxy) -2-oxo-2H-) - was obtained as a yellow oil. cyclopenta [b] furan.

Yield: 28.9 g (59.2%);

R _f = 0.3 (5% methanol / ethyl acetate)

IR (liquid film): 3080, 2900, 1780, 1720, 1700, 1650, 975, 755 and 695 cm ^-1,

NMR (CDCl 3): δ = 7.2 - 8.2 (m, 9H aromatic protons), δ = 6.2 - 7.2 (d + dd, 2H, trans olefinic protons, J - 36 Hz), δ = 4.9-55 (m, 2H, OCH), δ = 4.3 (s_, 2H, COCH 2 N), δ = 3.0-34 (m, 2H, CH 2 N), ......... ..

δ 2.13 (s, 3H, COCH 3), δ - 0.9 (t, 3H, CH 2 CH 3).

Example 1 a d 3

In a 250 ml four-necked round-bottomed dried flask equipped with a stirrer, resistance thermometer and gas inlet, tetrahydrofuran bubbling device and a silicone rubber stopper was charged 30 ml (0.03 mol) of lithium tri (sec.). butyl) borohydride in tetrahydrofuran (1 mol), 160 ml of anhydrous ether and 20 ml of anhydrous tetrahydrofuran. The solution is cooled to -130 ° C in a slow stream of argon on a bath of methylcyclohexane or a mixture of ether and petroleum ether and liquid nitrogen. With vigorous stirring, 4.9 (0.01 mol) of (-) - 3-3a0,4,5,6,6a0-hexahydro plug is added to said lithium tri (sec-butyl) borohydride solution over 30 minutes. -40- [3-oxo-4- (N-propylacetylamino) -1-tris-butenyl] -5- (4-phenylbenzoyloxy) -2-oxo-2H-cyclopenta [b] furan in 20 mL of anhydrous tetrahydrofuran . The reaction mixture was stirred at a temperature in the range of -127 to -130 ° C for 1 hour. The reaction mixture was monitored by thin layer chromatography (5% methanol in ethyl acetate). ·. ·. '1

Rf of the compound of formula VIII = 0.3, Rf of the compound of formula IX = = 0.27.

The excess reducing agent is quenched with 5 ml of methanol and the reaction mixture is poured into 500 ml of cold 1 M aqueous sodium bicarbonate solution. The organic phase was separated. and shake with three 100 ml portions of ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under reduced pressure to a volume of 100 ml, diluted with 200 ml of petroleum ether and the solution obtained was chromatographed on silica gel (290 g, particle size 0.063-0.2 mm). The alkali metal borates are eluted with a mixture of petroleum ether and ethyl acetate (2: 1) and (-) - 3,3a0,4,5,6,6a0-hexahydro-2-oxo-40 - [(3S) -3-hydroxy- 4- (N-Propylacetylamino) -trans-1-butenyl] -5α- (4-phenylbenzoyloxy) -2H-cyclopenta [b] furan was eluted with 5% methanol-ethyl acetate.

The fractions corresponding to the R _f - 0.27 (5% methanol / ethyl acetate) were combined .and evaporated. Yield: 3.1 g (63.3% of theory), as a yellow oil, another product from the intermediate fraction: 0.4 g (8.15% of theory). Total yield: 3.5 g (71.5% of theory)

Rf = 0.27 (5% methanol / ethyl acetate)

IR (liquid layer): 3,450, 3,080, 2950, 2980, 1770, 1725, 750, 700 cm ¹ ,

NMR (CDCl3):

δ = 7.4 - 8.3 (m, 9H, aromatic protons), δ = 5.8 (m, 2H, olefinic protons), δ = 5 - 5.5 (m, 2H, OCH), δ = 4 .45 (m, 1H, OCH, allyl), .delta. = 3-3.6 (m, 4H, NCH2), .delta. = 2.13 (s, 3H, COCH3), .delta. = 0.9 (t, 3H, J = 6Hz, CH2CH3)

Example 1 a d 4

Dissolve in 50 ml of anhydrous methanol in a 250 ml round-bottomed flask

4.9 g (0.01 mol) of (-) - 3,3a0,4,5,6,6α-hexahydro-2-oxo-40- [(3S) -3-hydroxy-4- (N-propylacety lamino) 1-trans-1-butenyl] -5- (4-phenylbenzoyloxy) -2H-cyclopenta [b] furan and 1.5 g (0.011 mol) of calcined and ground potassium carbonate are added. The flask is equipped with a drying tube filled with calcium chloride, and the suspension is stirred with a magnetic stirrer at room temperature.

