IL49286A - 1-iodo-1-trans-alkenes their preparation and pharmaceutical compositions containing them - 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

oniR n»V»3»n hirrpn Hovel l^iodo^l^v ^ l exiQ , their preparation and^pharmaoeutical compositions containing thesi WISCOHSIK ALUMNI RESEARCH FOUNDATION 0. 46589 49286/3 THIS INVENTION relates to certain iodo-aikon useful as antibacterial agents and as 'intermediates in the preparation of prostaglandins and to a process for preparing the iodo-alkenes.

The iodo-alkenes have the general formula wherein R is hydrogen, a straight or branched chain alkyl group comprising from 1 to 5 carbon atoms or cyclohexyl; and X is hydroxy' or an a-ethoxy-ethoxy group.

The iodo-alkenes of formula I above can be prepared reacting a compound of general formula: H (a) wherein R and X are as defined above, with either/ 2 moles of diisobutylaluminium hydride, or (b) 1 mole of triisobutyl- aluminium and reacting the resulting alkoxide with diisobutylaluminium hydride, and iodinating the hydroalumination product resulting from (a) or (b) and recovering the desired product from the iodination product. Suitably, the iodination product is reacted with a basic amine (e.g. trimethylamine or triethylamine) prior to recovering the desired product.

The general procedures of the above process are discussed in more detail in G. Zweifel et ol, J. Amsr. Che¾ Soc, 89, 2753 (1967).· The compounds of the invention have antibacterial activity against gram positive bacteria. The invention therefore also provides pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier or diluent.

The iodo-al!kenes of general formula (I) can be readily converted into a compound of general formula: H wherein R and X are as defined above. These lithium compounds can be used in the preparation of prostaglandin derxvates, as described in Patent Specification No. 41305, for example as shown below.

The invention is illustrated by the following Examples.

EI-AKPLS 1 • 2 IJolar equivalents of diisobutylaluminium hydride were added to 1 molar equivalent of l-occyn-3-ol in dry heptane (40 ml/100 mmoles of l-octyn-3-ol ) while maintaining the temperature below 40°C, VThcn 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 mmole.s of diisobutylaluminium 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 colour disappeared at the beginning and a gas, probably hydrogen, was given off. After about 1 molar equivalent of iodine had been 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 v/arm up to room temperature, whereupon the diisobutylalane was decomposed at 20-30°C, by the dropwise addition of 20% sulphuric acid, VJhen the isobutane evolution had subsided, the reaction mixture was poured into ice - 20% sulphuric acid. The reaction mixture J was extracted four times wi •th pentane and the combined ji organic extract was washed successively with sodium thiosulphate, saturated sodium bicarbonate and saturated sodium chloride solutions and dried ever magnesium sulphate.

Evaporation of the dried extract gave a yellow oil. The nmr. spectrum (CDC13) of the product, after all volatile — material had been distilled off, showed that some of the saturated iodide, 3-hydroxy~l-iodooctane was present.

