IL41305A - Method for preparing prosta-glandins of the a,e,f and 11-deoxy-e series and certain novel 15-deoxoprostaglandins - Google Patents

Abstract

1419181 Prostaglandins; organolithium compounds WISCONSIN ALUMNI RESEARCH FOUNDATION 24 Jan 1973 [26 Jan 1972 22 May 1972 29 Sept 1972] 3660/73 Headings C2C and C2J The invention comprises a process for preparing prostaglandins of the Formula I wherein R is H, CH 3 or CH 3 CH 2 ; R<SP>1</SP> is H, C 1 -C 9 saturated hydrocarbyl, pentenyl, hexenyl or benzyl; X is H, OH, 2-tetrahydropyranyloxy, OR<SP>11</SP>, wherein R<SP>11</SP> is C 1 -C 5 hydrocarbyl or benzyl, OCOR<SP>111</SP>, wherein R<SP>111</SP> is C 1 -C 8 hydrocarbyl or benzyl, or OCH(R 1 )OR 2 , wherein R 1 and R 2 each are C 1 -C 5 hydrocarbyl; n is 0 to 5; B is -CH 2 CH 2 - or -CH=CH-; Q is OH, OCH 3 or OCH 2 CH 3 ; and the ring A is by reacting compounds of the Formula II wherein B and ring A are as defined above with the proviso that any free hydroxy groups in ring A are protected, and Q is OCH 3 or OCH 2 CH 3 with compounds of the Formula III trans-Li-CH = CH-C(R)(X<SP>1</SP>)(CH 2 ) n R<SP>1</SP> wherein X<SP>1</SP> is H or protected hydroxy as defined above, and if desired removing any protecting groups and/or ester groups, and if desired converting in known manner one ring A to another ring A, and the novel compound of the formula which are obtained by the above process. The following intermediates and starting materials are also prepared: ethyl 1,3-cyclopentadieneheptanoate, ethyl 3-hydroxy-5-oxo- 1 - cyclopentene - 1 - heptanoate ethyl 5- hydroxy - 3 - oxo - 1 - cyclopentene - 1 - heptenoate ethyl 5 - oxo - 3 - (2 - tetrahydropyranyloxy) - 1 - cyclopentene - 1 - heptanoate, ethyl 3,5 - dioxo - 1 - cyclopentene - 1 - heptanoate, isopropyl 3 - hydroxy - 5 - oxo - 1- cyclopentene - 1 - heptanoate, 1 - iodo - 4 - cyclohexyl - 1 - trans - butene, 1 - iodo - 5- cyclohexyl - 1 - trans - pentene, 1 - iodo - 6- cyclohexyl - 1 - trans - hexene, 1 - iodo - 7- cyclohexyl - 1 - trans - heptene, 1 - iodo - 8- cyclohexyl - 1 - trans - octene, 1 - iodo - 5- phenyl - 1 - trans - pentene, 1 - iodo - 6 - phenyl- 1 - trans - hexene, 1 - iodo - 7 - phenyl - 1- trans - heptene, 1 - iodo 8 - phenyl - 1 - transoctene and 1 - iodo - 9 - phenyl - 1 - transnonene. 1 - Lithio - 1 - trans - octene and 1 - lithio- 3 - (1 - ethoxyethoxy) - trans - 1 - octene are obtained by reacting lithium powder in diethyl ether with solutions of 1-iodo-1-trans-octene and the 3 -(1 - ethoxyethoxy) - 1 - iodo - 1- trans-octene respectively. Pharmaceutical compositions contain the above novel compounds and pharmaceutically acceptable carriers or diluents. The compounds possess prostaglandin-like activities. Reference has been directed by the Comptroller to Specification 1,377,258 also Reference has been directed by the Comptroller to Specifications 1,314,292, 1,314,291, 1,282,661 1,198,071, 1,097,533, 1,097,157 and 1,040,544. [GB1419181A]

Description

-15-1 ,1 -»0fiKm-tl-iF,B,A :.-! -.-"-'tiie 6od for preparing prostagl ndins of the A,E>F and ll-dsoxy-E series and certain fcovel 15-deoxoprost3glandins WISCONSIN ALUMNI RESEARCH FOUNDATION C. 39415 This invention relates to prostaglandins and to intermediates used in the manufacture of prostaglandins and to methods for making such intermediates and prostaglandins.

The prostaglandins are cyclic, oxygenated fatty acids based on the prostanoic acid skeleton and elicit widespread physiological responses, for example, in the cardiovascular, nervous, reproductive, renal and gastric systems of animals, including man, even at extremely low concentrations and amounts . Individual prostaglandins can manifest qualitatively different activities despite the commonality, of the carbon skeleton of the various compounds. (For a comprehensive discussion of the prostaglandins, including nomenclature, methods of preparation, and physiologic activity see Annals of the New York Academy of Sciences, Vol, 180, April 30, 1971 - a compilation of papers presented at a conference entitled Prostaglandins, held by the New York Academy of Sciences on September 17-19, 1970.) At the present time the supply of prostaglandins is limited. The total chemical syntheses heretofore suggested involve long and tedious steps and produce only minute quantities of the desired compounds. Derivation from natural sources is also not - la - feasible because of the severe limitation, on the supply of s sources, the consistency of their availability and the difficulties in extracting the desired compounds and obtaining them in significant amounts.

It is the principal purpose of this invention to overcome these problems by providing a relatively simple and straightforward process for preparing, in good yield, prostaglandins which exhibit prostaglandin-like activity or which can function as intermediates in the preparation of known prostaglandins.

The invention thus provides a new process for the preparation of compounds of the general formula: wherein R is hydrogen, a straight or branched-chain alkyl group containing from 1 to 5 carbon atoms, pentene group or a cyclohexyl group; X is hydrogen, hydroxy, tetrahydropyran-2-yloxy, a-ethoxy- ethoxy or a group OR" wherein R" is an alkyl group comprising from 1 to 5 carbon atoms, the benzyl group or the acetyl group and II III IV V which comprises reacting a compound of the formula in which ALK is lower,alky1, Rx is oxygen (keto)and R2 is with a compound of the formula in which R and X are as defined above , The novel process of the invention is illustrated in the following Examples and reaction diagrams.

Preparation of dl- 15-deoxo prostaglandin E Example 1 The Roman numeral designations followed specific compounds recited in this Example are identical with like designations in the schematic of the process set forth at the end of this Exa ) e. A solution of CH3Li(l„95 , 0.65 mole, 333 ml.) was added under nitrogen to a magnetically stirred solution of freshly distilled cyclopentadiene (60 ml., 0.68 mole) in dry tetrahy-drofuran (THF) (550 ml.) with ice bath cooling. To this resulting white suspension ethyl 7-bromoheptanoate (120 g., 0.54 mole) was added dropwise over a period of 1/2 hour. The mixture was allowed to warm to room temperature and stirred for 3 hours „ The resulting clear solution was poured into water and extracted with ether (3:1). The extract was washed twice with water, once with saturated brine, dried (MgSO^) and evaporated at room temper ture. This process gave almost pure 2-carboethoxyhexyl-cyclo- penta-1 ,4-diene (I).

The crude diene (I, 119 g„, 0.54 mole) from the last reactio was dissolved in ethanol (6:1). This was cooled to -10°C„ and to this chilled solution 30% hydrogen peroxide was added (125 G., 1,1 mole). To this mixture a solution of potassium hypochlorite (840 ml., 1.15 mole, 1.37 N solution) was added dropwise over a period of 2 hours. After stirring at -10°C. for an additional hal hour, the reaction mixture was made acidic with 2 N HC1 and ethanol was removed on a rotary evaporator. The residual oil was diluted with water and extracted with ether (3:1). The extract was washed with water, saturated brine solution, dried (MgSO^) and stripped off the solvent to yield a yellow oil (120 g.).

The yellow oil (20 g.) was chromatographed over a silicic acid-Celite (85:15) column (1-1/2 x 25"). The column was washed with two volumes of benzene-ethyl acetate (8:2"). The desired 2- (6 'carboxyethoxyhexyl) -4-hydroxy-cyclopent-2-en-l-one (1.5 g.) (II) was eluted from the column with 35% ethyl acetate in benzene while the positional isomer, 2- (6 ' -carboethoxyhexyl) ~l-hydrox¾L (cyclopent-2-en-4-one (5 g.) (Ill) was eluted from the colunui ^ with 45% ethyl acetate in benzene.

Compound II (1 g. ) was purified by rechromatography on another silicic acid-Celite (85:15) column (3/4 x 16"). The column was eluted with a gradient system consisting of 400 ml. of benzene-ethyl acetate (95:5) in the mixing chamber and 400 ml. of benzene-ethyl acetate (65:35) in the reservoir. 7 ml. fractions were collected. Fractions 53-94 were pooled and evaporated to dryness to yield 884 mg. of II which exhibited the following characteristics: 2220 A..(elO, 000) ; λ^01 2.90, 5.72 and . IUcU ITlcU 5.87μ; nmr (CDC13) 61.21 (t, 3, J = 6.7 HZ, CHj), 64.13 (q, 2, J = 6.7 HZ, CH3CH2), 64.93 (m, 1, H-C-OH), 67.23 (m, 1 vinyl H) ; molecular ion at m/e.254.

