MXPA97006883A - Procedure for preparing prostaglandins e1 and e2 and analogues of them using reagents of furilo-co - Google Patents

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Description

PROCEDURE FOR PREPARING PRQSTAGLANDINAS AND E2 AND ANALOGS OF THESE USING FURILO-COPPER REAGENTS TECHNICAL FIELD This invention relates generally to methods for synthesizing prostanoic acid derivatives, and more particularly a "one step" method for synthesizing prostaglandin El ("PGEi"), pros + aglandin E2 ("PGE2") and derivatives thereof using reagents of furi locobre.

BACKGROUND OF THE INVENTION Prostaglandms are a family of biologically active lipid acids that have as a common characteristic the structure of prostan-1-o? The prostaglandmas are grouped into types E, F, A, B, C and D based on the presence or absence of certain functionalities in the cyclopentane ring. The numerical subscripts, such as n, for example, the prostaglandin "Ei" and the prostaglandin "E2", refer to the number of msaturated bonds in the side chains; the subscripts "« "or" f3"as in the prostaglandin" F? a "or the prostaglandma" Fiu ", refer to the configuration of substituents in the ring. The biological activities of prostaglandins include smooth muscle stimulation, small artery dilatation, bronchial dilatation, decrease in blood pressure, inhibition of gastric secretion, lipolysis and platelet aggregation, induction of labor, abortion and menstruation, and increase in ocular pressure. PGEi, specifically, is known to be a bronchodilator and a vasodilator, and it is also known to stimulate the release of erythropoietin from the adrenal cortex and to inhibit allergic responses and the aggregation of blood platelets. PGE2, the most common and most biologically potent mammalian prostaglandin, contracts the uterine muscle, inhibits the secretion of gastric acids and protects the lining of the gastric mucosa and, like PGEi, has established that a bronchodilator and a stimulant of the release of erythropoietin from the adrenal cortex. The properties of the different prostaglandins have been extensively reviewed; see, for example, Ramwell and Others, Nature 22JL..1251 (1969). The biosynthesis of prostaglandins occurs by the enzymatic conversion of unsaturated fatty acids of twenty carbon atoms. For example, the endoperoxides PGG2 and PGH2 are prepared by the action of the enzyme complex prostaglandma-cyclooxygenase on the precursor of arachidonic acid lipids, while the PGEi is biosynthesized by enzymatic conversion of 8,11,14-eicosatpenoic acid. The biosynthetic studies of prostaglandins are reviewed in Sarnuelsson, Prog. Biochern. Phar acol. 5: 109 (1969). Several synthetic routes for the different prostaglandins have been explored. A synthesis of twenty steps for PGE2 and PGF2a, starting with tallow cyclopentadiene, was developed by Corey et al. It has also been shown that the procedure is useful in the synthesis of the series one prostaglandins. The catalytic reduction of the bis-protected PGF2ß results in the selective saturation of the double bond 5,6 to produce followed by transformations leading to PGEi and PGF? a - See, for example, Corey et al., 3. Arn. Chern. Soc. 9 ^: 5675 (1969), Corey et al., 3. Am. Chem. Soc. 92: 2586 (1970) and Corey et al., Tetrahedron Letters 307 (1970). Another synthetic route uses norbornadiene as starting material, while yet another approach involves the use of racemic bicycloC3.2.03hept-2-en-6-one as the starting material. This last synthesis implies an enantioconvergent approach, so that the following two enantiores are used, avoiding the need for optical resolution: However, there remains a need in the art for a simpler and more direct route to the different prostaglandins, particularly prostaglandin Ei, prostaglandin E2, and derivatives thereof. It is also convenient that said synthesis provide the desired product in relatively high yield, be simple and direct to classify, and include economic reagents and existing in commerce. The present invention is directed to said method, and involves the use of a lithium-copper reagent in a "one step" synthesis of PGEi, PGE2 and analogs thereof. RELATED TECHNIQUE Apart from the publications identified in the previous section, the following references are also of interest, since they refer to methods for synthesizing prostaglandin derivatives. The Patent of E.U.ñ. 4,031,129 and 4,088,536 per Sih, refers to a method for preparing 15-deoxyprostag.landina Ei racérnica by reacting cyclopentadiene with lithium 7-brornoheptanoate, oxygenating the alkylated diene thus provided, recovering 2- (6'-carboethoxyhexyl) -4 -hydroxycyclopenten-1-one from the reaction mixture, reacting with dihydropyran to give the tetrahydropyranyl ether and, finally, reacting that intermediate with 1-lithium-1-trans-octene in the presence of tri-n-iodide butylphosphine-copper to produce ethyl ester of 15-deoxy prostaglandin Ei racérnica. The Patent of E.U.A. No. 4,149,007, by Buckler et al., Refers to a method for synthesizing prostaglandin Ei derivatives having a phenyl substituent at the C-14 position; the method involves the use of an organolithium cuprate reagent that is added to the side chain at the