SE406462B - PROCEDURE FOR PREPARING 2- (6-CARBALCOXYHEXYL-4 (R) -HYDROXY-CYCLOPENT-2-ENON - Google Patents

Description

73159824; _ i 2; A main object of the present invention is to provide processes for the preparation of chiral compounds which constitute important intermediates in the preparation of prostaglandins or prostaglandin-like compounds.

In general, the invention can be said to relate to a process for the preparation of a 2- (6-carbalkoxyhexyl) -α (β) -hydroxy-cyclopent-2-enone of the formula CO ROHW / "x / sv-f '2 wherein above and in the the following R represents an alkyl group having 1-H carbon atoms; Characteristic of the invention is that a) a 2- (6-carbalkoxyhexyl) -4 (fi) -hydroxycyclopentane-1,3-dione of the formula - HO "O U Ü.,., CO R \ -f 2. React either with an alkyl iodide of the formula R 'I wherein above and hereinafter R' represents isoamyl, isopropyl or pivalyl, to form a C1 and a C3 enol ether of the formulas OR 'w (g / rr or with an acid chloride of the formula R "COCl wherein above and in the following R" represents an alkyl group having 1-6 carbon atoms or phenyl, to give a Cl and a CB enol ester having the formulas: ocon "; l / co RJ,. ï \\ // ~ ///>» _ / '/' -. / 2 TGSP- '* co R f. ff] _ “ B) separates the C1 enol ether and the ester from the C3 enol ether and the ester, respectively, c) reduces the separated substituted C1 enol ester and the ether, respectively, and: d) recovering said 2- (6-carbalkoxyhexyl) -H- (§) -hydroxy-cyclopent-2-enone from the reaction mixture.

This process together with a previous step for the preparation of the starting material can be illustrated, for example, by the following reaction sequence:, 0 O (GHQg-COOR (says-coon 0 "/ _ \ 0 Hoëš ön O ~ R '0-3' f / (0H2) 6-COOR _____9 '(cH2) 6-coon ____l__9 H0§ Qñ ~ Ho @ on ol (cH2) 6-coon Ho * In the above formulas, R and R' have the meanings given above- well .. _7z1sae2-4 Previously, R Pappo et al. (Annals of the New York Academy 'ef sciences vei. 180 eid. 64/1971 /) stated the following method for the preparation of the methylene ether from 2- (6'-carbomethoxyhexyl) -4-hydroxy-cyclopentene -l, 3-dion: O 2 g> <íc fi j 4 '3 fe en; Ho (Afo! go _ den; t (eng) óçoocnš one) 6coocH3 + Ho _ oc fi j .i Ho * o (ä): (å ) This process was carried out by refluxing the hydroxide ion ester Q together with dimethoxypropane under acidic conditions to give the two indicated isomeric enol esters Q and Q.

The disadvantages of the procedure according to Pappo et al. are: 1) with this process only about 0% of the desired C-1 enol ether g is obtained, een 2) the asymmetry center at 0-4 is pre-stored.

The latter disadvantage is extremely serious in the production of prostaglandin by means of 1,4-addition reactions, since the stereochemistry of the prostanoic acid skeleton (at positions C-8 and C-12 in prostaglandin1 becomes dependent on the stereochemistry at C-4).

The disadvantages of the method of Pappo et al. Are eliminated in the methods of the present invention. In this context, it is particularly important that in the processes of the invention it is possible to maintain the asymmetry center at C-4, so that the 2-substituted 4-hydroxy-2-cyclopenten-1-one formed is a chiral compound; After all, chirality is of the utmost importance when it comes to producing prostaglandins. In addition, the methods of the invention preferentially promote acylation or alkylation of the oxygen atom attached to the C-1 carbon atom of the molecule to obtain the molecular configuration which is desired for the subsequent reduction to the desired compound, namely 2-substituted (§) -hydroxy-2-cyclopenten-1-one.