Similarly Compound III (1 g.) was repurified by chromatography over a silicic acid-Celite (85:15) column (3/4 x 15").

The column was eluted with gradient system consisting of 500 ml. of benzene -ethyl acetate (95:5) in the mixing chamber and 500 ml. of benzene-ethyl acetate (60:40) in the reservoir; 7 ml. fractions were collected. The desired compound, III, resided in fractions 134-149 which were pooled to yield 798 mg. of III which exhibited 9 the following characteristics: max 2240 A (ε13,500); nmr (CDC13) 61.22 (t, 3, J = 6.7 HZ , CH^) , 64.13 (q, 2, J = 6.7 HZ, (CH3CH2), 64.88 (m, 1, J = 6 and 2.5 HZ, H-C-OH), 65.98 (m, 1, vinyl H); λ^01 2.92, 5.77 and 5.91y; molecular ion at m/e 254.

Example 2 Preparation of the Tetrahydropyranyl ether (IV) 1 drop of concentrated hydrochloric acid was added to a mixture of 3.2 g. (13.3 mmoles) of the hydroxy ester (II) and 3.28 g» (~40 mmoles) of dihydropyran. The solution was shaken in order to effect mixing and was allowed to become warm and t £ allowed to stand at room temperature for 16 hours. The solution was rapidly diluted with ether. The resulting ether solution was washed successively with saturated sodium bicarbonate and saturated sodium chloride solutions and dried over magnesium sul fate. Evaporation of the ethereal solution yielded a yellow oil, wt: 4.557 g. which is shown by mnr analysis to be the required product. This oil was chromatographed on a silicic acid-Celite (85:15) column (1-1/2 x 16"). The column was eluted with a gradient system consisting of 50,0 ml. of benzene in the mixing flask and 500 ml. of benzene- ethyl acetate (85:15) in the reservoir flask and 7 ml. fraction were collected. Fractions 68-120 were ooled and evaporated to dryness to give 2.7 g. of 2- (6 ' -carboethoxyhexyl) -4-tetrahydropyranyloxy cyclopent-2-en-l- one (IV) which exhibited the following characteristics: ^max 1110 A (ε9,500); ^οΧ 5.73, 5.82 and 9.6ΐμ; nmr (C0C13) molecular ion at 338.209310 (theory for CigH3()05> 338.212530).

Example 3 A solution of tri-n-butylphosphine-copper (I) iodide complex (1.6127 g.) in 21 ml. of dry diethyl ether was treated with 34 ml. of 0.242 M solution of 1-1ithium- 1-trans - etene in ether at -78°C. under a blanket of nitrogen. After stirring at -78°C. for 30 minutes, 1.33 g. of the tetrahydropyranyl ether derivative (IV) in 25 ml. of dry diethyl ether was added dropwise to the yellow vinyl copper solution. The solution was allowed to warm to 0°C. (ice-bath) and stirred at this temperature for 1.5-2 hours. The reaction mixture was allowed to warm to room temperature and 28 ml. of a 20% aqueous ammonium chloride solu extracted three times with ether. The combined ether extrac^ were washed twice with a saturated sodium chloride solution and dried over magnesium sulfate. Evaporation of the ethereal extract afforded a reddish yellow oil. This oil was dissolved in 10 ml. of acetic acid-water (65:35) and tetrahydrofuran in the ration of 1 to 0.1 ml. and was stirred at 30°C. overnight according to the procedure of E.J. Corey, T.K. Schaaf, W. Huber, U. Koelliber and N. Weinshenker, J. Amer. Chem. Soc . , 92_: 397 (1970). The solvent was removed and the oily product was chroma-tographed over a silicic acid-Celite (85:15) column (3/4 x 14").

The column was eluted with a gradient system consisting of 400 ml. of benzene in the mixing chamber and 400 ml. of benzene- ethyl acetate (75:25) in the reservoir. 7 ml. fractions were collected. Fractions 33-48 afforded 155 mg. of ultraviolet positive material which had the following characteristics: nmr (CDClj 61.21 (t, 3, J = 6.7 HZ, CH3 , 63.23 ( m, 1, H at C-12), 64.13 (q, 2, J = 6.7 HZ, CH3CH2 , 65.62 (m, 2, vinyl H at C-13 and C-14) , 66.17 (m, 1, H at C-10), 67.49 (m, 1, H at C-ll) m/e at 348; 2170 A in (εΙΟ,ΟΟΟ), and was identified thereby as dl 15-deoxo PGA^ ethyl ester.

Fractions 65-100 were pooled and evaporated to dryness to yield 717 mg. of a material having the following characteristics: nmr (CCl^, 100 mHZ) 61.21 (t, 3, J = 6.7 HZ, CHj , 64.13 (q, 2, J = 6.7 HZ, CH3CH2), 64.20 (m, 1, H-C-OH), 65.28 (d of d, J12»13 7 HZ, J13>14 = 16 HZ - C13H=), 5.58 (d of t, ^13,14 » 16 HZ, J14»15 = 6 HZ» ¾Ci4H")i ir (Nujol) 962 cm'1 (trans CH=CH) ; molec lar ion at m/e 366.28145 (theory for ¾Η38°4» 366.27699) and which was determined to be dl- 15 -deoxopros taglandin E^ ethyl ester (VI.) The ester (VI) can be readily converted to dl-15-deoxo l^GEj (VII) by methods which are well known in the art, such as, for example, by exposing it to the action of an esterase-producing microorganizm. An example of the microorganism- induced conversio is set forth below.

Example 4 To 15 g. of Red Star dry yeast, dissolved in 500 ml. of 0.1 M phosphate buffer, pH 7.0 was added 500 mg„ of dl-15-deoxo-prostaglandin E^ ethyl ester (VI) in a two liter Erlenmeyer flask The reaction mixture was incubated on a rotary shaker at 25°C. for 13 hours. The reaction mixture was then acidified to pH 2.5 with 5 N HC1 and extracted with three volumes of ethyl acetate three times. The combined ethyl acetate layer was dried over sodium sulfate and evaporated to dryness. The residue was chroma tographed over a silicic acid-Celite (85:15) column (9/16 x 10"). The column was eluted with a gradient system consisting of 400 ml of benzene-ethyl acetate (95:5) in the mixing flask and 400 ml. of benzene-ethyl acetate (1:1) in the reservoir flask; 7 ml. fractions were collected. Fractions 22-40 contained 202 mg. of recovered starting material, VI, whereas fractions 41-85 were pooled to yield 137 mg. of dl-15-deoxoprostaglandin E^ (VII) [nmr (CDC13, 100 m HZ) 64.08 (q, 1, H-C-OH) , 65.29 (d of d, 15 HZ, J14»15 = 6 HZ, =ei4H-); molecular ion at m/e 338.23891 (theory for <½0Η3404, 338.24569)].

Alternative to the procedure of Example 1, the mixture of hydroxycyclopentenones obtained from oxygenating the alkylated cyclopentadiene can be treated as follows in lieu of chromato-graphically separating the said mixture.

Example 5 7 7 g. of the oily mixture of hydroxycyclopentenones was dissolved in 700 ml. of acetone and cooled in ice bath. To this solution was added 20 ml. of Jones reagent (chromic oxide and sulfuric acid in water) dropwise (1 ml. per minute) under stirring. After 30 minutes ? 15 ml. of absolute methanol was added o destroy excess Jones reagent. The mixture was diluted with 500 ml. of water and evaporated to 700 ml. The aqueous layer was extracted with 250 ml. of ethyl ether three times. The combined ether layer was washed with J^CO^, dried over Na2S0 and evaporated to dryness, to yield 4 g. of an oily residue. The residue was chromatographed over a column (1-1/2 x 16") containing silicic acid-Celite (85:15). The column was eluted with a gradient consisting of 500 ml. of benzene-ethyl acetate (90:10) in the mixing chamber and 500 ml. of benzene- ethyl acetate (7:3) in the reservoir flask; 7 ml. fractions were collected.

Fractions 128 - 141 contained a material having the following characteristics: m.p. 43-45°C; nmr (CDClj) 61.21 (t , 31 J = 6.7 HZ, CH3) ,' 62.83 (S, 2, 10-CH2), 64.13 (q , 2, J = 6.7 HZf CH3CH2) 67.0 (t , 1, J = 1 and 1.5 HZ, Vinyl H) ; UV (methanol) o Amax 2320 A Cel2 s 800) ; m/e at 252, which was identified as 2- (6,-carboethoxYhe xyl-cyclopent-2-en-l,4-dione VIII.

This dione was then reduced as follows: A solution of 220 mg. (1 mmole) of freshly distilled aluminum isopropoxide (bp 130-140/7 mm) in 10 ml. of anhydrous isopropyl alcohol (freshly distilled over CaH2) was heated to reflux and 100 mg . (0.4 mmole) of the diketone (VIII) in dry isopropyl alcohol (1.5 ml.) was added by syringe over a period of 15 minutes.