The product was further treated to remove any 3-hydro:cy-l-iodooctane and possible 1,1-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° 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 extracts were v/ashed successively with dilute hydrochloric acid, saturated sodium bicarbonate, sodium thiosulphate, saturated sodium bicarbonate and saturated sodium chloride solutions and dried over magnesiim sulph te. 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-octene, wt: 12,5 g. (24, 6¾), As an alternative to the procedure set out above, the hydroalumination can be carried out by complexing the hydro;_y group of l-octyn-3~ol with triisobutylaluminium to give an aluminium allcoxide and isobutane gas, one molar equivalent of diisobutylaluminium hydride then being added to form the vinylalane. This procedure, which is set out with greater specificity in Example 4 below, offers certain advantages over the procedure of Example 1 in that the quantity of undesired l-iodo-3~hydroxyoctane and 1,1- reduced and the desired product, 3-hydro:-v-1-iodo-1-1r nn-octene, can be obtained in higher yields by vacuum —^ distillation, ;E?vAMFLK 2 To 1,26 g, (0.01 moles) of lr-octyn-3-ol in 8 ml, in dry heptane were added djropwise 6.18 ml, (0.03 moles) of triisobutylalurninium at 10-15 °C.j 1.82 ml, (0.01 moles) ; of diisobutylaluminium hydride v/as then added and the reaction mi:ture was heated at 50-55 °C, for 2 hours. The solution v/as then cooled and the heptane removed under reduced pressure. The residue obtained v/as diluted ..with 12 ml, of dry tetrahydrofuran. After cooling the solution i to -50°C, , 10,26 g. (0,04 moles) of iodine in 16 ml. of dry tetrahydrofuran were added drop ise. The dark solution v/as warmed to room temperature and the alane v/as decomposed at 20-30°C. , with 2f i^SO^. 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 KaHCO^, sodium thio- ■ . . . . . . · - I sulphate, saturated NaHCO- and saturated NaCl solutions. j After drying the pentane over ISgSO^, it was evaporated to j give a dark oil. To remove the iodo-3-hydroxyoctane, the j mixture v/as heated for 16 hours at 90°C. , with 0.005 moles of triethylamine. The excess triethylamine was evaporated off and v/ater v/as added to the residue, flost of the dark . oily residue dissolved .in the aqueous layer and the total , mixture v/as e tracted with pentane. The pentane extract v/as washed with dilute hydrochloric acid, saturated sodium j bicarbonate and saturated sodium chloride solutions and dried over magnesium sulphate. After evaporation cf the pentane, the residue \r s distilled in vacuo, to yield pure 3~tydro:^/~l~iodo-l~trans-OCtene (4Ο-50ϋ molar basis). SI.

Sojne l-octyn-3~ol was recovered. 2 molar equivalents of diisobutylaluminum hydride was added to 1 molar equivalent ofj propargyl: alcohol in dry heptane (40 ml/100 m - ··. . ' · ί ; " . . . '. · moles ofj propargyl alcohol)7 : 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 mol 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 mixtu 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 diminish the reaction mixture was poured into ice — 20$ sulfuric acid. The reacti mixture was extracted four times wit pentane and the combined organic extract was washe m bicarbonate and s magnesium sulfate ■The nmr spectrum .1 The product was further treated to remove any 3-hydroxy-l-iodo- 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 chlor de solutions and dried over magnesium sulfate. The product obtained after evaporation of the pentane was chromatographed on silica gel and elution-with benzene produced__piire j . ' . . ' · · · 3-hydroxy-l-iodo-trans-propene (20-30% molarbasis) as ' evidenced by the following physical data: ". ' A mixture of 5.82 ml (100 m ol) of propargyl alcohol (Aldrich) and 80 ml of dry heptane was stirred under argon with ice-bath cooling as 25 ml (121 mmol) of triisobutylaluminum (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 mtaol) portion of diisobutylalumlnum hydride (Ethyl Corp.) waa then added, j 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- < Euran. 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 slo -dropwise addition of 150 ml of 20Z 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 N ^SO^) and evaporated in vacuo to give a dark oil. This -—-oil was dissolved in 25 ml of dry trlethylamine and heated under argon at.85-95° for 23 hr. The excess trlethylamine 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 (22.81) of pure 2z bp 015-120° (28 mm) ; nmr(CDCl3) 63.1(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); ir(film) .920, 960, 1005, 1070, 1170, .1235, 1610, 2860, 2925 and 3100 to 3600 cm"1(broad).

Example 4 3-Hydroxy-l-iodo-l-trans-heptene A. One-step reduction 2 molar equivalents of diisobutylaluminum hydride was added to ■ 1 molar equivalent of ' l-heptyn-3-ol 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 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 6n 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 0 sulfuric acid. When the isobutane evolution had diminished, the reaction mixture was poured into ice - 20 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 -chat some of the saturated iodide, 3-hydroxy-1-iodo-heptane was present. ', .