Although the invention is not dependent on possible Theoretical explanations can be mentioned as follows: It seems to be the case that a? 315982-Å rather or to some extent extensive group must be used for acyl- at the oxygen at C-1. In addition, the O-alkylation is probably favored at C-1 under basic conditions; the size of the alkylation group should be of less importance than is the case. the size of the group at the acylation. - In any case, it has been found that when one adheres to the above conditions, one can maintain the asymmetry center at Cf4 and that then no racemization occurs either. In the process of the invention, the asymmetric reduction of the 2-substituted cyclopentane-1,3,4-trione to the corresponding 2-substituted 4 (3) -hydroxy-cyclopentane-1,3-dione can be achieved by catalytic hydrogenation in the presence of a rhodium complex with a chiral phosphine ligand as catalyst. (Catalysts of this type are disclosed in Chem. Soc., Chem. Comm., 10 / l972 / by W.S. Knowles et al.).

The preferred catalyst in the present process may be designated L2Rh + COD BF4 '(available from Monsanto Go. St. Louis, Mo., USA, Identification No. CP 71327), where L is o-anisyl-cyclohexylmethylphosphine and COD is 1.5 -cyclooctadiene.

A process for the hydrogenation of 2- (6β-carbomethoxyhexyl) -cyclopentane-1,3,4-trione using the aforementioned preferred catalyst is as follows: Example 1 \ / \ / \ / \ / co2cr13 H, Lanr fi con BF; o °° 2 ° H3 Ho * DO J / O g 2 (6'-carbo ethoxyheyl) -c kl t -l 4-t '' 8 of the specified catalysis oåh ggåg äf tí; ëtylšmfæ'f§Étegæi 35 ml methanol and subjected to hydrogenation at 1 atmosphere After 92.6% of the theoretical amount of hydrogen had been consumed, the reaction was quenched by pouring the hydrogenation reaction mixture into HCl-H 2 O (about pH 2).

The resulting mixture was extracted three times with ethyl acetate and the organic layers were separated and washed with a 5% sodium bicarbonate solution until the aqueous phase became colorless. The combined bicarbonate extracts were extracted with ethyl acetate; the yellow water layer then obtained was carefully acidified to pH 2 'with hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated to dryness. The dried material was dissolved in and then crystallized from ethyl acetate to give 1.7 g of product (34% yield) having the following properties = UvA ::; H 272 nm tan ooo); cDi281 nn, e = - 58.3 x 105; e = +60 x 103 vidieóa nn (68% ept1sk purity). By Uv is meant ultra-violet dichroism and by CD is meant circular dichroism. A second portion of recovered product (1.6%) showed no optical activity; and in the filtrate there was almost no optical activity. The trionmethyl ester, which was used as starting material in the above-described hydrogenation reaction, can be easily obtained from the corresponding trionic acid according to the following procedure, the trionic acid in turn being easily obtained according to Pappo m.fl. described method (see loc. cit): - ° 9H5 o> <°° Hß o '' t 9: š fi> ¥ ~ '^ * \ c // ”\\» / ”A \\ y // COQCH3 .O A mixture of 1 g of trionic acid, 2 ml of methanol, 0.2 ml of concentrated H01 and 2.5 ml of dimethoxypropane was allowed to stand at room temperature overnight. Then the solution was evaporated to dryness (rotary evaporator) and the residue was dissolved in 10 ml of ethyl acetate. The ethyl acetate layer was extracted with a saturated NaHCO 3 solution (2 x 15 mL).

The bicarbonate solution was acidified and extracted with 4 x 25 ml of ethyl acetate. The extract thus obtained was washed with a saturated NaCl solution and dried over MgSO 4. Evaporation of the solvent gave a reddish oil which solidified on standing to give a yellow solid; it may be mentioned that solidification is facilitated by grafting with a crystal of the trionmethyl ester.

Alternatively, the dione can be prepared microbiologically, as shown in U.S. Patent Application 293,457, filed Sept. 29. 19 72.