The isopropyl alcohol was distilled slowly through a short path distillation apparatus over a period of 2 hours keeping the ^ volume in the reaction flask constant, by addition of fresh iso-propyl alcohol. The remaining alcohol was removed on a rotary evaporator.1 Ether (20 ml.) and water (5 ml.) were added and the mixture was acidified with 2 N HC1. The aqueous layer was extracted twice with ether. The combined ethereal layers were washed with water, dried and evaporated to afford a yellow gum (110 mg.).

The gum was dissolved in a benzene-ethyl acetate mixture (8:2 volume ratio) and chromatographed over a silicic acid-Celite (85:15) column (1-.1/2 x 25") . The column was washed with two volumes of benzene- ethyl acetate (8:2) and the desired 2-(6'car-boisopropoxyhexyl) -4-hydroxy-cyclopent-2-en-l-one (II) was eluted from the column with 35% ethyl acetate in benzene.

Following elution and recovery of the isopropyl ester corresponding to compound II, the procedure of Example 1 was follo in subsequent steps beginning with the preparation of the tetra-hydropropanyl ether (IV) through the recovery of dl-deoxoprosta-glandin E^.

Following is a single schematic diagram including the processe as described in the foregoing Examples.

VI Baker's IX Yeast VII Example 6 In the preceding Examples the 1-lithium-l- trans -octene *" reactant was made as follows: In a three-necked round bottom flask equipped with a mechanical stirrer (wire blade) and pressure equalizing dropping funnel was placed 4-6 molar equivalents of fine lithium powdeT and dry diethyl ether (2 ml/1 mmole of vinyl iodide) freshly distilled over lithium aluminum hydride. A blanket of argpn was maintained at all times. To this rapidly stirred mixture, which was cooled in an ice-bath, was added 1 molar equivalent of 3-hydroxy 1-iodo-l- trans -octene (vinyl iodide) in dry diethylether (2 ml/1 mmole of vinyl iodide).

After a few drops. of the vinyl iodide in ether was added, a Gilman test was performed. If the test was positive, the addition of the vinyl iodide was continued. If the test was negative, the addition of the vinyl iodide was stopped and the rapid stirring of the lithium solution continued. The Gilman test was performed at various intervals. When a positive test was obtaine the addition of the vinyl iodide was recommended. The vinyl iodide solution was added over 2 hours. The solution was stirred with ice-bath cooling for a further 4 hours. The solution of the vinyl lithium was transferred to a storage bottle under argon through a glass wool filter (to filter out any unreacted lithium) . Before use the vinyl lithium was titrated with an HCl solution to determine concentrate of the vinyl lithium solution.

The vinyl iodide reactant in the above described process for making vinyl lithium was prepared in accordance with the general procedure described by G. Zweifel et al. , J. Amer.

Chem. Soc. 89, 2753 (1967) and as described below. 2 molar equivalents of diisobutyaluminum hydride were added to 1 molar equivalent of l-octyn-3-ol in dry heptane (40 ml/100 mmoles of l-octyn-3-ol) while maintaining the temperature below 40°C. When the exothermic reaction had subsided, the reaction mixture was heated at ca 50°C. for 2.5 hours. The heptane was then removed under reduced pressure (0.2 mm Hg) and the residue obtained was diluted with dry ' tetrahydrofuran (40 ml/100 mmoles of diisobutylaluminum hydride). To this solution cooled to— 50° was slowly added a solution of 2 molar equivalents of iodine in dry tetrahydrofuran (40 ml/100 mmoles of iodine) while maintaining the temperature at about -50°C. The iodine color disappeared at the beginning and a gas, probably hydrogen, was given off. After about 1 molar equivalent of iodi was added, the gas evolution ceased and the iodine color disappeared more slowly, the solution taking on a red color. After all the iodine had been added, the Reaction mixture was allowed to warm up to room temperature, whereupon the diisobutylalane was decomposed at 20-30°C. by the dropwise addition of 20% sulfuric acid. When the isobutane evolution had diminished, the reaction mixture was poured into ice - 201 sulfuric acid. The reaction mixture was extracted four times with pentane and the combined organic extract was washed successively with sodium thiosulfatej saturated sodium bicarbonate and saturated sodium chloride solutions, and dried over magnesium sulfate. Evaporation of the dried extract gave a yellow oil. The nmr spectrum (CDClj) of the product after all volatile material had been distilled off, showed that some of the saturated iodide, 3-hydroxy -1-iodo-octane was present.

The product was further treated to remove any 3-hydroxy-l -iodo-octane and possible diiodo-3-hydroxyoctane present. To accomplish this the reaction product was mixed with an excess (3-5 times) of triethylamine and the mixture heated at ca 94° 1 for 20 hours. The excess triethylamine was evaporated off aifi. water was added to the residue. The mixture was shaken for some time. Most of the black oily residue dissolved in the water and the total mixture was extracted five times with pentane. 5 The combined pentane extract was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, sodium thiosul- fate, saturated sodium bicarbonate and saturated sodium chloride solutions and dried over magnesium sulfate. The product obtained after evaporation of the pentane was chromatographed on silica 10 gel and elution with benzene produced pure 3-hydroxy-l-iodo-l -trans-octene,wt : 12.5 g. (24.6%).

As an alternative to the procedure of Example ,6 above, the hydroalumination can be carried out by complexing the hydroxy function in l-octyn-3-ol with trisobutylaluminum to give an 15 aluminum alkoxide and isobutane gas, one molar equivalent of diisobutylaluminum hydride then being added to form the vinyla- lane. This procedure, which is set out with greater specificity in Example 7 below, offers certain advantages over the procedure of Example 6, above, in that the quantity of undesired l-iodo-3 20 -hydroxyoctane and diiodo-3-hydroxyoctane formed in the reaction mixture is reduced and the desired product, 3-hydroxy-l-iodo-l -trans-octene, can be obtained in higher yields by vacuum distillation.

Example .7 25 To 1.26 g. (0.01 moles) of l-octyn-3-ol in 8 ml. in dry heptane was added dropwise 6.18 ml. (0.03 moles) of triisobutyl- aluminum at 10-15°C. ; 1.82 ml. (0.01 moles) of diisobutylaluminum hydride was then added and the reaction mixture was heated at ·' . ., '.·· ..: rl4- ..· . ' .·.· ..·-- .' r 1 50-55°C. for 2 hours. The solution was then cooled and the heptane removed under reduced pressure. The residue obtained was diluted with 12 ml. of dry tetrahydrofuran. After cooling the solution to -50°C, 10.26 g. (0.04 moles) of iodine in 16 ml. of S dry tetrahydrofuran was added dropwise. The dark solution was warmed to room temperature and the alane was decomposed at 20-30°C. with 20% H2S04. After the isobutane evolution had diminished, the reaction mixture was poured into ice and extracte four times with pentane. The pentane extract was washed succes-0 sively with saturated NaHCO^ , sodium thiosulfate, saturated NaHCOj and saturated NaCl solutions. After drying the pentane over MgSO^ , it was evaporated to give a dark oil. To remove the iodo-3-hydroxyoctane, the mixture was heated for 16 hours at 90°C. with 0.005 moles of triethylamine.. The excess triethylamine :: was evaporated off and water was added to the residue. Most of the dark oily residue dissolved in the aqueous layer and the total mixture was extracted with pentane. The pentane extract was washed with dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride solutions and dried over magnesium , sulfate. After evaporation of the pentane, the residue was distilled in vacuo to yield pure 3-hydroxy-l-iodo-l- trans -octene (40-50% molar basis). Some l-octyn-3-ol was recovered.

A. ^Ohe-step reduction 2 molar equivalents of diisobutylaluminum hydride was added to ^ 1 molar equivalent of propargyl alcohol in dry heptane (40 ml/100 m moles of propargyl alcohol) while maintaining the temperature below 40° C. When the exothermic reaction had subsided, the xeaction mixture was heated at about 50° c. for 2.5 hours. The heptane was then removed under reduced pressure (0.2 mm Hg) and the residue obtained was diluted with dry tetrahydrofuran (40 ml/100 m moles of diisobutylaluminum hydride) . To this solution, cooled -to —50° C. , was slowly added a solution of 2 molar equivalents of iodine in dry tetrahydrofuran (40 ml/100 m moles of iodine) while maintaining the temperature at about -50° C. The iodine colour disappeared at the beginning and a gas (probably hydrogen) was given off. After about 1 molar equivalent of iodine was added, the gas evolution ceased and the iodine colour disappeared more slowly, the solution taking on a red colour. After all the iodine had been added, the reaction mixture was allowed to warm up to room temperature, whereupon the diisdbutylalane formed in the reaction was decomposed at 20-30° C. by the dropwise addition of 20# sulfuric acid. When the isobutane evolution had diminished the reaction mixture "was poured into ice — 20$ sulfuric acid. The reaction mixture was extracted four times with pentane and the combined organic extract was washed successively with sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride solutions, and dried over magnesium sulfate. Evaporation of the dried extract gave a yellow oil.