C-12 position. This coupling is followed by deprotection with a weak acid and hydrolysis. The Patent of E.U.A. No. 4,282,372 by Matsuo et al., Describes a process for preparing cyclopentenolone derivatives that have been established as useful intermediates for producing, inter alia, prostaglandins. The process includes the conversion of substituted furans under acidic conditions, or with chlorine or bromine in the presence of an alkali and an alcohol. The Patent of E.U.fi. No. 4,360,688 by Floyd, Jr relates primarily to methods for synthesizing prostaglandin derivatives in which a slope portion of -S-Aryl is present within the side chain extending from the C-8 position. A method for reacting said compounds in order to convert the ethylene portion possessing the -S-Aryl group into a vinylene group is also described. The Patent of E.U.A. No. 4,452,994 by Hill et al., Refers to a method for isolating an 11,16- or 11,15-dihydroxyprogestaglandin from a reaction mixture. The procedure involves the use of a lithium halide. The Patent of E.U.A. Nos. 4,474,979, 4,644,079, 4,983,753 and 5,166,369 by Floyd, Jr and others, refers to a synthetic process involving the protection of the 4-hydroxyl group of a cyclopentenyl moiety of a cyclopentenoyl compound with, for example, a trirnethylsilyl group or tetrahydropyranyl, followed by conversion to the desired prostaglandin (a 1-rnet? l -16, 16-d? met il-llcr, 15cf-d? h? droxi-9-oxo-2,13-trans, t -rans-prostadienoate ) using a lithium tablet reagent such as l? t? o-cuprate ~ l-pentmo. The Patent of E.U.A. No. 4,535,180 by Grudzms et al., Describes methods for synthesizing prostaglandin analogues as claimed. However, all of the claimed compounds have a methyl group or an alkenyl of C2 ~ CA attached directly to the cyclopentane ring. The Patent of E.U.A. No. 4,543,421 by Corey et al., Discloses a method for adding a "Ri" side chain to a prostaglandin analogue at the C-12 position. The rne-all involves the use of an alkyllithium reagent with CuCN to form a lithium cyanoacuprate; This compound is then reacted with a substituted cyclopentenone, the step of which is optionally followed by hydrolysis. The Patent of E.U.A. Nos. 4,785,124 and 4,904,820 by Campbell et al., Describe the preparation of higher order cuprate complexes derived from the reaction of a cuprate complex with a stannane such as 1,2-bis-tp-n-buti-stanil etiien, which in turn they are used to prepare the omega side chains of prostaglandins. The Patent of E.U.A. No. 4,952,710 by Babiak et al., Describes the preparation of cyclopentenoheptenoic acid derivatives by reacting higher order cuprate complexes with a chiral cyclopentene. The Patent of E.U.A. No. 5,055,604 by Babiak et al., Refers to a synthesis for preparing a prostaglandin derivative which involves (1) producing an "E-alkenyl" zirconium compound by reacting an alkyne with zirconocene hydrochloride; (2) reacting that compound with a lithium cyanoacrylate reagent to produce an intermediate of the cuprate complex; and (3) reacting the intermediate of the cuprate complex with a cyclopentenone. The Patent of E.U.A. No. 5,191,109 by Minai et al., Describes a process for preparing an optically active 4-hydroxycyclopentenone. The process involves reacting a henester (VI) with furan in the presence of trifluoroacetic acid anhydride to obtain a furfuryl ketone, then reducing to a furancarbinol. The furancarbinol. it is treated in an aqueous solvent at a pH of 3.5 to 6 to give a racemic 3-hydroxycyclopentenone or 4-hydroxycyclopentenone, followed by further treatment with an aliphatic carboxylic acid to give the product. Japanese Patent Publication (Kokai) No. 63-077837, describes the conversion of a substituted furan compound to cyclopentenone compounds. Lipshutz, "Applications of Higher-Order Mixed Organocuprates to Organic Synthesis", Synthesis 4.325-341 (1987), presents a review of the use of cuprate complexes to create new carbon-carbon bonds in various synthetic contexts. Specifically, the preparation and use of higher order cuprate complexes of formulas Rt.RCu (CN) LÍ2 and RtRCu (SCN) Í2 is described. "Rt" represents the group that is transferred to an organic compound to form a carbon-carbon bond, R representing a residual group.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, it is a primary objective of the invention to cite the aforementioned need in the art, providing a direct "one step" reaction towards the synthesis of prostaglandins such as PGEi, PGE2 and derivatives thereof. It is another object of the invention to provide such synthesis involving the reaction of an appropriately substituted cyclopentenone with a furyl-copper reagent. It is still another object of the invention to provide such synthesis, wherein the furyl-copper reagent is provided by reacting 2-furyl lithium, copper cyanide (CuCN), lower alkyl lithium and an (E) -alkenylstannane or a halide. It is still another object of the invention to provide such synthesis, wherein the reaction of the aforementioned compounds is carried out simultaneously rather than sequentially, without the need to distinguish between the steps of the synthetic process and without isolating the intermediates, etc.