In this case, 2-substituted-cyclopentane-1,3,4-trione or 2-substituted-3-alkoxy-2-eykiepenten-1,4-ion is subjected to the fermentation-inducing enzyme action of a microorganism belonging to the class \ l / tAscomycetes,. or the production can take place via optical resolution with brucine as shown in the following diagram: ¶ 0. ozcnzcus Hol Ä 4 'cH om ~ s (ßRuc1N-1o, 11- s-nrmsrosæsænyxurn) cH o /' \ / \ / \ / C02CH2CH3 nä 'Q o c fl so / I l \ m3 @ "-' ... IJ? C1 * * / [/ '/ \ / C ° zCH2C "s' -§ Ho -P BRUCINHYDNOCLONID vznsssz-in 2- (6'-carbomethoxyhexyl) -4-hydroxy-cyclopentane-1, §-dione (6 g, h 0.022 mol) was mixed with brucine (8; 7 g, 0.022 mol). To this mixture was added 35 ml of acetone, and the resulting solution was refluxed under a nitrogen atmosphere for 15 minutes, then cooled to room temperature and allowed to stand for 3 hours at room temperature and then overnight at refrigerator temperature (+ + 10 ° C). The product, a brucine hydroxide ion salt, precipitated as fine crystals. These were filtered off on a Éüchner funnel, washed with cold acetone and recrystallized until a constant torque was obtained from ethyl acetate and Skelly B (five recrystallizations). Skelly B is Qyhexan.

Optical rotation of the salt in CHCl3: 2nd recrystallization = -28.50 3 = dje - "- = -31.51 4 = dje -" - = -35.92 (c 0.56): dje "" "' 33192 (C) The optically dissolved brucine hydroxide ion salt (2.2 g) was dissolved in 50 ml of ethyl acetate. To this solution was added 30 ml of 0.25 N HCl and the heterogeneous mixture was stirred very vigorously for 2 minutes.

After standing, two layers were formed, which were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers from the two extractions were combined and washed with water and with saturated brine, then dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 2- (6'-carbomethoxyhexyl) -α (§) -hydroxy-cyclopentane-1,3-dione as a solid white crystalline substance (790 mg).

As stated above, the enolization of the 2-substituted dione can be accomplished for conversion to the enol ester or enol ether by selective O-acylation or selective O-alkylation according to the general procedures set forth below.

Enolysis by Selective O-Acylation In general, this reaction can be carried out according to the scheme given below: 73159-82'l | / (cH2) 6 -coon _ R'-co-x or R fl soa-x (CHECHQEN V o-co-R '_ ß. (cH2 -_) 6 -cooH Ho \\\ o wherein R has the meaning given above, R 'is unsubstituted or halogen-, alkyl- or alkoxy-substituted phenyl, benzyl, biphenyl or naphthyl, or is alkanyl or alkenyl having from about 1 to 6 carbon atoms, pivalyl or isobutyl, and X represents iodine, chlorine, bromine or -O- CO-R 'or -OSO 2 R', in which formulas R 'have the meanings given above.

In the case of the above-mentioned acylation, it is most convenient to use only 1 equivalent of the acylating agent, since when the excess avylating agent is used, it can very easily happen that the hydroxyl group is also aoylated. The size of the acylating group is also important for the formation of the desired enol ester, in that a larger group promotes the formation of larger amounts of the desired enol forms, i.e. O-acylation of the C-1 position. If, for example, acetyl chloride is used as acylating agent and 2 (6'-carbomethoxyhexyl) -4 (§) -hydroxy-2-cyclopentane-1,1-dione is used as substrate, the two enol acylates O-CO-CH O 3 cna are formed. -coocH and I / (cH2) 6-coocH 3 S \ o cH3-co-o $ \ 3 cnö-co-o o-co-cnñ li - ä in the proportions 70-75% A and 30-25% §. If, on the other hand, a larger alkylating substance is used, for example pivaloyl chloride, the ratio of the desired substituted C-phenol pivaloylate will be -. 73159_82 ~ l | . to the substituted C-3 enol pivaloylate about 90:10.