•The nmr spectrum (CDCl^) of the product after all volatile material had been distilled off, showed that some of the saturated iodide, ; 3 hydroxy-l-iodo-propane -was present. j propane present. To accomplish this the reaction product was mixed with an excess (3-5 times) of triethylamine and the mixture heated at about 94° C. for 20 hours. The excess triethylamine was evaporated^ off and water was added to the residue. The mixture was shaken for some time. Most of the black oily residue dissolved in the water and the total mixture was extracted five times with pentane. The combined pentane extract was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride solutio s and dried over magnesium sulfate. The product obtained after evaporation of the pentane was chromatographed on silica gel and elution with benzene produced pure 3-hydroxy-l-iodo- rans-propene (20-30% molarbasis) as evidenced by the following physical data: 3-hydroxy-l-iodo-l-tran3-propene- ir (fam 920, 960, 1005, 1070 1170, 1235, 1610, 2δ"δ0 2925, and 31C0 to 36C0 cm"1 (broad nmr^3. 1 (IK, broad S OH), 4.07 {2H,d,]=4,5HZ CH20H), 6. 34 - | (lH,d,j=15HZ &- H), and 6.73 ppm (lH.d of t,J=15, 4.5HZ). . : Anal, calcd for C3K5IO C. 1959, H, 2. 72. Found: C, 19. 72, H, 2. 97. j A mixture of 5.82 ol (100 mmol) of propargyl alcohol (Aldrlch) and 80 ml of dry heptane was stirred under argon with Ice-bath cooling as 25 ml (121 nmol) of trllsobutylalumlnum (Ethyl Corp.) was added dropwlse at a rate such that the Internal temperature of the reaction mixture never went above 10°. A 22 ml (123 mmol) portion of dllsobutylalumlnum hydride (Ethyl Corp.) was then added, and the resultant solution was heated to 50-60° for 3 hr. Sovent was removed by distillation at 20 mm, care being taken to release the vacuum with argon. The residue was cooled to 0° and then slowly·diluted with 100 ml of dry tetrahydro- ' furan. The resultant solution was stirred at -78° under argon as a solution of 62 g of Iodine in 120 ml of dry tetrahydrofuran was added dropwise. The dark solution was allowed to come to room temperature, and then It was quenched by the slow-dropwise addition of 150 ml of 20X sulfuric acid. An ice-bath was used to keep the reaction mixture cooled to 20-30°. The resultant mixture was diluted with 250 ml of water and extracted with A x 250 ml of ethyl acetate.

The combined extracts were washed successively with saturated aqueous sodium bicarbonate, aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate again. It was dried and evaporated in vacuo to give a dark oil. This oil was dissolved in 25 ml of dry triethylamine and heated under argon at 85-95° for 23 hr. The excess triethylamine was removed by evaporation in vacuo. The residue was partitioned between ethyl acetate and 10Z HC1. The aqueous phase was extracted .three more times with ethyl acetate, and the combined extracts were washed with brine, dried (MgSO^) and evaporated in vacuo to yield 7.3 g of a dark oil. This crude product was distilled in vacuo to give 4.2 g (22.8Z) of pure 2_: b -115-120° (28 mm); nmr(CDCl3) £3.1(1H, broad e), 4.07(2H, d, J -4.5Hz), 6.34(1H, d, J - 15Hz) and 6.73 ppm(lH, d of t, J - 15, 4.5Hz); Ar(film) 920, 960, 1005, 1070, 1170, 1235, 1610, 2860, 2925 and 3100 to 3600 cm*"1(broad).

EXAMPLE 9 3-Hydroxy-l-iodo-l-trans-heptene A. One-step reduction 2 molar equivalents of diisdbutylaluminum hydride was added to 1 molar equivalent of ' l-heptyn-3-ol ' i in dry heptane (40 ml/100 m moles of l-heptyn-3-ol) while maintaining the temperature below 40° C. When the exothermic reaction had subsided, the reaction mixture was heated at about 50° C. for 2.5 hours. The heptane was then removed under reduced pressure (0.2 mm Hg) and the residue obtained was diluted with dry tetrahydrofuran (40 ml/100 m moles of diisobutylaluminum hydride) . To this solution, cooled to -50° C. , was slowly added a solution of 2 molar equivalents of iodine in dry tetrahydrofuran (40 ral/100 m moles of iodine) while maintaining the temperature at about -50° C. The iodine colour disappeared at the beginning and a gas (probably hydrogen) was given off. After about 1 molar equivalent of iodine was added, the gas evolution ceased and the iodine colour disappeared more slowly, the solution taking on a red colour. After all the iodine had been added, the reaction mixture was allowed to warm up to room temperature, whereupon the diisobutylalane formed in the reaction was decomposed at 20-30° C. by the-dropwise -- - addition of 20% sulfuric acid. When the isobutane evolution had diminished, the reaction mixture was poured into ice - 20j£ sulfuric acid. The reaction mixture was extracted four times with pentane and the combined organic extract was washed successively with sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride solutions, and dried over magnesium sulfate. Evaporation of the dried extract gave a yellow oil.

-The nmr spectrum (CDCl3) of the product after all volatile material had ' been distilled off, showed xJiat some of the saturated iodide\ 3-hydrbxyrl-.'·**"' iodo-heptane was presenti- heptane present. To accomplish this the reaction product was mixed with an excess (3-5 times) of triethylamine and the mixture heated at about 94° C. for 20 hours. The excess triethylamine was evaporated off and water was added to the residue. The mixture was shaken for some time. Most of the black oily residue dissolved in the water and the total mixture was extracted five times with pentane. The combined pentane extract was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride solutions and dried over magnesium sulfate. The product obtained after evaporation of the pentane was chromatographed on silica gel and elution with benzene produced pure 3-hydroxy-l-iodo-l-trans-heptene (20-30# molar basis) as evidenced by the following physical data: 3-hydroxy-l-iodo-l~&ans-heptene- ir (CCl4) 3620 (OH) 1600 (C-C) ! and 940 cm"1 (tran3 CH*CH), nmr cf4.05 (m, 1, 03H) and 6.51 ppm (m#2, C-l and C-2H). Anal, calcd for C7Hx310 C, 35.03; H. 5.42.

Found: C, 35.28; H. $7ύ5 B. . in 8 ml. in dry heptane was added drppwise 0.03 moles of triisobutylaluminum at 10-15° C. ; 0.01 moles of diisobutylalum nuia hydride was then added and the reaction -mixture was heated at 50-55°. C. for 2 hours. The solution was then cooled and the heptane removed under reduced pressure. The residue obtained was diluted with 12 ml. of dry tetrahydrofuran. After cooling the solution to -50° , 0.04 moles of iodine in 16 ml. of dry to room temperature and the alane was decomposed at 20-30° C. with 20$o R~S0A. After the isobutane evolution had diminished, the reaction mixture was poured into ice and extracted four times with pentane.

The pentane extract was washed successively with saturated sodium thiosulfate, saturated NaHCO^ and saturated NaCl solutions.

After drying the pentane over MgSO^, it was evaporated to give a dark oil. To remove the 3-hydroxy-l-iodo-heptane , the mixture was heated for 16 hours at 90° C. with 0.005 moles of triethylamine. The excess triethylamine was evaporated off and water was added to the residue. Most of the dark oil residue dissolved in the aqueous layer and the -total mixture was extracted with pentane* 3¾e pentane extract was washed with dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride solutions and dried over magnesium sulfate After evaporation of the pentane, the residue was distilled in vacuo to yield pure 3-hydr0xy-l-iodo-l-trans-heptene ! (40-50# molar -basis) . ί EXAMPLE 10 3-Hydroxy-1-iodo-1-trans-hexene A. One-step reduction . 2 molar equivalents of diisobutylaluminum hydride was added to 1 molar equivalent of l-hexyn-3-ol in dry heptane (40 ml/100 m moles of l-hexyn-3-ol) while maintaining the temperature below 40° C. When the exothermic reaction had subsided, the reaction mixture was heated at about 50° C. for 2.5 hours. The heptane was then removed under reduced pressure (0.2 mm Hg) and the residue obtained was diluted with dry tetrahydrofuran (40 ml/100 m moles of diisobutylaluminum hydride) . To this solution, cooled to -50° C. , was slowly added a solution of 2 mola equivalents of iodine in dry tetrahydrofuran (40 ml/100 m moles of iodine) while maintaining -the temperature at about -50° c. The iodine colour disappeared at the beginning and a gas (probably hydrogen) was given off. After about 1 molar equivalent of iodine was added, the gas evolution ceased ^ nd the iodine colour disappeared more slowly, the solution taking on a red colour. After all the iodine had been added, the reaction mixture was allowed to warm up to room -temperature, whereupon the diisobutylalane formed in the reaction was decomposed at ;20-30° C. by the dropwise addition of 20$ sulfuric acid. When the isobutane evolution had diminished "' he reaction mixture was poured into ice - 20# sulfuric acid. The reaction mixture was extracted four times with pentane and the combined organic extract was washed successively with sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride solutions, and dried over magnesium sulfate. Evaporation of the dried extract gave ¾ yellow oil.