The reaction was followed by thin layer chromatography (5% methanol / ethyl acetate) and was complete after 1 hour.

R _{f of the} compound of formula IX = 0.27, R _{f of the} compound of formula X = 0.05 and R _f of 4-phenylbenzoic acid methyl ester = = 0.95.

The reaction mixture was then neutralized to pH 6 with 1M methanolic hydrochloric acid, and then the methanol was distilled off under reduced pressure. The residue, containing multiple components and the solid and liquid phases, is dissolved in 100 ml of a 2: 1 mixture of petroleum ether and ethyl acetate (2: 1j) and the solution is chromatographed on a silica gel column, eluting with 4-phenylbenzoic acid methyl ester. (-) - 3,3α / 3,4,5,6,6α / 3-hexahydro-2-oxo-5'-hydroxy-4/3 - [(3S) -3-hydroxy-4- (N- propylacetylamino) -tris-1-butenyl] -2H-cyclopenta [b] furan was eluted with 10% methanol-ethyl acetate.

Yield: 2.93 g (93.4% of theory), as a yellow oil,

R _f = 0.33 (10% methanol-ethyl acetate)

IR (liquid layer): 3,450, 2,950, 2,980, 1,775, 1,635 cm -1,

NMR (CDCl3):

δ = 5.65 (m, 2H, olefinic protons), δ = 5.0 (m, 1H, OCH, lactone), δ - 4.35 (m, 1H, OCH allyl proton), δ - 4.10 (m, 1H, OCH), interchangeable OH protons 2H, δ = 3.1 - 3.5 (m, 4H, NCH 2), <5 = 2.13 (s, 3Η, COCl 3), δ = 0.9 (t, 3H, CH 2 CH 3, J = 7 Hz).

Example 5

To a 250 ml four-necked round-bottomed flask equipped with a stirrer, thermometer, gas inlet, dropping funnel and anhydrous tetrahydrofuran bubbler is added a solution of 3.1 g (0.01 mol) (-) - 2,3a (3,4,5,6,6a) 3-Hexahydro-2-oxo-5α-hydroxy-4/3 - [(3S) -3-hydroxy-4- (N-propylacetylamino) -tr-1- butenyl] -2H-cyclopentaflufuran in 70 ml of anhydrous tetrahydrofuran, the flask was purged with anhydrous argon and cooled to -78 ° C in an acetone / dry ice bath while a gentle stream of argon was passed through the flask.

With vigorous stirring, 6.4 g (0.046 mol) of diisobutylaluminium hydride in 70 ml of anhydrous toluene are added to the cooled solution over 30 minutes. Gas evolution ceases before the addition is complete. After the addition was complete, the reaction mixture was stirred at -78 ° C for 1 hour. The progress of the reaction was monitored by thin-layer chromatography, and the reaction was complete after stirring for 1 hour (treatment of the sample with a mixture of ethyl acetate and ammonium chloride).

The reaction was quenched by the addition of 10 mL of a 2 N sodium hydrogen sulfate solution. The cooling bath was removed, the temperature of the mixture was allowed to rise to 0 ° C, and the pH of the mixture was adjusted to 3-4 by addition of 2M sodium hydrogen sulfate solution. The organic phase was separated in a separatory funnel. The aqueous phase is shaken 6 times with 50 ml of ethyl acetate each time, the combined organic phases are dried over sodium sulphate and evaporated under reduced pressure. 3 g (97% yield) of crude (-) - 3,3,3,4,5,6,6a / 3-hexahydro-2,5of-dihydro-4 (3 - [( 3S) -3-hydroxy-4- (N-propylacetylamino) -trans-1-butenyl] -2H-cyclopenta [b] furan.

