US3033884A - Unsaturated aliphatic compounds and process for the manufacture thereof - Google Patents

Abstract

The invention comprises acetylenically unsaturated acids and esters of general formula: <FORM:0859897/IV(b)/1> where c is an integer from 2 to 5 and d an integer from 0 to 8, but where c is 2, d is other than 6 and the corresponding ethylencially unsaturated acids or esters other than linoleic, homolinoleic, y-linoleic, and arachidonic acids and those compounds in which c and d are 2 and 8, 3 and 5, 4 and 6, 4 and 4, and 5 and 1, and a process for the preparation thereof which comprises condensing a halogen compound of general formula: CH3-(CH2)4-(C­CH2)s-X with an acid or ester of formula <FORM:0859897/IV(b)/2> group, s and t being integers from 0 to 4 but totalling 4, and X being a chlorine, bromine or iodine atom, in a Grignard reaction, in th presence of a copper or cuprous salt, hydrolysing the adamantyl group if present esterifying if desired, or selectively hydrogenating to the ethylenically unsaturated acid or alkyl ester. Specified compounds are 1-ethyloxy-carbonyloctadecadiyne-(9, 12), and -nonadecadiyne-(10, 13), 1-methoxycarbonyl-octadecatriyne -(6, 9, 12), docosapentayn- (4, 7, 10, 13, 16)-oic acid, octadecatriyne- (6, 9, 12)-oic-(1) acid, eicosatetrayn -(5, 8, 11, 14)-oic-(1) acid, and examples describe, their preparation and hydrogenation to the ethylenically unsaturated compounds such as linoleic, homolinoleic, y-linoleic, docosapentaen- (4, 7, 10, 13, 16)-oic, and arachidonic acids and esters. The acetylenic halogeno compounds are prepared in repeated stages from pentyl bromide by condensing with a dimagnesium bromide derivative of propargyl alcohol in the presence of cuprous chloride and brominating the resulting octyn-(2)-ol-(1) with phosphorus tribromide to form octyn-(2)-yl bromide. The 1-bromo-octyne -(2) may also be prepared by reacting acetylene with amyl bromide in loquid ammonia and condensing the resulting heptyne- (1) with formaldehyde in a Grignard reaction and hydrolysing the resulting magnesium bromide derivative of octyn-(2)-ol-1. The acetylenic acids are prepared by the condensation of an acid of general formula: <FORM:0859897/IV(b)/3> with propargyl halide in a Grignard reaction with copper or a cuprous salt; and the adamantyl hindered esters are prepared in stages from a nitrile of general formula: CH ­ C-CH2-(CH2)b-C ­ N byconverting into an imino ether hydrochloride with ethanol and hydrogen chloride, and reacting with ethanol and ether to yield ortho-ester which is reacted with cis 1, 3, 5-trihydroxycyclohexane in the presence of boron trifluoride etherate to give the hindered ortho ester which is condensed if necessary with propargyl halide in a Grignard reaction until the required chain length is obtained. The hydrogenation to the ethylenically unsaturated compounds is preferably by lead inhibited palladium catalysts. Specification 859,898 is referred to.

Description

3,h33,84 Patented May 8, 1962 UNSATURATED ALIPHATIC COMPOUNDS AND The present invention relates to unsaturated aliphatic compounds. More particularly, the invention relates in one of its aspects to compounds having the general formula wherein stands for an integer of from to 5, and the alkyl esters thereof.

In still another aspect, the invention relates to cornpounds having the general formula CH (CH (CECCH (CH -COOH wherein b stands for the integers 7 or 8, and the alkyl esters thereof (e.g. nonadecadiyn-(l0,l3)-oic-(1) acid ethyl ester).

In a further aspect, the invention relates to compounds having the general formula CH (CH (CH:CH-CH -(CH COOH wherein b stands for an integer of from 0 to 5, and the alkyl esters thereof.

In still a further aspect, the invention relates to com- 4 pounds having the general formula CH3'-( CH2 4 3'- -CO wherein b stands for an integer of from 0 to 2, and the alkyl ester thereof.

The invention also pertains to nonadecatrien-(7,l0,l3)- oic-(l) acid and the alkyl esters thereof.

Then, the invention concerns compounds having the general formula wherein h stands for an integer of from 6 to 8, and the alkyl esters thereof.

Furthermore, the invention includes such compounds having the general formula CH CH CH=CHCH CH -CO OH wherein ,5 stands for the integers 0 or 1, and the alkyl CH CH CH=CHCH CH --CO OH wherein b stands for the integers 7 or 8, and the alkyl esters thereof do also fall within the invention.