■The nrar spectrum (CDClg) of the product after all volatile material had been distilled off, .showed that some of the saturated .iodide, :3-hydroxy-1-iodo-hexane '·"·. ··-■- - was present. hexane present- To accomplish this the reaction product was mixed with an excess (3-5 times) of triethylamine and the mixture heated at about 94° C. for 20 hours. The excess triethylamine was evaporated^ off and water was added to the residue. The mixture was sha en for some time. Most of the black oily residue dissolved in the water and the total mixture was extracted five times with pentane. The combined pentane extract was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride solutions and dried over magnesium sulfate. The product obtained after evaporation of the pentane was chromatographed on silica gel and elution with benzene ^produced-pure 3-hydrox^-l-iodo-l-trans-hexene (20-30$ molar basis) as evidenced by the following physical data: 3-bydroxy 1-iodo-l-trans-hexene- ir (CC14) 3620(OH). 1600 (C=C) - | and 940 em" 1 (trans CH=CH. nmr cf 4.05 (m, l, C-3 H) and 6. 50 ppm - j (m, 2, Ol and C-2 H). Anal, calcd for C6Hn 10 C, 31. 89; H, 4. 87. j Found: C, 31. 93; H. S.EoT" j B. Two-step reduction To 0.01 moles of l-hexyn-^-ol in 8 ml. in dry heptane was added dropwise 0.03 moles of triisobutylaluminura at 10-15° C. ; 0.01 moles of diisobutylaluminum hydride was then added and the. reaction mixture was heated at 50-55° C. for 2 hours. The solution was then cooled and the heptane removed tinder reduced pressure. The residue obtained was diluted with 12 ml. of dry tetrahydrofuran. After cooling the solution to -50° C. , 0.04 moles of iodine in 16 ml. of dry to room temperature and the alane was decomposed at 20-30° C. with 20¾ E SO.. After the isobutane evolution had diminished, the reaction mixture was poured into ice and extracted four times with pentane. f The pentane extract was washed successively with saturated NaHCO^, sodium thiosulfate, saturated NaHCO^ and saturated NaCl solutions.

After drying the pentane over MgS04, it was evaporated to give a . dark oil. To remove the 3-hydroxy-l-iodo-hexane , the mixture was heated for 16 hours at 90° c. with 0.005 moles of triethylamine. \ The excess triethylamine was evaporated off and water was added to the residue. Most of the dark oil residue dissolved in the aqueous layer and the total mixture was extracted Adth pentane. The pentane extract was washed with dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride solutions and dried over magnesium sulfate After evaporation of the pentane, the residue was distilled in vacuo to yield pure 3-hydroxy-l-i0do-l-trans-hexene (40-50 molar -basis) . 3-Hydroxy-l- odo-l-trans-pentene A. One-step reduction .2 molar equivalents of diisobutylaluminum hydride was added to £ 1 molar equivalent of l-pentyl-3-ol n dry heptane (40 ml/100 m moles of l-pentyh-^S-ol) while maintaining the temperature below 40° C. When the exothermic reaction had subsided, the reaction mixture was heated at about 50° C. for 2.5 hours. The heptane was then removed under reduced pressure (0.2 mm Hg) and the residue obtained was diluted with dry tetrahydrofuran (40 ml/100 m moles of diisobutylaluminum hydride).

To this solution, cooled to -50° c. , was slowly added a solution of 2 mola equivalents of iodine in dry tetrahydrofuran (40 ml/100 m moles of iodine) while maintaining the temperature at about —50° C. The iodine colour disappeared at the beginning and a gas (probably hydrogen) was given off.

After about ί molar equivalent of iodine was added, the gas evolution ceased and the iodine colour disappeared more slowly, the solution taking on a red colour. After all the iodine had been added, the reaction mixture was allowed to warm up to room temperature, whereupon the diisdbutylalane formed in the reaction was decomposed at 20-30° C. by the dropwise addition of 20$ sulfuric acid. When the isobutane evolution had diminishe ^the reaction mixture was poured into ice - 20<¾> sulfuric acid. The reactio mixture was extracted four times with pentane and the combined organic extract was washed successively with sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride solutions, and dried over magnesium sulfate. Evaporation of the dried extract gave a yellow oil.

The nmr spectrum (CDCl^) of the product after all volatile material had been, distilled off, showed that some of the saturated iodide, , 3-hydroxy-l- iodo-rpentine : *'<·· '·* *. i was present." . '. pentane present. To accomplish this the reaction product was mixed with an excess (3-5 times) of triethylamine and the mixture heatc at about 94° C. for 20 hours. The excess triethylamine was evaporated off and water was added to the residue. The mixture was shaken for some time. Most of the blacl oily residue dissolved in the water and the total mixture was extracted five times with pentane. The combined pentane extract was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride solutions and dried over magnesium sulfate. The product obtained after evaporation of the pentane was chromatographed on silica gel and elution with benzene produced pure 3-hydroxy-1-iodo-l-trans-pentene (20-30$ molar basis) as evidenced by the following physical data: Found: C.2S.47;H.4.*¾7T I Two-step reduction To 0.01 moles of l-pentyn-3-ol > * i 8 ml. in dry heptane was added dropwise 0.03 moles of triisobutylaluminum at 10-15° C. ; 0.01 moles of diisobutylaluminum hydride was then added and the reaction mixture was heated at 50-55° C. for 2 hours. The solution was then cooled and the heptane removed under reduced pressure. The residue obtained was diluted with 12 ml. of dry tetrahydrofuran. After cooling the solution to -50° C. , 0.04 moles of iodine in 16 ml. of dry tetrahydro uran was a e ropw se. e ar so u on was warmec to room temperature and the alane was decomposed at 20-30° C. with 20$ I^SO^. After the isobutane evolution had diminished, the reactionj^. mixture was poured into ice and extracted four times with pentane.

The pentane .extract was washed successively with saturated NaHCO^, sodium thiosulfate, saturated NaHC03 and saturated NaCl solutions.

After drying the pentane over MgSO^, it was evaporated to give a dark oil. To remove the 3-hydroxy-l-iodo-pentane , the mixture was heated for 16 hours at 90° C. with 0.005 moles of triethylamine.

The excess triethylamine ^ s evaporated off and water was added to the residue. Most of the dark oil residue dissolved in the aqueous layer and the total mixture was extracted with pentane. The pentane extract was washed with dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride solutions and dried over magnesium sulfate. After evaporation of the pentane, the residue was distilled in vacuo to yield pure 3-hydroxy-l-iodo-l-trans-pentene (40-50 molar basis) .

Example 11a , l-Iodo-3RS-hydroxy-3-cyclohexyl-l-trans-propene Preparation of l-cyclohexyl-2-prop¾3T-l-ol A 500 ml 3-necked, round -bottomed flask was fitted with a condenser, gas inlet tube, additional funnel, septum -and magnetic stirring was dried under nitrogen, then charged with 12. 0 g (0. 5 g atom) of magnesium turnings. Ethyl bromide (54 g, 0. 5 mol) was dissolved in 300 ml of THF and the solution added dropwise over 50 min, using external ice cooling to moderate the reaction. The reaction mixture was stirred for 1. 75 hr. at 25° C, then transferred over a 1. 75 hr. period into a stirred, saturated solution of acetylene in 200 ml of THF. Acetylene was continuously passed through the reaction mixture during the addition. After addition of ethyl magnesium bromide was complete, the acetylene inlet tube was replaced by a nitrogen inlet tube. A solution of 40. 4 g (0. 36 mol) of cyclohexane carboxaldehyde in 50 ml of THF was added dropwise over 0. 6 hr. with external ice cooling. The reaction mixture was stirred for 17 hr. at 25° C, then poured into saturated aqueous ammonium chloride and extracted with ether. The extracts were dried (MgS04), filtered and distilled to yield 20. 4 g of l -cyclohexyl-2-propyn- l -ol as a clear oil , bp 59. 0-69. 0° C, 0. 5 mm; NMR (CDCl- ) 8 0- 8-2. 2 (complex, 11 H) 2. 45 (d,J=2Hz, 1 HJ 2. 30 (broad S, 1 H) 4. le(m,l H); ir(CCl . ) 2. 8, 2. 95, 3. 05, 6. 9μ [ ir from HCA-Vol 1-p 1] . ~~ 4 Preparation of l- iodo- 3RS- hydroxy-3-cyclohexyl-l-trans-propene A solution of 1. 38 g (10. 0 mmol) of l-cyclohexy-2-propyn- l-ol in 4. 0 ml of heptane was stirred at 0° C under argon. Triisobutyl aluminum hydride (3. 96 g) was added dropwise, maintaining the internal temperature at 10-20° C. Diisobutyl aluminum hydride (7. 1 ml of a 1. 4 M solution in toluene) was added dropwise and the reaction mixture heated at 55-57° C for 2 hr. The heptane was removed by evaporation in vacuo. The reaction mixture was cooled to 0° C and a solution of 2. 54 g iodine in 12 ml THF added dropwise. When gas evolution ceased, the reaction mixture was allowed to warm to 10° C. Saturated aqueous ammonium chloride (50 ml) was added, maintaining the internal temperature at .5 30° C. The mixture was extracted with ethyl acetate. The extracts were washed . with saturated aqueous sodium bicarbonate, aqueous sodium Thiosulfate and brine, then dried (MgSO filtered and evaporated in vacuo to afford 1. 2 g of crude prod NMB (CDCl ) indicates starting materiaTand product in a 9: 1 ratio: 6. 2 (d,J=l5. ΟΗΖΛΗ) 6. 6 (dd,d=6, 15. ΟΗζ, ΙΗ) 2. 36 (d,J=2Hz, 1H).