Prepare a sample for chromatographic analysis on a silica gel column using 20% methanol / ethyl acetate; the fractions corresponding to R _? - 0.095 (20: 4 ethyl acetate / acetic acid) were combined with IR (liquid layer): 3400, 2950, 2975, 1630, 1090, 1060, 1070, 1110 cm ' ¹ ,

NMR (CDCl3):

δ = 5.65 (m, 3H, 2 olefinic protons +

OCHO), δ = 4 - 4.7 (m, 3H, OCH allyl, OCH 5/3,

OCH 6a / 3) interchangeable protons 3H, δ = 3.1 - 3.6 (m, 4H NCH 2), <S = 2.13 (s, 3H, COCH 3), δ = 0.9 (t, 3H, CH 2 CH 3) ).,

Example

After flushing with argon, 10.8 g (0.09 mol) was weighed into a 500 ml four-necked round-bottomed flask equipped with a magnetic stirrer and a gas inlet, silicone rubber stopper, vacuum port and ground plug. 20% suspension of sodium hydride in paraffin oil. 10 ml of anhydrous petroleum ether are then added to the suspension.

The mixture was stirred with a magnetic stirrer, then allowed to settle and the petroleum ether oil phase was aspirated by syringe. The above procedure was repeated twice and the remainder of the petroleum ether was removed under reduced pressure. 150 ml of anhydrous dimethylsulphoxide in a flask equipped with a thermometer and a dlmethylsulphoxide bubbling device was added to the oil-discharged sodium hydride, which was purged with argon. The suspension was then heated slowly to 75 degrees Celsius in an oil bath. When the temperature reaches 60 ° C, an increasing amount of hydrogen begins to evolve, which evolves after approximately 30 minutes. The resulting pale yellow solution was stirred at 70-75 ° C for about 60 minutes, then cooled to 15-20 ° C and 20 g (0.045 mol) triphenyl (4-carboxybutyl) phosphonium bromide was added in four portions, the measuring cylinder is rinsed with 50 ml of anhydrous dimethylsulfoxide. The formation of phosphorous is immediately indicated by the red color of the reaction mixture. The solution was stirred at room temperature for 30 minutes, after which 3.12 g [0.01 mol] of (-) - 3,3α, 4,5,6,6a-hexahydro-2,5- was added to the reaction mixture. dihydroxy-4? - [(3S) -hydroxy-4- (N-propylacetylamino) -trans-1-butenyl] -2H-cyclopenta [b] furan in solution in 100 ml of anhydrous dimethylsulfoxide. The resulting mixture was stirred at room temperature. After 18 hours, the reaction is complete as determined by thin layer chromatography (after decomposition of the sample taken from the reaction mixture, ethyl acetate and sodium hydrogen sulfate). For a compound of formula XII R _f = 0.23 and for a compound of formula XI R _f = 0.09 (20: 4j ethyl acetate: acetic acid).

The reaction mixture was then poured into a mixture of 400 mL of 2M sodium hydrogen sulfate solution, 100 mL of ice water and 150 mL of ethyl acetate. The mixture is shaken in a separatory funnel, the organic phase is separated and the aqueous phase (pH = 1) is extracted 6 times with 100 ml portions of ethyl acetate. The organic phase was cooled, combined and washed 3 times with 50 ml portions of sodium hydroxide at 0 ° C. The alkaline extracts were combined, 100 mL of ethyl acetate was added, and the solution was acidified to pH 3 by carefully adding 2 M sodium hydrogen sulfate solution at 0 ° C. The organic phase was dried over sodium sulfate and evaporated to give 3.7 g of crude product as a dark brown oil.

The crude product is chromatographed on 300 g of silica gel using a 20: 4 mixture of ethyl acetate and acetic acid.

Fractions of the products corresponding spot at R _f = 0.62 in methanol, ethyl acetate and acetic acid (5: 20: 4). Yield: 2.2 g (62.5% of theory). The obtained (+) - 9a, 11a, 15 (S) -trihydroxy-16- (N-propylacetylamino) -17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid is contaminated with traces of acid (N -acetyl-7-aza-prostaglandin (Jof) -acetic acid. Purify by repeated column chromatography on 100 g silica gel using acetone as eluent.

The main fraction yielded 1.73 g (78%, calculated on chromatographed crude product) of a yellow viscous oil liquid,

_Rf = O 62 (methanol: ethyl acetate: acetic acid (5: 20: 4)

NMR (CDCl3):

$ = 5.6 and δ - 5.4 (m, 2H + 2H, trana and cis olefinic protons), δ = 3.9; 4.15 and 4.3 (1-lm, 3H, 9-OCH,

11-OCH and 15-allyl-OCH protons) interchangeable protons, δ = 3.15 to 3.6 (m, 4H, NCH 2), = 2.13 (s, 3H, COCH 3), δ = 0.95 (t (3H, CH 2 CH 3, J = 7 Hz),

IR (liquid layer): 3400, 1730, 1630, 1445, 1260, 1025, 960 cm ^-1, specific rotation: [a] _D ^2f) = + 19 ° (+ 2) (c = 1.2, tetrahydrofuran).