Other objects of the invention will be apparent to those skilled in the art of synthetic organic chemistry after having reviewed the present description and claims. According to the invention, then, a method is provided for synthesizing the prostaglandin Ei, prostaglandin E2 and derivatives thereof, all of which can be represented generically by the structure of the formula (I) In the formula (I): Ri and R2 may be the same or different, and are selected from the group consisting of wherein R3 and R "are independently selected from the group consisting of hydrogen, 0RS and lower alkyl; A is selected from the group consisting of at. that R5 is selected from the group consisting of hydrogen, te rahydropyranyl, tetrahi-rofuranyl, trialkylsilyl, l-methyl-l-rnetoxyethyl, 1-methyl-1-ethoxyethyl and - (CO) -Rβ, wherein R8 is hydrogen, lower alkyl or lower alkyl substituted by halogen; R6 is ethylene or vinylene; and R7 is R5, lower alkyl or lower alkenyl. The process involves the reaction of the cyclopentenone of the formula (II) ' wherein A, R6 and R7 are as defined above, with L2 a mixture of 2-fur? l lithium, copper cyanide, a reagent of lower alkyl lithium, and halide (Til) or (E) - l ueni iesthane (IV) B ~ CH = CH - R 1 - ~ R 2 - R 10 (IV) H - CH = CH - R 1 - R 2 - R 10 In the compound (III), B is halide, and R and R2 are as defined above. In the compound (IV), M is (R9) 3, wherein R9 is lower alkyl. The Rio substituent in the compounds (IIT) and (IV) is lower alkyl.