The hydroalumination methods of the foregoing Examples are readily applicable to compounds having the formula H X where R and X are as defined above so as to produce the following iodo compounds: 3-hydroxy-l-iodo-l-trans-pentene 3-hydroxy-1-iodo-1-trans-hexene 3-hydroxy-l-iodo-4-methyl-l- trans-heptene 3-hydroxy-l-iodo-4-ethyl-l-trans-hexene 3-tetrahydropyran-2 ' -yloxy-l-iodo-l-trans-octene 3- (a-ethoxy-ethoxy) -1-iodo-l-trans-octene 3-benzyloxy-l-iodo-l-trans-octene 3-acetoxy-l-iodo-l-trans-octene 3-hydroxy-l-iodo-l-trans-l , 6-octadiene Of the compounds which respond to the above formula 1-octyn 3-ol is a preferred reactant. Other of the compounds responding to the said formula which find ready application include those inwhich X is an ether configuration which is susceptible to hydrolysis by mild acid, including cyclic ether, or where X is an ester configuration (for example 3-acetoxy-l-octyne) .

The aluminum complexing agent in each case will be chosen to provide the greatest possible yield of desired product. For example, it has been found that when 3-tetrahydro- pyran-2 * -yloxy-l-octyne , 3- (a-ethoxy) -ethoxy- octyne or 3-acetoxy-l-octyne are the compounds of choice for hydroalumination, the process described in Example 6 provides a better yield of the desired compound, 3-hydroxy-l- iodo-1- trans-octene , than does the procedure of Example 7. However, as is pointed out more specifically below, when diisobutylaluminum is used as the hydroalumination agent, it is essential to use that agent in the ratio of two molar equivalents to one molar equivalent of the particular compound which is being complexed. On the other hand, when triisobutyl- aluminum is used, as in the process of Example 7, such agent can be used in a molar equivalent ratio to the compound being complexed of 1:1 or greater.

The hydroalumination process as described in Example 7 above, and where diisobutylaluminum is used as the hydroalumination agent, is similar to the general procedure described by G. Zweifel et al., referred to above. There are, however, some major, and critical differences. With the 3- position substituted, compounds which must be used as the starting materials to produce the novel compounds of this invention, the Zweifel et al. process is inoperative. It is only when two molar equivalents of the hydroalumination agent, diisobutylaluminum hydride, are used - 29- - that the hydroalumination proceeds to produce the desired corn^ pounds. In addition, the treatment with triethylamine or other basic trialkylamines , such as, for example, trimethylamine , is essential to the elimination of undesirable by-products from the reaction mixture and to the production of the desired compound in essentially pure form.

The processes of this invention permit the ready recovery of the products thereof in the trans isomeric configuration, the preferable isomer for the preparation of physiologically-active prostaglandins or compounds having prostaglandin- like activity.

Pharmacological assays were conducted with dl-15-deoxoprosta glandin E^ using the guinea pig tracheal strip (smooth muscle) methods described by: J.W. Constant ine, Journal Pharmacy § Pharmacology, 17:3184 (1955); and R„ Patterson, Journ. Allergy, 2 165 (1958). dl-15-deoxoprostaglandin E.^ exhibited an ED50 concentration (effective dose giving 50% of maximum response) on - 6 -6 separate determinations of 1.4 x 10" M and 1.06 x 10 M indicating its pharmacological applicability in place of natural prostaglandins where smooth muscle controlling or responsive effects are being sought.

It will be evident to those skilled in the art that dl-15 -deoxoprostaglandin E^, can be functional!zed at the C-15 position to yield prostaglandin E^ using standard methods of allylic oxidation such as, selenium dioxide oxid tion, n-bromo -succinimide and silver acetate or n-bromo-succincimide and lead tetraacetate (see Fieser and Fieser, Reagents for Organic Synthesis, John Wiley § Sons, Inc.* 1967).

Also, the dl-deoxo PGA^^ series can be obtained by well known means, i.e. by treating dl-15-deoxo PGE1 with an acid or base to convert it to the PGAj^ series.

In addition, the 9-keto function in dl-15-deoxoprostaglandin E-j^ can readily be reduced by metal hydrides, such as sodium borohydride to yield a hydroxy function at the 9-position, giving rise to the PGFj^ series of prostglandins . Alternatively, the PGF^ series can be obtained by incubating dl-15-deoxoprosta- glandin with baker's yeast as described in Example 4 but , allowing the microorganism- induced conversion to proceed for a longer period of time without termination.

In the aforedescribed procedure vinyl lithium is reacted with a soluble form of copper to produce vinyl copper for reaction with the tetrahydropyranyl derivative. Forms of soluble copper other than tri-n-butylphosphine copper- iodide complex may be utilized for the production of the vinyl copper. For example, (n-Bu2S)2 Cu I is also suitable for such reaction.

Example 12 Preparation of Prostaglandin E^ Ethyl Ester In the following Example the reactant 3- (ct-ethoxy-ethoxy) - 1-iodo-trans-l-octene was prepared as follows: One drop of concentrated hydrochloric acid was added to a mixture of 1.53 g. (6 mmoles) of 3^hydroxy-l-iodo-trans-l-octene and 0.864 g (12 mmoles) of ethyl vinyl ether. The solution was mixed and allowed to become warm and allowed to stand at room temperature for 4 hours. The solution was rapidly diluted with diethyl ether. The resulting solution was washed with a saturated^ sodium bicarbonate solution and a saturated sodium chloride solution and dried over magnesium sulfate. Evapora- ^ tion of the ethereal solution yielded a yellow oil which was identified as 3- (ot-ethoxy-ethoxy) -1-iodo-l-trans-octene .

Into a 25 ml. three-neck round bottom flask equipped with a mechanical stirrer (wire blade) and pressure equalizing dropping funnel was placed 160 mg. (23 mmoles) fine lithium powder and 10 ml. dry diethyl ether (freshly distilled over lithium aluminum hydride). A blanket of argon was maintained at all times. To this rapidly stirred mixture which was cooled in an ice-bath was slowly added a solution of 652 mg. (2 mmoles) 3-(a-ethoxy- ethoxy) -1-iodo-trans-l-octene in 8 ml. dry diethyl ether over a period of 2 hours. (After about 0.5 ml. of this solution had been added a positive Michler's ketone test was obtained) . The reaction mixture was rapidly stirred for a further 3 hours .

The resulting vinyl lithium solution cooled to -10°C. 15°C (ice-salt bath) was siphoned through a glass wool filter into a solution of 196 mg. (0.5 mmoles) of copper iodide-tri-n -butylphosphine complex in 5 ml. dry diethyl ether cooled to -78°C. The resulting solution was stirred for 1 to 4 hours.

To this solution was added 170 mg. (0.5 mmoles) of 2- (6· -carboethoxyhexyl) -4-tetrahydropyranyloxy-cyclopent-en-l-one IV the preparation of which was accomplished as set forth in Example 1. This solution was allowed to warm to -15°C. (ice-salt bath) and stirred as the solution warmed from -15°C. to 0°C. over an hour. The solution was stirred at 0° (ice bath) for a further 2 hours and was then allowed to warm to room temperature. 15 ml. of a 20% aqueous ammonium chloride-ammonia solution of pH 8.1 was added and the resulting solution stirred. The upper ether solution was separated from the blue aqueous solution which ether extract was washed with a saturated sodium chloride solution and dried over magnesium sulfate. Evaporation of the ethe^ gave a dark red solution.