Example 7

In a similar manner to Example 1, but using 19.3 g (0.1 mol) of N-propylbenzylurethane instead of N-propyl acetamide, 39.7 g (78% of theory) of triphenyl (N-propylbenzyloxycarbonylamino) acetones were obtained.

Melting point 111-112 ° C,

IR (KBr): 1705, 7,520, 1,390, 1230, 1100, 740, 705, 695 cm ^-1 ,

NMR (CDCl3):

δ = 7.1 - 8 (m, 20H, aromatic protons), δ = 5.2 (s, OCH 2, 2H) δ = 3.9 - 4.8 (m, 3H, PCH + COCH 2 N).

Example

In a similar manner to Example 1, but using 13.1 g (0.1 mol) of N-propylethylurethane instead of N-propyl acetamide, 35.1 g (78.3% of theory) of triphenyl (N-propylethoxycarbonylamino) acetonylphosphorane are obtained. Mp 92-94 ° C.

IR (KBr): 1695, 1580, 1390, 1240, 1100, 750, 715 & 695 cm &^lt; -1 ^&gt;

NMR (CDCl3):

δ = 7 - 7.9 (m, 15H, aromatic protons), δ = 3.9 - 4.6 (m, 5H, PCH + CHCH 2 N + + OCH 2), quartet, 4.1, J = 8Hz).

Example 1 9

Similar to Example 2, but using 41.8 g (0.082 mol) of triphenyl (N-propylbenzyloxycarbonylamino) acetonylphosphonate instead of triphenyl (N-propylacetylamino) acetonylphosphonate, 35.9 g (63% of theory) were obtained. (-) - 3,3α, 4,5,6,6α-hexahydro-2-oxo-4 / 3- [3-oxo-4- (N-propylbenzyloxycarbonylamino) -tr-butenyl] -5a- ( 4-phenylbenzoyloxy) -2H-cyclopenta [b] furan;

_Rf = 0.3 (petroleum ether-ethyl acetate 1: 1) and 0.85 (ethyl acetate)

NMR (CDCl3):

δ = 7.4 - 8.3 (m, 14H, aromatic protons), δ = 6.15 - 7.2 (d + dd, 2H, trans-olefinic protons, J = 36 Hz), 5.5 (m, 4H, 5 $ and 6a-protons and benzyl CH 2),

W = 4.25 (s, 2Η, COCH 2 N), δ = 3.3 (t, 2Η, NCH 2, J = 7 Hz), δ - 0.9 (t, 3H, aliphatic methyl protons).

Example 10

The procedure is as in Example 3, but instead of (-) - 3, 3a / 8,4,5,6,6a / S-hexahydro-4 / 3- [3-oxo-4- (N-propylamino) amino (5-Phenylbenzoyloxy) -2-oxo-2H-cyclopenta [b] furan is used as 5.7 g (0.01 mol) of (-) - 3,3a ₍ 3) 4,5,6,6a + hexahydro-2-oxo-4 / 3- (3-oxo-4- (N-propylbenzyloxycarbonylamino) -1-trans-butenyl] -5a- (4-phenylbenzoyloxy) -2H- cyclopenta [b] furan to give 4.4 g (76.5% of theory) of (-) - 3,3a / 3,4,5,6,6a / 3-hexahydro-2-oxo-4 / 3- [ (3S) -3-hydroxy-4- (N-propylbenzyloxycarbonylamino) -1-trans-1-butenyl) -5- (4-phenylbenzoyloxy) -2H-cyclopenta [b] furan,

R _f = 0.39 (ethyl acetate petroleum ether 3: 2)

R _f for a compound of formula IX having the (R) -configuration = 0.31 (3: 2 ethyl acetate / petroleum ether),

NMR (CDCl3):

δ - 7.3 - 8.2 (m, 14H, aromatic protons),. 5.7 (m, 2H, olefinic protons), δ - 4.9 - 5.45 (m, 4H, 5/3 and 6a / 3 and benzyl CH2 protons);

δ = 4.35 (m, 1H, CHOH) δ = 3 - 3.5 (m, 4H, CH 2 N).