As will be readily appreciated by those skilled in the art, the substituted C-1 enol sulfonates can be exchanged for alcohols to give C-1 enol ether derivatives. Enolization by selective O-alkylation The O-alkylation reaction can be carried out in accordance with the following reaction scheme: o () p 'ia oR "to _. _ (ca) -coon R" x (CH) -coon 2_6, --- --- à 2 6 p Kacoš <> "~ cs Hd \ ° Ho \ \\\ ° where R has the meaning given above, R" denotes saturated or unsaturated alkyl having about 1 to 6 carbon atoms, benzyl, diphenylmethyl or an ester group having the formula -CHQ-co-R "'or -cH (R"') -co-on "'where R"' is a hydrocarbon radical having about 1-6 carbon atoms and X is the chlorine, bromine, iodine, sulfate When the reaction was carried out under alkaline conditions, no racemization could be observed. As stated above in connection with the O-acylation, the degree to which the alkylating agent is bulky has an effect on the automobile. isocyanate or alkyl substituted or unsubstituted arylsulfonate radical. the relative proportions of the enol ethers, ie the amount / ratio of the substituted C-1 enol ether to the substituted C-3 'enol ether. ropyl iodide as the alkylating agent and 2 (6'-carbomethoxyhexyl) -4- (E) -hydroxy-2-cyclopentane--1,3-dione as the substrate the two enol ethers were formed o - <<: ou (cH2) 6- coocH5 f ch Os \> ° Hos @ _ / \ cH2) 6-coocnj H _ A _ É in the ratio A: B = 6: 4. On the other hand, when isoamyl iodide, which is a more bulky group, was used as the alkylating agent, the ratio of the desired substituted C1-enol ether to the substituted C-3-enol ether to about 7: 5.

The table below shows the relative proportions of the two enol ethers when using the specified alkylating agents: f "l alkylating agent OR 'O (m) _ H - W 1 \\ \ s * \ I Hb« 0 Ho QR (Preferred ether) I 4053 605% (Sec.butyl iodide II 60% 407; (isopropyl iodide) 70% 30% (isobutyl iodide)> 70% 30% (isoamyl iodide) As the person skilled in the art will readily understand, instead of performing the above The O-acylation or O-alkylation described also fulfill the objects of the invention, in a suitable manner, by selective formation of enamines or silanes, For example, instead of the above-mentioned acylating or alkylating agents in the enolysis processes pyrrolidine or morpholine or the conventional ones may be used. Reduction of the C1-substituted enol ester or enol ether 'can be readily accomplished by sodium dihydro-bis (2-methoxyethoxy) aluminate (called the "Red-Al" agent), as shown by Pappo et al. ., Tetra- hedon Letters No. 2 6, p. 2627 (1972), Pergamon Press. Other reducing agents, such as e.g. lithium borohydride, diisobutylaluminum hydride and lithium aluminum hydride, can likewise bring about reduction of the carbonyl function of the C1-substituted enol ester or ether in accordance with the procedures of the present invention, to give the desired 2-substituted 4- (2) -hydroxy - -cyclopenten-l-on products.

The following examples are illustrative only; they are in no way - not in any respect - to be construed as having any limiting effect on the scope of the invention.

Example 2. Preparation of the di-enol benzoates: ï I _ \\\\ «///,.\\\\{// ,, co2cH5 Ho * 5> ° * b 1 II o-co-ß, co2cH3 IIIa Q ï Q-co-os “so +“ F co ca \ \\ __ / \ K23 t IIIb § + co-o “\ \ o-coat _To a solution of 120 mg (0.467_mmol) 2 (6 ' -carbomethoxyhexyl) -4- (Q) -hydroxycyclopentane-1,3-dione (II), and 0.4 ml (about 5 mmol) of triethylamine (Et 3 N) - distilled over CaH 2 - in 10 ml of tetrahydrofuran (THF) , which was cooled to -15 ° C, was added within 5 minutes and with stirring 0.5 ml = 4.34 ml of benzoic acid chloride. After the reaction mixture was stirred at + 5 ° C for 3 hours, water was added and the mixture was extracted 3 times with diethyl ether. The ether layer was washed successively with dilute H01, water, saturated NaHCO3 / saturated NaCl solution. Then the ether layer was dried over Na 2 SO 4 and evaporated to dryness. Analysis by proton magnetic resonance, PMR, showed that the dried product contained 90% of the desired C1-substituted dibenzoate (IIIa), which can be easily separated by chromatography using a silica-Celite (85:15) column. with the dimensions 21 x 2.5 cm, with a benzene-ethyl acetate gradient as described in Example 4.