The product was further treated to remove any 3-hydroxy-l-iodo · heptane present. To accomplish this the reaction product was mixed with an excess (3-5 times) of triethylamine and the mixture heated at ab^t 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 pentarie 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- 1 - iodo- 1-trans-hepteae- ir (CG14) 3620 (OH) 1600 (C=C) ! and 940 cm" 1 (trans C ~CH), nmr £ .05 (m, 1. C-3H) and 6. 51 ppm - i (m,2, C-l and C-2x4). Anal. calcd for CyHjslO C, 35. 03; H, 5. 42.

Found: C, 35. 28; H, 57oX B. Two-step reduction . · To 0.01 moles of l-heptyn-3-ol .. in 8 ml. in dry heptane was added drppwise 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° , 0.04 moles of iodine in 16 ml. of 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 extracted four times with pentane.

The pentane extract was washed successively with saturated NaHCO.-., 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. 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-heptene (40-50 molar -basis) .

Example 5 3-Hydroxy-1-iodo-l-trans-hexene — . / i 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 v/as 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 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 - 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-hexane - was present.

The product was further treated to remove any j S^ydroxy-l-iodo- / 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 -of-f-and -water was added--to- he-res ue^ h^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 as chromatographed on silica gel and elution with benzene produced pure 3-hydroxy-l-iodo-l-trans-hexene (20-30 molar basis) as evidenced by the following physical data: 3-hydroxy 1-iodo- 1-trans-hexene- ir (CCl4) 362C(OH), 1600 (C=C) - | and 940 cm" 1 (trans CH=CH, nmr tf 4.05 (m, l, C-3 H) and 6. 50 ppm - j (m, 2, C-l and C-2 H). Anal. calcd for CQH^ IO C, 31. 89; H, 4. 87. j Found: C, 31. 93; H. 5.ΌΤ" | B. Two-step reduction To 0.01 moles of l-hexyn-3-ol in 8 ml. in dry heptane was added dropwise 0.03 moles of triisobutylaluminuru 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 tetrahydrofuran was added dropwise. The dark solution was -warmed to room temperature and the alane was decomposed at 20-30° c. with 20$6 H2S04- 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 NaHCO^, sodium thiosulfate, saturated NaHCO^ and saturated NaCl solutions .

After drying, the pentane over gSO^, it was evaporated to give a dark oil. To remove the 3-hydroxy-l-iodo-hexane ', the mixture was heated for 16 hours at 9.0° 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. The pentane extract was washed with dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride solutions and dried over magnesium sulfat After evaporation of the pentane, the residue was distilled in vacuo to yield pure 3-hydroxy-l-iodo-l-trans-hexene (40-50^ molar -basis) .

Example 6 3-Hydroxy-l-iodo-l-trans-pentene A. One-step reduction .2 molar equivalents of diisobutylaluminum hydride was added to 1 molar equivalent of. l-pentyl-3-ol in dry heptane (40 ml/100 m moles of l-pentyn-3-ol) 1 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 hydri To this solution, cooled to -50° C. , was slowly added a, solution of 2 m equivalents of iodine in dry tetrahydrofuran (40 ml/100 m moles of iodi while maintaining the temperature at about -50° C. The iodine colour disappeared at the beginning and a gas (probably hydrogen) was given of After about 1 molar equivalent of iodine was added, the gas evolution ceased and the iodine colour disappeared more slowly, the solution taki on a red colour. After all the iodine had been added, the reaction mix was allowed, to warm up to room temperature, whereupon the diisobutylala formed in the reaction was decomposed at 20-30° C. by the dropwise addition of 20 sulfuric acid! When the isobutane evolution had dimini the reaction mixture was poured into ice - 20 sulfuric acid. The reac mixture was extracted four times with pentane and the combined organic extract was washed successively with sodium thiosulfate, saturated sodi 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 iodo- pentane w s present. ' . ' The product was further treated to remove any 3-hydroxy-1^-iodo- pentane j 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-pentene (20-30 molar basis) as evidenced by the following physical data: Found: C, 23.47; H, Γ5ΤΓ . . ! ·.