Example 11

Using a similar procedure to that of Example 5, but using 3.0 g (0.01 mol) of (-) - 3,3a / 3,4,5,6,6a; N-hexahydro-2-oxo-5α-hydroxy -4 / S '

- [(3S) -3-hydroxy-4- (N-propylbenzyloxycarbonylamino) -trans-1-butenyl] -2H-cyclopenta [b] furan instead of (-) - 3,3a / 3,4,5,6,6a (3-Hexahydro-2-oxo-5α-hydroxy-4/3 - [(3S) -3-hydroxy-4- (N-propylacetylamino) -trans-1-butenyl) -

Claims (5)

OBJECT Process for the preparation of novel optically active prostaglandin derivatives F 2a or their racemates of the general formula XII, 4 0 -2H-cyclopenta [b] furan, 2.9 g (97 percent) of theory are obtained (-) * 3,3a / 3, 4,5,6,6a / 3-hexahydro-2,5a-dihydroxy-4/3 - [(3S) -3-hydroxy-4- (N-propylbenzyloxycarbonylamino) -trans-1-butenyl] -2H-cyclopenta [ b] f uranium, R _f = 0.09 (ethyl acetate: petroleum ether 2: 1) NMR (CDCl3): Δ = 5.75 (m, 3H, olefinic protons + -I- OCHO protons), Δ = 5.2 (s, 2H, benzyl CH2 protons), Δ = 4.25-4.8 (m, 3H, δ / 3.6a / 3 and allyl) CHOH protons), δ = 3 - 3.5 (m, 4H, CH 2 N). Example 12 Using the procedure of Example 6, but using 3.0 g (0.01 mol) of (-) - 3,3a (3,4,5,6,6a) 3-hexahydro-2,5a-dihydroxy-4) 3 - [(3S) -3-hydroxy-4- (N-propylbenzyloxycarbonylamino) -1-trans-butenyl] -2H-cyclopenta [b] furan instead of (-) - 3,3a; 6α / 3-hexahydro-2,5α-dihydroxy-4/3 - [(3S) -3-hydroxy-4- (N-propylacetylamino) -trans-1-butenyl] -2H-cyclopenta [b] furan, 3.17 g (65% of theory) of (+) - 9a, 11a, 15 (S) -trihydroxy-16- (N-propylbenzzyloxycarbonylamino) -17,18,19,20-tetranor-5-cis- 13-trans-prostadienoic acid, _Rf = 0.28 (20: 20: 1 benzene / dioxane / acetic acid), NMR (CDCl3): δ = 5.6 and δ = 5.4 (m, 2H + 2H, trans- and cis-olefinic protons), δ 5.15 (s, 2H, benzyl CH2 protons), <3 = 3.95, 4.1 and 4.3 (1-lm, 3H, 9-OCH, 11-OCH and 15-allyl QCH proton), δ = 3 - 3.5 (m, 4H, CH 2 N), Δ = 0.85 (t, 3H, terminal methyl protons). YNALEZU R ¹ is hydrogen, C 1 -C 4 alkanoyl, C 1 -C 4 trihaloalkanoyl, henaoyl, C 1 -C 4 alkoxycarbonyl (C 1 -C 4) alkoxy, (C 1 -C 4) trihaloalkoxycarbonyl or phenoxycarbonyl or benzyloxycarbonyl group, optionally substituted by (C 1 -C 4) alkoxy, nitro or halogen; R ² is hydrogen or alkyl having 1 to 4 carbon atoms, R ^{4 is} hydrogen or a protecting group; and Q is hydrogen, an alkyl group having 1 to 4 carbon atoms, or a pharmaceutically acceptable non-toxic cation; the general formula XI, where R 1 and R 2 are as defined above, and R 4 is hydrogen or a protecting group, reacted with a hypophosphite prepared from a triphenyl- (4-carboxybutyl) phosphonium salt, and optionally protecting the R 1 group from the compound of formula XII thus obtained and optionally or a compound of formula XII wherein Q is hydrogen, is converted to a C1-C4 alkyl ester in the alkyl moiety or a pharmaceutically acceptable salt.