DETAILED DESCRIPTION OF THE INVENTION Before describing the present invention in detail, it should be understood that unless otherwise stated, this invention is not limited to particular reagents, reaction conditions or the like and that, as such, may vary. It should also be understood that the terminology used in the present invention is for the purpose of describing only particular embodiments, and is not intended to be limiting. It should be noted that, as used in this specification and in the appended claims, the singular forms "a" "an" and "the" are plural references, unless the content clearly indicates otherwise. Thus, for example, reference to "a cyclopentenone" -includes mixtures of cyclopentenones, reference to "an alkyl lithium reagent" includes mixtures of said reagents, etc. In this specification and in the claims that follow, reference will be made to to various terms that will be defined to have the following meanings: The term "prostaglandin", as used in the present invention, refers to compounds having the skeleton of prostan-1-oic acid The prostaglandins prepared using the present synthesis are PGEi, PGE2 and derivatives thereof, ie, compounds having the structure of formula (I) mentioned above. The term "alkyl", as used in the present invention, refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , t-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. The term "lower alkyl" refers to an alkyl group of one to eight, preferably one to six, and more preferably one to four, carbon atoms. The term "halogenated lower alkyl" refers to a lower alkyl group of one to six carbon atoms in which at least one hydrogen atom, typically one to three hydrogen atoms, but more typically only one hydrogen atom, is replace with a halogen atom. The term "alkenyl" refers to a branched or unbranched hydrocarbon chain containing from 2 to 24 carbon atoms and at least one double bond. "Lower alkenyl" refers to an alkenyl group of two to eight, more preferably two to six, and most preferably two to four, carbon atoms. The term "halogenated lower alkenyl" refers to a lower alkenyl group in which at least one hydrogen atom is substituted with a halogen atom. The term "alkoxy", as used in the present invention, refers to an alkyl group linked through an individual terminal ether bond; that is, an "alkoxy" group can be defined as -OR, where R is alkyl as defined above. A "lower alkoxy" group refers to an alkoxy group containing one to eight, more preferably one to six, and most preferably one to four, carbon atoms. "Halo", "halogen" or "halide" refer to fluoro, chloro, bromo or iodo, and often refer to the substitution of the halogen for a hydrogen atom in an organic compound. Of the halogens, lc1 gold is typically preferred. "Optional" or "optionally" means that the circumstance subsequently described may or may not occur, and that the description includes cases where said circumstance occurs, and cases where it does not occur. For example, the phrase "optional covalent bond" means that a covalent bond may or may not be present, and that the description includes the case where the covalent bond is present, as in the case where the covalent bond is not present. As noted above, the compounds having the structure of the formula (I) where A, Ri, 2, R6 and R? they are as defined above, they are prepared by reacting the cyclopentenone subs ituida Ib with 2-fur? l lithium, copper cyanide, a reagent of lower alkyl lithium and halide (III) or (E) -alkenylantan (IV). It is preferred that the latter four reagents are present in approximately equimolar amounts, although some variation in the relative amounts, generally