. Two-step reduction To 0.01 moles of l-pentyn-3-ol in' 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 tetrahydrofuran was added dropwise. The dark solution was warmed to room temperature and the alane was decomposed at 20-30° C. with 20g£ H^S0„. After the isobutane evolution had diminished, the reaction 2 4 mixture was poured into ice and extracted four times with pentane.

The pentane .extract was washed successively with saturated NaHCO^, sodium thiosulf te, 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-pentane , 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. 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 49286/2 The hydroalumination reaction of the above Examples is readily applicable to the preparation of the following iodo-co pounds of formula I: 3-hydroxy-l-iodo-4-methyl-l-trans-heptene 3-hydroxy-l-iodo-4-ethy1-1-trans-hexene 3- [ (g-ethoxy) ethoxy] -1-iodo-l-trans-octene Example 7 3- (g-ethoxy-ethoxy)-l-iodo-l-trans-octene 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. Evaporation of the ethereal solution yielded a yellow oil which was identified as 3- ( -ethoxy-ethoxy) -1-iodo- l-trans-octene .

Example 8 l-Iodo-3RS-hydroxy-3-cyclohexyl-l-trans-propene Preparation of l-cyclohexyl-2-propy¾-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; NMB (CDCl.) S 0. 8-2, 2 (complex, 11 H) 2. 45 (d,J=2Hz, 10) 2. 30 (broad S, 1 H) 4. l¾m,l H); ir(CCl ) 2. 8, 2. 95, 3. 05, 6. 9^ [ ir from HCA-Vol I-pT] . ~ 4 Preparation of 1 -iodo-3RS- hydroxy- 3 -cyclohexyl-1- 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. Triisobutylaluminum 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 ≤ 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 NMR (CDCl ) indicates starting material and product in a 9: 1 ratio: 6. 2 (d,J=l5. 0Hz,¾ H) 6. 6 (dd,d=6, 15. ΟΗζ,ΙΗ) 2. 36 (dJ=2Hz , 1H).

Of the compounds of the above formula II, l-octyn-3-ol is a preferred reactant. Other compounds which find ready application include those in which X has an ether configuration which is susceptible to hydrolysis by mild acid, including cyclic ethers.

The aluminium 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-tetrahydropyran^2-' ^yloxy-l^octyne , 3- [ (a-ethoxy) ethoxy] -octyn '\s or 3^acetO- However, as is pointed out more specifically below, v/hen diisobutylaluminium' s used as the ydroalurination agent, it is essential to use that agent in the ratio of two molar equivalents to one molar equivalent of the particular compound v/hich is being completed. On the other hand, v/hen triisobutyialuminium is used, such agent can be used in a molar -equivalent ratio to the coiupound being completed of 1:1 or greater.

It is also to be understood that the alkyl chain R does not have to be a straight chain configuration but can be branched. For example, 4-, 5-, or 6-, methylheptyne or other branched chain configurations can be readily substituted for the hydrocarbon chain in the l-octyn-3-ol reactant.

The hydroalumination process as described in Example 1 above, and v/here diisobutylaluiTiiniux is used as th hydroalumination agent, is similar to the general procedur \ described by G. Zweifel e .al, , referred to above, There are, however, soma major, and critical dif erences. With the 3-substituted compounds 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 hydroalundnation agent, diisobutyl-aluminium hydride, are used that the hydroalumination proceeds to produce the desired compounds. In addition, the treatment with triethylamine or other basic trialkyl-aminesi for example trimethylamine, is essential to the elimination of undesirable by-products f om the reaction mixture and to the production of the desired compound in essentially pure form.

The above processes permit the ready recovery of the products thereof in the trans isomeric configuration, the preferred isomer for the -preparation of physiologically-active prostaglandins or compounds having prcsstaglandin-liie activity.