Example 3. Preparation of acetylenol ether 11 f; i Cozc fl j II High gšo (cH3cH2) 3N cH5coc1 THF OAc I co CH ”\\\ ~ /// ^ \\\, /// ¿\\\ v /// 2 5 IIIC Aco * § '* o + o I 118/, \\\ Y //, co2cH3 \ / IIId I Aco * oAc To 118 mg of II (0,46 mmol) and 0.4 ml (3 mmol) of Et3N (which was freshly distilled over CaH2) in 10 ml of THF, 0.3 ml of acetyl chloride was added, which was done dropwise and within a period of 5 minutes, with stirring at -5 ° C. The reaction was allowed to proceed for 4 hours (a time chosen for convenience), after which 2 ml of methanol were added and the reaction breath was stirred for 15 minutes at 0 ° C. Then water was added to the Ehndningen. The mixture was extracted twice with diethyl ether and the ether layer was washed successively with dilute H01, water and saturated NaHCO3 solution. The ether fraction was dried over sodium sulfate and concentrated in vacuo to give 140 mg of an orange oil. PMR analysis showed that the oil contained 70-75% of the desired enol ether (III c). Separation of III c from III d can be easily accomplished by chromatography in the system described in Example 2. Example 4. Preparation of the t-butyl enol ester.

O | . 1 C02CH5 'Ho $ “* p t-bu-yl-co-cl TCH3CH2) 5N 0-CO-tBu' CO CH 2 \\ /“ // 5 t-Bu-co-o $ “šo + III 6 0-CO To a solution of 0.512 g (2 mmol) of II and 1.74 ml (about 13 mmol) of Eujn (aes fi derived from cana) in 40 ml of THF, which is cooled to -15 ° C. , 1.1 ml (9.06 mmol) of pivaloyl chloride were added, which was done within a 10 minute period and with stirring. The solution thus obtained was then stirred for 3 hours at -15 to 0 ° C. Follow the same work-up scheme as in Example 2, dissolve the dried residue (500 mg) in benzene and chromatograph it in a column of silica and Celite (85:15) with dimensions 21 x 2.5. The column was eluted with a gradient system consisting of 300 ml of benzene in the mixing chamber and 300 ml of ethyl acetate on benzene in the reservoir flask. Fractions of 7 ml were collected. Fractions no. 25-36 (251 mg) consisted of the diacyl derivative (IIIe). In PMR analysis, two t-butyl groups were found at E§1, 21 and 1.32, ester-methoxy at δ 3.66 and a prouon at S 5.25 (da, J = 3.5, w. Fractions no. 55 -575 (264 mg) consisted of IIIf, i.e. the desired product, in PMR analysis only one t-butyl group was found, namely at δ 1.30, ester-ocH at δ 3.67, a procon at about 4 (broad OH) and a proton at J4,38 (dd, J = 3,5 7), which results were consistent with IIIf. There was no trace of the isomeric enol-? S1s9e2e4 ester derivative.

Example 5. Preparation of the mono-enol benzoate ester.1 E »CO CH 2 ('\, // \\ í /' 2 3 \ 'II Hd§ * * ö t-co-cl o-co-t) ~} cH3cH2 ) 3N CV //, / ~ \\\ (/, / ^ \\\\ ///, OQCH3 IIIg Hof * * b To a solution cooled to -11 ° C and stirred by 102.4 mg (0.4 mmol) of the hydroxide ion methyl ester III and 0.112 ml (about 0.84 mmol) of triethylamine distilled over calcium hydride in 8 ml of tetrahydrofuran (under N2) were added 0.046 ml (0.4 mmol) of benzoyl chloride within minutes. The resulting solution was stirred. minutes at -10 ° C.