up to 10 to 20 mole%, can be accommodated without any significant loss in performance. The reaction is carried out in an appropriate organic solvent, preferably a non-polar aprotic solvent such as tetrahydrofuran (THF) or diethyl ether, at a reaction temperature in the range of about -50 ° C to approximately 50 ° C. , preferably on the scale of about -30 ° C to about 30 ° C. The reaction must be carried out under inert conditions, that is, under dry nitrogen or a blanket of argon gas, for a reaction time of at least about 30 minutes. Initially, it is preferred that 2-furyl lithium (prepared by mixing approximately equirnolar amounts of furan and an alkyl lithium reagent at a temperature of about 10 ° C or less) be combined with copper cyanide, lower alkyl lithium and (III) or (IV) before adding the cyclopentenone. The mixture of furan, the reagent of alkyl lithium and copper cyanide, gives rise to the reagent (V) a compound that is stable at 0 ° C for relatively long periods, typically up to at least about 6 months. The addition of (TIT) or (IV) followed by the addition of a cyclopentenone (II) step to the reaction mixture, at a mole ratio on the scale of about 0.3: 1 to about 1: 1 (ie when approximately one mole of furan, of alkyl lithium and of (III) or (IV) are present, 0.3 to mole of cyclopentenone will be added), produces the desired prost glandin derivative. The reaction is quenched with base, for example, ammonium hydroxide or its like. The organic materials are separated and dried (for example, on magnesium sulfate); the product is then deprotected with, for example, dilute hydrochloric acid, and isolated by conventional means, for example, using chromatography, crystallization or the like. With respect to the specific reagents used, those skilled in the art of synthetic organic chemistry will appreciate that reagents that are functionally equivalent to those specifically described can be substituted, if. it is desired; for example, the 2-furyl magnesium chloride or bromide can be replaced by 2-furyl lithium, and various lower alkyl lithium reagents can be used, for example, methyl lithium, ethyl lithium, isopropyl lithium, n-propyl lithium, or the like. Examples of preferred halides having structural formula (III) include, but are not limited to, the following: B-CH = CH-CH-CH-C5H11 0R5 0R5 CH3 B-CH = CH-CH2 -C-C4H9 0R5 CH3 B-CH = CH-CH- C-C4H9 ORS 0 O1RS B-CH = CH-CH- CH-C4H9 ORS ORS Examples of (E) -alkenylstannanes appropriate? include, but are not limited to, the following: M-CH = CH-CH- CH-CsH ?? ORS ORS CH3 M-CH = CH-CH2 -C-CA H9 ORS ORS ORS CH3 I M-CH = CH-CH2 -C-C5H11 ORS CH3 M-CH-CH-CH- C-CsHn I I ORS ORS and M-CH = CH-CH- CH-C4H9 0R5 ORS It should also be noted that if the halogenide (III) or the (E) -alkenylantan (IV) is used in pure enantio form, the product can also be obtained in an enantiomerically pure form. This is exemplified in the experimental section that follows. All starting materials and reagents used in the present synthesis are commercially available or can be easily synthesized using conventional techniques. For example, reagents of quillitium, furan, and copper cyanide can be obtained from various commercial sources, while the cyclopentenone race ica of formula (II) can be prepared using the method of Collins et al., 3. tled. Chern. 20: 1152 (1970); the enanomerically pure cyclopentenones of formula (TI) can be prepared using the method of Pappo et al., Tet. Lett. , 1973, p. 943; Formula halides (Til) can be prepared using the methods of 3ung and others, Tet. Lett. , 1982, p. 3851, Leyes and others, 3. Org. Chem., 1979, p. 1438, or Collins and others, 3.