The iodo-compounds are readily converted into the corresponding lithium. compounds in accordance with th procedure described above and illustrated below for the preparation of l-lithio-l-trans-octenc. In a three-necke* round bottom flask equipped with a mechanical stirrer (wi: blade) and pressure equalising dropping funnel was placed 4-6 molar equivalents of fine lithium powder and dry diethyl ether (2 ml/l mmole of vinyl iodide) freshly distilled over, lithium aluminium hydride, A blanket of argon was maintained at all times. To this rapidly stirr mixture, which was cooled in an ice-bath, was added 1 mol. equivalent of 3hydro:-y-l"iodo~l-trans~octene. (vinyl iodia in dry diethyl ether (2 ml/l mraole of vinyl iodide). Aft addition of a few drops of the vinyl iodide in ether a Gilman test v/as performed. If the test was positive, tl addition of the vinyl iodide v/as continued. If the test was negative, the addition of the vinyl iodide" v/as stoppe and the rapid stirring of the lithium solution continued. The Gilman test was performed at various intervals, VThen positive test was obtained, the addition of the vinyl iod was recommenced. 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 v/as titrated with an HC1 solution to determine concentrate of the vinyl lithium solution.

To 10. ml. of Penicillin assay seed agar (J-1095-C, Pisher Scientific Co. ) per Petri dish was added 0.1 ml, of a 24 hour culture of the test organisms in a nutrient broth. The test compounds, 3~hydro^/~l-iodo-l»-trans~octene (IIVI) and l~iodo-l-trans-octene (VI), were dissolved in ~2 methanol to give a concentration of 1.9 10 II. 0.1 ml. of each of the test compounds was added to a -filter-paper disc (12.7 mm,), which v/as placed on top of the agar plate.

The Petri dish was incubated at 25 °C. , for 48 hours, and the zone of inhibition was measured.

Test, rganisms . Zone diameter (mm) VI HVJC Bacillus subtilis — 23 Sarcina utea — 22 Escherichia coli ■ — . .

Staphylococcus aureus · — . ~- It is evident from the above that the 3-carbon- substituted compounds of this invention e;diibit substantial antibacterial activity against gram positive organisras as compared with similar compounds hot having a su?ostituent at that position in the hydrocarbon chain.

Claims (11)

49286/3 WHAT WE CLAIM IS:

1. A compound of general formula wherein R is hydrogen, a straight or branched chain alkyl group comprising from 1 to 5 carbon atoms or cyclohexyl; and X is hydroxy or an -ethoxy-ethoxy group.

2. 3-Hydroxy-l-iodo-trans-octene

3. 3- (a-Ethoxy) ethoxy-l-iodo-l-trans-octene .

4. A process for preparing a compound of formula I in Claim 1 which comprises reacting a compound of general formula : X wherein R and X are as defined in clain 1, with either (a) 2 moles of diisobutylaluminium hydride, or (b) 1 mole of triisobutylaluminium and reacting the resulting alkoxide with diisobutylaluminium hydride, and iodinating the hydroalumination product resulting from (a) or (b) and recovering the desired product from the iodination product.

5. 'A process according to claim wherein the iod nation product is reacted with a basic amine prior to recovering the desired product,

6. ,1 A process according to claim -4 or 5, wherein the. basic amine is trimethylamine or triethylamine*

7. -· A process according to claim 7 ; substantially as described in Examples l to 6,

8.' A compound of general formula (I) prepared by a process according to any one of claims 4 to 7

9. · A pharmaceutical composition comprising a compound according to claim 1 or 8 wherein X is othor than hydrogen and a pharmaceutically acceptable carrier or. diluent.

10. A pharmaceutical composition comprising the compound according to claim 2 and a pharmaceutically acceptable carrier or diluent.

11. A pharmaceutical composition comprising the compound according to claim 3 and a pharmaceutically acceptable carrier or diluent. ND:mr