4 ml of methanol were added, and the temperature of the solution was allowed to rise to room temperature; then the solution was poured into 60 ml of water. The resulting solution was extracted 4 times with 50 ml of ethyl acetate each time, and the combined extracts were washed successively with 0.1N HCl (10 ml), water (10 ml), saturated sodium bicarbonate solution (10 ml), the sodium bicarbonate washing liquid acidified and extracted with ethyl acetate; the extract was washed with a saturated sodium chloride solution and dried (MgSO 4); evaporation of the solvent gave unreacted hydroxide ion methyl ester (30 ml) II_7 and saturated sodium chloride solution (10 ml) and dried over MgSO 4. Evaporation of the solvent gave an eel oil having the following characteristics: PMH8j5.65 (s, 3H, ocH3); 84.48 (kv 13, gfc-oH); 87.70 (m, 3H) and 8.18 (m, 2H) of aromatic protons, m / e at 360; + δ / Za + 35 ° (C, 2.0 cHc15); λ max 241 nm (¿ 270 nm (s85oo). Hereby the product identified as Iïïg. Example 6. Preparation of the isopropyl enol ether. To 514 mg (2.0 mmol) of the hydroxide ion ester II was added 546 mg (4 mmol): (2003 and 5 mL (8.5 g, 50 mmol)). The mixture was heated for 24 hours under reflux, under an N 2 atmosphere. After cooling, the reaction mixture was diluted with Et 2 O and the ether layer was washed successively with water, NaHCO 3, water and saturated NaCl, then the solvent layer was dried. over Na 2 SO 4 and evaporated to dryness to give 560 mg of oily residue which was dissolved in isopropyl ether to give 316 mg (53%) of a product having the following characteristics: melting point <6 ° -6 ° -6 ° C; 259 nm (62 ° 60 ); PMR (c fl clj) 1,35 (d. A fi cfm fi); 55,65 (s, 3, óoocnjnëluæ (kv. 1, Cgo fl haïlußv cH. 5 JCH; 21 -! - '> (s, 1, Gå _); m / e 298; [Q] + 35.1 (C, 1.02 MeOH); this vi- \ cH D said that the product was IIIh. 731598241 17 e ~ as- Example 7. Preparation of the isoamyl enol ether. . \ Z. \ Z. \ / Oozc fl j \ _ II of Ho * §o _ IIIi To 121 mg of II and 287 mg of K2 CO3 in 15 ml of dry acetone was added to 2 ml of isoamyl iodide. After refluxing overnight, the reaction mixture was worked up in the same manner as in Example 5. The residue weighed 165 mg. In PMR analysis, an isopropyl doublet (.S0.95, J = 6HZ), a complex range, (¿"1.1 - 3.1), methoxy (5'3,65), multiplet (^ fo $ IgO - 4.5, about bra based on methoxy) and a broad doublet (¿'5.0 J = 6, 30% 1H, based on methoxy), about 4H in total in the whole range6 "4.0 -¿ "5,10. These values indicated that the following groups were present in the product: -OH, -OCH 2 -CH 2 CHMe 2 and OH-Go. According to the determination based on this, the product thus contained about 70% of the desired substituted C1-enol ether IIIi, which can be easily separated from the substituted C-3 enol ether by column chromatography, as described in Example 4.

Example 8. Reduction of mono-enol benzoate ester with "Red-Al". o -coe-o / ,, »\\\ w //,» \\\ v /, / COQCH3 Q \\ IIIg Hm OI 1) Red-Ai 2) nAo / HQO 731É982-4 18 J / O e0 < To a cooled (# 78 ° C) stirred solution of 50 mg (0.147 mmol) of mono-enol benzoate (IIIg) in 10 ml of dry tetrahydrofuran under N 2 was added "Red-A1" -1 solution (1.5M). The solution then obtained was stirred for a further 30 minutes at -78 DEG C. But 2 ml of ethyl acetate were added, and the temperature of the solution was allowed to rise to room temperature. The solution was poured into 40 ml of water and extracted with 4 x 30 ml of ethyl acetate, the ethyl acetate layer was washed with 10 ml of saturated sodium bicarbonate solution and 10 ml of saturated sodium chloride solution and dried over MgSO 4, an evaporation of 10 ml of this oil. acetic acid-water (75:25) The resulting solution was stirred for 24 hours at room temperature, the solvent consisting of acetic acid and water was evaporated under reduced pressure, the resulting oil was dissolved in 10 ml of ethyl acetate and washed. with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over MgSO 4. Evaporation of the solvent gave a yellow oil (about 25-30 mg).

Crystallization from ethyl acetate-Skelly B gave 20 mg of compound IV, which was identified by the following characteristics: Melting point 60-61%; [α] D 25 = +.17.82 ° (c, 0.49 meon »PMR (cDc113) 63.65 (5.3, coocnj), 54.93 (m, 1, gc-oH), 57.25 (m, 1, vinyl-rn; Uvx 2:25 aaanm (s 8400) cD 231 nm e -9.9 ° x 10-3 (meon). - Example 9. Reduction of the isopropyl-enol ether with Red-Al O- ll.