Med. Chem., 1977, p. 1152, and the alkenylstannanes of formula (TV) can be synthesized using Chen's method and others, 3_¡_ g. 43: 3450 (1978). The advantages of this procedure are excellent isolating performances - in most cases over 80 to 90% - and very good reproducibility. The procedure is simple to scale up and allows the production of hundreds of grams of prostaglandins in a "one step" operation. Secondary products are easily separated using conventional techniques such as crystallization or chromatographic methods, and a high purity prostanglandin product is isolated. From a manufacturing point of view, it is advantageous that the mixture of reagents be stable and when necessary can be stored for long periods, of the order of six months or longer, without appreciable decomposition. All the chemical agents in the process are cheap and available at the same time. The following examples are given to provide the expert with a description and full disclosure of how to perform the synthetic procedure present, and they are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure accuracy with respect to the numbers used (for example, quantities, temperatures, etc.) but of course some error and experimental deviation may be allowed. Unless stated otherwise, the parts are parts by weight, the temperatures are in degrees centigrade, and the pressure is atmospheric or close to it.

EXPERIMENTS All organometallic reactions were carried out under dry nitrogen or under a blanket of argon gas using anhydrous solvents. The reaction flasks were dried with a heat gun before the addition of starting materials or reagents and all the air-sensitive reagents were transferred through a cannula. The identity of the products was confirmed by * H and * 3c NMR (using a 270 MHz 3eol spectrometer), infrared spectroscopy (using a Mattson Galaxy 5020 furier series transformation spectrometer), gas chromatography (using a system, Hewlett -Packard 5890 TC / MS) and HPLC (using a Hewlett-Packard 1050 LO and by comparison with authentic standards when available.

EXAMPLE 1 In situ formation of complex of (E) -alkynyl-2-furyl-copper-cyanide and its conversion to misoprostol To copper cyanide (2.6 g, 28.9 rnmoles) (Aldrich) in a 250 ml round bottom three-necked flask, dried by heat gun, anhydrous THF (35 ml) was added, followed by a solution of 2 ml. -furillitio (1 eq.) at 0 ° C. The solution was treated with methyllithium (1 eq.) And R, S-stannane 1 ^ (1.5 eq.) (Synthesized according to the method of Chen et al., Supra) by means of a cannula.

The resulting homogeneous solution was stirred at room temperature for 3 hours, cooled to -65 ° C and protected R, S-enone 2 (7 g, 19.8 nmrnols) (synthesized according to the method of Collins et al. supra), in THF (35 ml) in one portion. The temperature was observed to be increased approximately -35 ° C.

The homogeneous reaction mixture was stirred at ~ 30 ° C to about -40 ° C for 30 minutes and quenched with a saturated aqueous solution of ammonium chloride (500 mL, containing 50 nL of concentrated ammonium hydroxide) and ethyl acetate. ethyl (150 ml). The organics were separated, dried over magnesium sulfate and evaporated in vacuo at about 45 ° C to 55 ° C to give R, S-metii-i3E, ll-triethylsilyloxy-16-trimethylsilyloxy-16-rnetyl-9- crude oxo-roet-13-ene-1-oate, which was then deprotected with 3 M HCL in acetone (30 minutes) to give crude rnisoprostol as a light yellow oil. The. Misoprostol was purified by chromatography on silica gel using a mixture of hexane and rilethyl-t-butyl ether or a gradient eluent. Pure misoprostol yield 3. 6.95 g (92%) as a colorless oil. * H NMR (CDC13, ppm): 3.63 (s, OCH3), 2.64 and 2.74 (dd, C -.10), 5.50 (m; C-13, 1.4).

E3EMPL0 2 In situ formation of lithium (E) -alkenyl-furyl-copper-bromide complex and its conversion (with n-butyllithium) to misoprostol The procedure of Example 1 was repeated except that a 1.6 M solution of n-butyllithium in hexane (18 rnl, 29 mmol) was used instead of rnetillithium. Insulating performance, 6.8 g (90%).

EXAMPLE 3 In situ formation of lithium (E) -alkenyl-2-furyl copper complex and its conversion to prostaglandin The procedure of Example 1 was repeated, except that 18.6 g (35 mmol) of S-stannane 4 ^ was used. 1 in THF (35 ml) (synthesized according to the method of Chen et al., Supra), in place of reagent 1 and 9.5 g (21 mmol) of R-enone 5. in THF (35 ml) (synthesized in accordance with the method of Pappo et al., supra), 1973, p. 943), instead of 3, S-enona 3.

H3 Prostaglandin Ei (6.3 g, 85%) was isolated after deprotection (2 M HCl ~ acetone 1: 1, 30 rnin TA) and chromotography. 1 H NMR (C0DCl 3v ppm): 2.61 and 2.65 (dd, 10-C) 0.90 (t, C-20).

Prostaglandin The EXAMPLE 4 In situ formation of lithium (E) -alkenyl-2-furyl-copper-bromide complex and its conversion to prostaglandin E2 The procedure of Example 1 was followed using S-stannane 6 (synthesized according to the method of Chen et al., Supra) in place of R, S-stannane 1. (where "THP" represents tetrahydropyranyl) and R-enone 7 (synthesized using the method of Pappo et al., supra) instead of R, S-enone 2_.