To remove the protecting tetrahydropyranyl and ethoxy-ethoxy ether groups from the product a mixture of the above crude product, 13 ml. of tetrahydrofuran was stirred at 37 °C. for 6 hours. The solvent was removed under reduced pressure and the product chromatographed on a silicic acid-Celite (85:15) column (3/4 x 12") . The column was eluted with 500 ml. of benzene- ethyl acetate (9:1) in the mixing flask and 500 ml. of benzene'- ethyl acetate (1:1) in the reservoir; 6 ml. fractions are collected. Fractions 97-110 were concentrated to dryness to yield 14 mg. of a material have the following characteristics: nmr (CDC13) 60.87 (t, 3, CH3 at C-20), 61.21 (t, 3, J = 6.7 HZ, CHj) , 64.13 (q, 2, J = 6.7 HZ, CH3CH2), 64.08 (m, 2 protons at C-ll and C-15), 65.65 (m, 2, vinylic protons at C-13 and C-14) , m/e at 382 (M+) ; which was identified thereby as 11,15-diepi PGE.^ ethyl ester. Fractions 111-136 were combined to yield 43 mg. of a material whose nmr spectrum were similar but the splitting pattern of the vinylic protons of which were different than 11 ,15-diepi-PGE^-ethyl ester and which, on thin layer chromatography (TLC) , developed in ethyl acetate-acetic acid-isooctane-water (110:20:50:100) was slightly more polar than 11, 15-diepi-PGE^ ethyl ester but slightly less polar than PGE^ ethyl ester. This material was identified as 15-epi-PGE^ -ethyl ester. Fractions 157-240 were pooled to give 53 mg. of PGE^ ethyl ester, whose nmr, mass spectrum and infrared spectrum were identical to aN known specimen of that material.

Also, TLC developed in the aforementioned solvent system showed it had the same mobility as the known specimen PGE^ ethyl ester.

The PGEj ethyl ester can be readily converted to PGE^ by methods well known in the art such as by exposure to the action of an esterase-producing microorganism such as baker's yeast.

Following is a simplified schematic of the process of this Preparation of dl-ll-Deoxoprostaglandin E^ Methyl Ester 3- (a-ethoxy -ethoxy)- 1- 1ithium- 1 -trans -octene was prepared as described supra. 326 mg. (1 mmole) of 3- (ct-ethoxy - ethoxy)-!- iodo- 1- trans -1 -octene in 4. ml. of ether was treated with 80 mg. of lithium powder in 5 ml. ether at 0°.

The resulting vinyl lithium ether solution was siphoned through a glass wool filter into 125 mg. (0.32 mmoles) of tri-n -butylphosphine-copper (I) iodide complex in 2 ml. dry diethyl ether at -78°C. (dry ice-acetone). This solution was stirred at -78°C. 20 minutes, whereupon 107 mg. (0.31 mmoles) of 2- (6 -carbomethoxyhexyl) -cyclopent-2-en-l-one in 2 ml. of ether was added. The reaction solution was allowed to warm to -10°C. and stirred at -10°-0°C. for 1 hour. Stirring was continued at 0°C for a further hour. 3 ml. of 20% aqueous NH^Cl/NH^ solution of pH 8.1 was added and the solution stirred until 2 clear layers were formed. The upper yellow organic layer was separated from the blue aqueous layer, which was extracted a further 3 times with ether. The combined ether extract was washed with a saturated sodium chloride solution and dried. Evaporation gave a dark red oil.

The oil (280 mg.) was chromatographed over a silicic acid -Celite (85:15) column (3/4 x 12"). The column was eluted with 400 ml. of benzene in the mixing chamber and 400 ml. of benzene -ethyl acetate (8:2) in the reservoir chamber. 6 ml. fractions were collected. Fractions 92-134 (53 mg.) were combined and treated with hydrochloric acid to remove the protecting group to yield, upon rechromatography, 30 mg. of a material having the following characteristics: molecular ion at 352 (M+) ; 281 (M-71), nmr 63.65 (3H, S, CH3), 4.0 (1H, m. carbinolic proton at C-15); 65.62 (2H, m, vinylic protons at C-13 and C-14) and which was identified as dl-ll-deoxo-prostaglandin E, methyl est Example ■ 14 Preparation, of dl-11 ,15-Dideoxoprostaglandin E^ A solution of copper (I) iodide-tri-n-butylphosphine complex (1.175 g., 3.0 mmoles) in dry diethyl ether (2.5 ml.) was treated with a solution of trans-l-lithio-l-octene (22.5 ml., 6.08 mmoles 0.27M; prepared in accordance with the procedure set forth herein- before and in the Zweifel article, supra. ) in ether (added drop- wise via syringe) at -78°C„ under a blanket of nitrogen. After stirring at -78°C. for 30 minutes , 2- (61 -carbomethoxyhexyl) -lcyclo pent-2-en-l-one 450 mg. ,2 mmoles) was added dropwise via syringe and the solution warmed to 0°C. and stirred for an additional*^ hours at 0°C. (ice bath). Finally, the mixture was allowed to warm to room temperature, whereupon the yellow solution began darkening after about 30 minutes. 20 ml. of 20% NH^Cl {aqueous) saturated with NH^ were added until pH 9 was reached. The resulting mixture was filtered with suction. The residue was washed well with ether (50 ml.) and the combined^filtrate and washings were shaken in a separatory funnel. The phases were separated and the aqueous phase was further extracted with ether (2 x 50 ml.). The combined ethereal extract was washed with a saturated aqueous sodium chloride solution (50 ml.) and dried (MgSO^) . After evaporation of the ether, the crude oily residue was chromatographed on 150 g. silica gel using a chloroform-benzene gradient starting with pure benzene and 2 liters of chloroform were used. After this elution was continued with pure chloroform. Approximately 500 mg. of the crude dl-11 , 15-dideoxo-prostaglandin methyl ester was treated with 400 mg. (10 mmoles) of NaOH in 5 ml. of water and 15 ml. of methanol. The mixture was stirred magnetically for 15 hours and the methanol was then removed by evaporation. The aqueous phase was diluted with 5 ml. of water and the resulting mixture was extracted with ether. The aqueous phase was then acidified with hydrochloric acid and extracted with ether. The combined ether layers were dried over magnesium sulfate and the solvent was removed to yield 255 mg. of a material having the following characteristics: molecular ion at m/e 322,25058 (theory 322,25078 for C20H34°3^ » nmr 65,5 (2H, m, vinylic protons at C-13 and C-14) and which was identified as dl-11, 15-dideoxoprostaglandin E, .

The dl-11 ,15-dideoxo PGE^ can be readily converted by Rftown procedures (see above on conversion of dl-15-deoxo PGE^) to dl-ll-deoxo PGE^ which can, via bromination and debromination (also known procedures) , be converted to PGA^ and which can in turn be converted by known procedures to -P-GB^, PGE^ , and PGF^ .

For the synthesis of optically -active PGE^ and 11-deoxo PGE^ as described hereinbefore, optically active octyn-3-ol 25 ' ([«]£) -23°) can be used to prepare the reactant 3-hydroxy-l -Iodo-l-trans-octene (foj -4.6° ethyl ether): +9.52° in MeOH).

Preparation of 2- (61 ^carbomethoxyhexyl) — - cyclopent-2-en-l-one The reactant, 2- (6 ' -carbomethoxyhexyl)- cyclopent-2-en-l-one in the preceding Examples was prepared as set out in the following Example wherein the Roman numerals identifying certain compounds identify the same compounds in the schematic diagram immediately following this Example.

Example 15 , Into a dry 3-necked flask equipped with a septum stopper, thermometer well adapter, pressure equilizing dropping funnel, and magnetic stirrer was placed dry tetrahydrofuran (200 ml/1 mole of octadiene) and 6.45 molar equivalents of octadiene (freshly distilled over calcium hydride). A blanket of nitrogen was maintained at all times. The flask was placed in a water bat at 25°C. Conversion to the trialkylborane was achieved by the dropwise addition of a solution of diborane in tetrahydrofuran (1 molar equivalent of hydride). The temperature of the solution was maintained at 25°C. by the addition of ice to the water bath. The solution was stirred at 25°C. for 1 hour, then methanol (13 ml/1 mole of hydride) was added to destroy excess hydride^ 0.28 molar equivalents of iodine were added all at once, followed by 0.28 molar equivalents of 3M solution of sodium hydroxide in methanol over a period of S minutes. The reaction mixture was allowed to warm up and stirred for a further 15-20 minutes. The reaction mixture was poured into water containing sodium thiosul-fate (lg/50 ml. of water) to remove excess iodine, and the aqueous layer was extracted three times with pentane. The combined pentane extract was dried over magnesium sulfate. The pentane and most of the excess octadiene was removed by rotary evaporator and the remaining material was distilled ,over calcium hydride under reduced pressure to give 8-iodo-l-octene . 0.086 mole of the 8-iodo-l-octene in 50 ml. of tetrahydro-furan was added dropwise to a mixture of 2.5 g. of Mg turnings in 20 ml. of dry tetrahydrofuran with mechanical stirring (under a blanket of nitrogen). After completion of the addition ("1 hr.) the mixture was boiled under gentle reflux for an additional 30 minutes. To this cooled Grignard reagent was added dropwise 0.085 mole of 2-methoxy- cyclopent-2-en-l-one followed by stirring at room temperature for 30 minutes. The resulting mixture was poured onto 200 g. of chipped ice and 30 g. of NH^Cl. One hundred ml. of 2 N HC1 was then added. After shaking for 30 minutes the product was extracted with several portions of Et20 (500 ml. total). The combined extracts were washed with two 50 ml. portions of saturated NaHCO^, then with 100 ml. of saturated NaCl , and dried over After evaporation of solvent approximately 14 g. of the crude product (I) was obtained. -239 Dehydration ^ To 9.4 g. o£ I, dissolved in 70 ml. of anhydrous methanol was added 2 ml. of concentrated ^SO^ and the mixture was refluxe for 14 hours. The cooled mixture was neutralized by the addition of solid NaHCOj. After removal of the methanol, 200 ml. of water was added and the resulting mixture was exhaustively extracted with Et20 (total of 600 ml.). The combined extracts were washed with 150 ml. of saturated aqueous NaCl and dried over gSO^. After filtration, the solvent was removed by rotary evaporation and the residual oil was distilled under reduced pressure. The fraction boiling 87-89° (0.2 mm.) was collected as pure 2-1 (1 ' -octen^r-8-yl) - cyclopent-2-en-l-one (II) (4.'3 g. , 40-50% yield).