/ \ / C ° 2 ° H5 D IIIh \ \\ H °° 0 1) Red-Ai 2) HQAc / H20 Q (_ «/ ^ \\\, // f °° 2 ° H§ IV

Claims (7)

To 125 mg of the isopropyl enol ether IIIh (0.1 μM mmol) in 10 ml of THF, with stirring at -7800 under N 2 atmosphere, were added dropwise, within 7 minutes, Ä portions (each 1.1 ml) of a 1.5M benzene solution of Red-Al. The reaction mixture was stirred for 5 minutes at -7800, then 2 ml of acetic acid were added. The temperature of the reaction mixture was allowed to rise to room temperature, after which it was evaporated to dryness. Then 10 ml of 75% acetic acid solution were added and stirred for 24 hours. The acetic acid water was evaporated under pressure. The oil then obtained was dissolved in 25 ml of ethyl acetate and washed with saturated NaHCO 3 and NaCl solutions, after which it was dried over MgSO 4. Crystallization of the residue from ethyl acetate-Skelly B gave 60 mg of compound IV, which was identified by the following characteristics: Melting point 606100; Å + 7 than + 17.820 (C, 0.49 MeOH); UvÅ 222 nm (6 81:00); cD 231 nm e = -9.9 ° x 10'3 (MeoH). The conversion of the compounds of the present invention, namely 2- (6-carbalkoxyhexyl) -N (§) -hydroxy-cyclopentene-2-enones, into prostaglandin or prostaglandin-like compounds can be carried out in accordance with those of Charles. J. Sih et al. described procedures 13. Amer. Chem. Soc, 23: 3643 (May 17, 197227. If one has thus come so far as to obtain the above-mentioned stereospecific compound, this can very easily be converted into prostaglandins or prostaglandin-like compounds while maintaining the desired stereospecificity. Attention requirements A process for the preparation of a 2- (6-carbalkoxyhexyl) -H (§) -hydroxy-cyclopent-2-enone of the formula OH z - \ '~. / L, \\ - »ff I H0-- wherein above and hereinafter R represents an alkyl group having 1H carbon atoms, characterized in that a) a) (2- (6-carbalkoxyhexyl) -N (5) -hydroxycyclopentane-1,5-dione of the formula Reacting either with an alkyl iodide of the formula R 'I wherein above and hereinafter R' represents isoamyl, isopropyl or pivalyl, to form a C1 and a C3 enol ether of formula N ORV r Z gš // ß 1 // h J /, // co2R R HO / s O _ »nresp. m »or also with an acid chloride of the formula R" coc1 wherein above and hereinafter R "represents an alkyl group having 1-6 kb atoms or phenyl, to form a C1 and a C3 enol ester of the formulas resp. I) co R i _, / "'\ _ /' \ -__ / 2, '- n HO OCOR b) separates the C1 enol ether or ester from the C3 enol ether or ester, e) reduces the separated substituted The C1-enol ester or -ether, and d) recovers the 2- (6-carbalkoxyhexyl) -4 (§) -hydroxy-cyclopent--2-enone from the reaction mixture. 2. ' Process according to Claim 1, characterized in that the enolysis in step a) is effected by reacting the dione with pivaloyl chloride. 3.; A process according to claim 1, characterized in that the enolysis in step a) is effected by reacting the dione with isoamyl iodide. 4. A process according to claim 1, characterized in that the enolysis in step a) is effected by reacting the dione with isopropyl iodide. " 5. A process according to claim 1, characterized in that the enolysis in step a) is effected by reacting the dione with benzoyl chloride. Process according to Claim 1 or 2, characterized in that the enolization in step a) is effected by reacting the dione with acetyl chloride. Process according to Claim 1 or 2, characterized in that the reduction in step c) is effected by the ester resp. ether brine gas to react with sodium dihydro-bis (2-methoxyethoxy) aluminate. fl ,,,. ~ f f PRESENTED PUBLICATIONS: _______________