Prostaglandin E2 (80%) was obtained after deprotection (HC1 2 M-acetone, 1: 1, 15 minutes at room temperature and chromatography).

Prostaglandin E-2 EXAMPLE 5 In situ formation of lithium (E) -alkenyl-2-furyl-copper-bromide complex and its conversion to prostaglandin methyl ether Ei The procedure of example 1 was repeated, except that S-stannane was used. (17 g, 35 mmol) (synthesized using the method of Chen et al., Supra) in THF (35 ml), instead of S-stannane 1 and R-enone 9 (6.55 g, 21 mmol) (synthesized in accordance with Pappo et al., Supra) in THF (35 ml), instead of R-enone 2.

He obtained methyl ester of protaglandin Ei (6.6 g; 85%) Prostaglandin Methyl Ester EXAMPLE 6 In situ formation of lithium (E) -alkenyl-2-furilcobrecianide and its conversion to prostaglandin Ei To copper cyanide (2.6, 28.9 mmol) in a flask of 3 collars of 250 ml were added THF (35 ml), followed by a solution of 2-furillithium in THF at 0 ° C (prepared by treating furan with n-butyl lithium in hexane at 0 ° C). The resulting solution was cooled down to -65 ° C and a solution of (E) -alkenyllithium (prepared from S ~ (E) -alkenyl x iodide, or S-stannane 11 and n-butyl lithium was added. at -70 ° C for 1 hour), through a cannula. The resulting amber mixture was stirred for 30 minutes (-60 ° C) and R-enone 12 (9.54 g, 21 moles) in THF (40 ml) was added. li The homogeneous mixture was stirred for 30 minutes at -50 ° C, and saturated aqueous ammonium chloride / ammonium hydroxide (10%) (500 ml) was immediately added, followed by continuous stirring for 1 hour at room temperature. . The organic layer was separated, washed (2x) with brine, dried, and evaporated. Crude PGEi was obtained after deprotection with 500 g of pyridinium p-toluenesulfonate in 150 ml of acetone and 30 ml of water for 5 hours. The product was purified by column chromatography on silica gel using ethyl acetate-hexane, 2: 1, as eluent and ether crystallization. Yield 6.6 g (89%).

Claims (17)

H. NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing prostaglandins having the structural formula (I) wherein, R * and R2 may be the same or different and are selected from the group consisting of wherein R3 and R * are independently selected from the group consisting of hydrogen, ORS and lower alkyl, A is selected from the group consisting of wherein R5 is selected from the group consisting of hydrogen, tetrahydropyranyl, tetrahydrofuranyl, tri-lower alkylsilyl, 1-methyl-1-methoxyethyl, 1-methyl-1-ethoxyethyl and - (CO) -Rβ, wherein, R8 is hydrogen, lower alkyl or lower alkyl substituted with halogen, R "is ethylene or vinylene, R7 is R5, lower alkyl or lower alkenyl; the method comprises: (a) preparing a reaction mixture containing (i) a first reagent selected from the group consisting of 2-furyl lithium chloride, 2-furylmagnesium and 2-furyl magnesium bromide, (ii) a second reagent comprising a lower alkyllithium compound, (iii) a third reagent comprising copper cyanide, and (iv) a fourth reagent comprising either halide (III) or (E) -alkenylastan (IV) (III) B-CH: = CH-R1-R2-R10 (IV) M-CH-CH-R1-R2-R10 wherein B is halide, M is -Sn (R9) 3, wherein R9 is lower alkyl, R10 is lower alkyl, and Ri and R2 are as defined above; (b) contacting cyclopentenone (II) with the reaction mixture under conditions effective to produce one or more products having the structural formula (I).