Epoxidation of II 1.77 g. of the olefin (II) was dissolved in 8 ml. of methylene chloride was treated dropwise with a solution of m-chloro-perbenzoic acid (1.7 g.) in 20 ml. of methylene chloride. The mixture was allowed to stand at 0°C. for two days. After the usual work-up, the crude mixture was chro atographed over a silicic acid-Celite (85:15) column. The column was eluted with a gradient system comprising benzene and benzene-ethyl acetate (1:1). The pure epoxide obtained was 0.89 g. and the unreacted substrate was 0.96 g. which can be recycled.

Periodic acid cleavage of the epo ide (III) The epoxide III (200 mg.) was dissolved in 10 ml. of ether. This was treated with a freshly prepared solution of periodic acid (assuming .9 mg/m'l; 24 ml. of this solution (2 moles)). The mixture was then diluted with water and the organic layer was separated, washed with water, dried over sodium sulfate and Ψ evaporated to dryness to yield the desired aldehyde (IV).

Oxidation of the aldehyde to acid (V) The aldehyde (IV) (200 mg.) was dissolved in ethyl ether (1 ml.) and added dropwise to a suspension of Ag20 at 0°C. The mixture was stirred for 1 hour; the silver oxide at this point turned black. The black precipitate was filtered off and the filtrate was extracted with methylene chloride three times to remove unreacted aldehyde (39 mg.). The aqueous layer was made acidic to pH 2 and exhaustively extracted with ethyl acetate.

The combined ethyl acetate layers were dried over sodium sulfate and evaporated to yield 139 mg. of pure acid.

Esterification of the acid (V) was achieved by treating the acid with diazomethane in accordance with known methods to yield 2- (6'-carbomethoxyhexyl)- cyclopent-2-en-l-one (VI). This compoun as is evident from the foregoing discussion and Examples, is a basic reactant in the preparation of dl-11 and dl-11,15 deoxo-prostaglandins .

In the foregoing Examples the conversion of the dl 11-deoxo PGE^ esters to, respectively, dl-ll-deoxdeoxo PGE^ and dl-15-deoxo PGE^ can be readily accomplished by mold organism such as, for example, aspergillus and penicillin. Also, the proportions and amounts of reactants is not critical although it is obvious that changes in proportions and amounts will have an effect on the yields of desired products obtained from the various reactions. - 42 -

Claims (6)

1. 41305/4 CLAIMS : 1. Process for the preparation of a compound of the formula wherein R is hydrogen, a straight chain or branched chain alkyl group comprising from 1 to 5 carbon atoms, a pentene group or a cyclohexyl group; X is hydrogen, hydroxy, tetrahydropyran-2-yloxy, o-ethoxy-ethoxy or a group OR " wherein R " is an alkyl group comprising from 1 to 5 carbon atoms, the benzyl group or the acetyl group and II III IV V which comprises reacting a compound of the formula in which ALK is lower alkyl, ^ is oxygen (keto) and R2 is H or OH with a compound of the formula in which R and X are as defined above, 41305/3

2. A method for preparing dl-15-deoxoprostaglandin which comprises: reacting lithium cyclopentadiene with ethyl- 7-bromo-heptanoate, oxygenating the resulting alkylated cyclopenta¾¾ne to produce a mixture of hydroxyc elopentenones , chromatographically separating the said mixture and recovering 2- (61 -carboethoxyhexyl) -4-hydroxy-cyclopent-2-en-l-one , reacting the said recovered hydroxy ester with an excess of di-hydropyran in the presence of an acid catalyst and recovering 2- (61 -carboethoxyhexyl) -4-tetrahydropyranyloxy-cyclopent-2-en-l-one from the reaction mixture, - 44 - 41305/2 reacting the said ether with 1- lithium- 1- trans-octene in the presence of tri-n-butyl-phosphine-copper iodide comple f and recovering the formed prostanoic acid derivative from the reaction mixture, removing the tetrahydropyranyl group from the said derivative and chromatographically recovering dl- 15-deoxoprosta- glandin ethyl ester, and exposing the said ester to the action of an esterase -producing microorganism and recovering dl- 15-deoxo-pros taglandin from the reaction mixture.

3. A method for preparing dl-15-deoxoprostaglandin which comprises: reacting lithium cyclopentadiene with ethyl-7-bromo-heptanoate, oxygenating the resulting alkylated cyclopentadiene to produce a mixture of hydroxycyclopentenones , oxidizing the said mixture with Jones reagent to produce 2- (6 ' carboethoxyhexyl) -cyclopent-2-en-l , 4-dione , reducing the said dione with aluminum isopropoxide and chromatographically recovering 2- (6 'carboisopropoxyhexyl) -4-hydroxy-cyclopent-2-en-l-one from the reaction mixture, reacting the said recovered hydroxy ester with an excess of dihydropyran in the presence of an acid catalyst and recovering 2- (6 ' -carboethoxyhexyl) -4-tetrahydropyranyloxy-cyclopent-2-en-1-one from the reaction mixture, reacting the said ether with 1-lithium-l- trans -octene in the presence of tri-n-butyl-phosphine-copper iodide complex and recovering the formed prostanoic acid derivative from the reaction mixture, - 41305/2 removing the tetrahydropyranyl group from the said deriva ψ tive and chromatographically recovering dl-15-deoxoprostaglandin E^ ethyl ester, and exposing the said ester to the action of an esterase-pro-ducing microorganism and recovering dl-15-deoxo-prostaglandin from the reaction mixture.

4. A method for preparing PGE^j^ which comprises: reacting lithium cyclopentadiene with ethyl-7-bromo-heptanoate, oxygenating the resulting alkylated cyclopentadiene to produce a mixture of hydroxycyclopentenones , chromatographically separating the said mixture and recovering 2- (6 '-carboethoxyhexyl) -4-hydroxy-cyclopent-2-en-l-one, reacting the said recovered hydroxy ester with an excess of dihydropyran in the presence of an acid catalyst and recovering 2- ( 6 ' -carboethoxyhexyl) -4-tetrahydropyranyloxy- cyclopent-2-en-l-one from the reaction mixture, reacting the said ether with the oxygenated vinyl lithiu derivative obtained from the reaction of lithium powder and 3-(a- -ethoxy -ethoxy)-!- iodo- trans- 1-octene in the presence of tri-n -butylphosphine-copper iodide complex and recovering the formed prostanoic acid derivative from the reaction mixture, removing the tetrahydropyranyl and ethoxy- ethoxy ether groups from the said derivative, chromatographically recovering PGEj^ ethyl ester from the reaction mixture, and exposing the said ester to the action of an esterase -producing microorganism and recovering PGEj from the reaction mixture. 41305/2

5. A method for preparing dl-ll-deoxoprostaglandin E^ ^ which comprises: reacting 2- (6 '-carbomethoxyhexyl) -cyclopent-2-en-l-one with the oxygenated vinyl lithium derivative obtained from reacting lithium powder with 3- (g-ethoxy-ethoxy) -1-iodo-trans- 1-octene in the presence of tri-n-butylphosphine-copper iodide complex and recovering the formed prostanoic acid derivative from the reaction mixture, treating the said derivative with hydrochloric acid to remove the ethoxy-ethoxy ether group therefrom and recovering dl-ll-deoxoprostaglandin E.^ methyl ester, and exposing the said ester to the action of an esterase -producing microorganism and recovering dl-ll-deoxoprostaglandin from the reaction mixture. .

6. A method for preparing dl-11 ,15-dideoxoprostaglandin which comprises : treating a solution of tri-n-butylphosphine-copper iodide complex with trans- 1-lithio- 1-octene, adding to the resulting mixture 2- (6 '-carbomethoxyhexyl) cyclopent-2-en-l-one and recovering dl-11 ,15-dideoxoprostaglandin methyl ester from the reaction mixture, and converting the said methyl ester to dl-11 , 15-dideoxoprostaglandin E, . 47 - 41305/4 Compounds of the general formula rhere represents the basic ring structure of the E and A type prostaglandins or the configuration 8. dl - 15-deoxoprostaglandin E 9, dl-ll-15-dideoxoprostaglandin E dl- 15.-deoxoprostaglandin A, ethyl ester. For the Applic mts C IN AND PARTNERS :mr 5 - 48 -