2. The process according to claim 1, further characterized in that the first reagent is 2-furyl lithium.

3. The process according to claim 2, further characterized in that the second reagent is selected from the group consisting of inetiiiitio, etillitio, n-propillio, isopropilli t, n- u 111 itio, isobutyllitio and t- Butyllithium

4. The method according to claim 1, further characterized in that the fourth reagent has the structural formula (III).

5. The method according to claim 2, further characterized in that the fourth reagent has the structural formula (III).

6. The method according to claim 5, further characterized in that the fourth reagent is selected from the group consisting of B-CH = CH- CH3 I B-CH = CH-CH2-C-C «H9 0R5 CH3 I B ~ CH = CH ~ CH ~ C-C4H9 ORS ORS CH3 I B-CH = CH-CH2 -C-C5 Hi 1 ORS CH3 I B-CH = CH-CH- C-C5H11 ORS ORS B ~ CH = CH-

7. - The method according to claim 1, further characterized in that the fourth reagent has the structural formula (IV).

8. The method according to claim 2, further characterized in that the fourth reagent has the structural formula (IV).

9. The method according to claim 8, further characterized in that the fourth reagent is selected from the group consisting of M-CH = CH-CH3 I M ~ CH = CH-CH2 -C ~ C "H9 ORS CH3 M-CH = CH- CH3 [M-CH = CH-CH2 -C-C5 Hi 1 ORS CH3 M-CH = CH-CH- C-CsHn ORS ORS and M-CH = CH-

10. - The method according to claim 1, further characterized in that the first, second, third and fourth reagents are present in the reaction mixture in approximately equimolar amounts.

11. The process according to claim 1, further characterized in that the molar ratio of cyclopentenone (II) to any of the first, second, third or fourth reagents is in the range of about 0.3: 1 to 1: 1.

12. - The method according to claim 1, further characterized in that the product is obtained without isolation of any intermediate species.

13. The process according to claim 1, further characterized in that step (b) is carried out in a non-polar aprotic solvent at a reaction temperature in the range of about -50 ° C to 50 ° C., for at least about thirty minutes.

14. The process according to claim 10, further characterized in that step (b) is carried out in a non-polar aprotic solvent at a reaction temperature in the range from about -50 ° C to 50 ° C, during which less approximately thirty minutes.

15. The method according to claim 1, further characterized in that it includes (c) quenching the reaction of step (b) with a base.

16. The process according to claim 15, further characterized by including (d) deprotecting the product of step (c) with dilute acid, and (e) isolating the product (I) using chromatography or crystallization.

17. A process for preparing prostaglandins having the structural formula (I) where, R1 and R2 may be the same or different and are selected from the group consisting of in which R3 and R * are independently selected from the group consisting of hydrogen, ORS and lower alkyl, A is selected from the group consisting of wherein R5 is selected from the group consisting of H, tetrahydropyramyl, tetrahydrofuranyl, tri-lower alkylsilyl, 1-methyl-l-methoxyethyl, 1-methyl-l-ethoxyethyl and - (CQ) -Rβ, wherein, Rβ is hydrogen, lower alkyl or halogenated lower alkyl, 6 is ethylene or vinylene, R7 is R, lower alkyl or lower alkenyl; the process comprises: (a) preparing a reaction mixture containing approximately equirnolar amounts of i) 2-furillithium, ii) a lower alkyllithium compound, (iii) copper cyanide, and (iv) either halide (III) or (E) -alkenylantan (TV) (III) B-CH = CH-R1-R2-R10 (IV) M-CH = CH-R1-R2-R10 wherein B is halide, M is -Sn (R9) 3 , wherein R9 is lower alkyl, and R1 and R2 are as defined above; (b) contacting cyclopentenone (II) with the reaction mixture in a non-polar aprotic solvent at a reaction temperature in the range of about -50 to 50 ° C for at least about thirty minutes, without isolation of any intermediate species; c) quenching the reaction of step b) with a base; d) deprotecting the product of step c) with dilute acid; and c) isolating the product (I) using chromatography or crystallization.