In one more of its aspects, the invention relates to heneicosapentaen-(3,6,9,l2,15)-oic-(1) acid and the alkyl esters thereof.

In the last of its aspects, the invention relates to compounds having the general formula wherein b stands for an integer of from 2 to 8, and the alkyl esters thereof.

The invention provides also a process which comprises condensing a halogeno compound having the general formula with a compound having the general formula CHECCH '-(CECCH )1;-(CH -Y wherein s and t stand for integers each ranging from 0 to 4 but totalling 1 to 4, b stands for an integer of from O to 8, X represents a chlorine, bromine or iodine atom, and Y represents a carboxyl or a hindered orthoester group, in a Grignard reaction in the presence of copper or a cuprous salt, hydrolysing the hindered orthoester group, if present, and subjecting the reaction product, if desired, to one or more reaction steps in any desired sequence, comprising partial hydrogenation of the triple bonds to double bonds, esterification and reduction of any acid obtained to the corresponding alcohol.

Of the halogeno compound to be used as starting material in the process of the invention, the bromides are preferred. As hindered ortho ester, an adamantyl compound is advantageously used.

The condensation of the halogeno compounds and the acids used as initial materials by means of a Grignard reaction is suitably carried out using tetrahydro-furan as a solvent. 2 molecular proportions of the Grignard reagent are utilised in order to form the acid complex required in the condensation.

The condensation step may suitably be carried out using cuprous chloride as the cuprous salt. However, it is preferred to use cuprous cyanide as the yields are thereby enhanced. When using copper powder the yields are of the same order as when using cuprous cyanide. The copper or cuprous salt is conveniently added to the Grignard complex when adding the halogeno compound.

The hydrolysis, where required, of the condensation product is suitably carried out using aqueous sulphuric acid.

The esterification of the acetylenic or ethylenic unsaturated acids formed in the process may be conducted by heating the acid with an alkanol in the presence of hy drogen chloride.

The transformation of the acetylenic compound produced in the process into the corresponding ethylenic compounds may preferably be achieved by hydrogenation in the presence of a catalyst which selectively catalyses the reduction of triple bonds to double bonds (e.g. lead inhibited palladium catalysts such as the Lindlar catalysts).

The reduction of the acids obtained according to the process of the invention to the corresponding alcohols can be elfected by treating with lithium aluminum hydride and decomposing the metal complex formed. It is preferred to work in ethyl ether and to heat the suspension for some hours. It is preferred to decompose the complex with sulfuric acid.

The acetylenic halogeno compounds used as initial materials may all be prepared from pentyl bromide and propargyl alcohol. Thus, l-bromo-octyne-(Z) can be prepared by heating pentyl bromide with a di(magnesium bromide) derivative of propargyl alcohol in the presence 3 of cuprousjchloride and brominating the resulting octyn ,(2.)-o1-.(1. with phosphorus tribromide. Again, l-bromoundecadiyne-(2,5) can be prepared from l-bromooctyne-(Z) (itself prepared from pentyl bromide and :prqpargyl alcohol) by'a similar series of -stepsnsing adi- (magnesium bromide) derivative of :propargyl alcohol,

:cuprous chloride and phosphorus tribromide. Similarly, :thethighermokcular weight halogeno compounds are prepared stepwise from the lower molecular weight icompounds.

The following formula scheme is illustrative of the preparation of thehalogeno compounds nsed'as-initial materials:

CHE- CH2) 4-131:

condensing the resulting heptyne-(l) with formaldehyde b in a Grignard reaction, hydrolysing the resulting magwith a propargyl :halide (preferably propargyl bromide) in a Grignard reaction in the presence of copper or of a cuprous salt and then, if necessary, similarly and repeated- 1y condensing the produced acid until the desired chain rM -oEo-oHi-oM Br and 011201,

omQomn-ozo-omai BrlVI-gCEOGHr-OMgBrand 0112011 CHr-(CHDr-(CEC-CHaM-Br The l-bromo-oetyne-(Z) can alsobe prepared 'by'reacting acetylene'with amyl bromide in liquid ammonia,

- iCHr-,(OHg)4(CECGH2)2Br BrMg-CEC-CHr-O-MgBr and 011 61 length is obtained. The following formula scheme is illustrative of this preparation:

+ CHEC-CHz-Br 2 Alkyl-Mg-X OHEC-CHr-Br wherein b and X have the significance hitherto given.

The adamantyl compounds (i.e'. the hindered orthoesters) used as initial materials can be prepared from a nitrile of the general formula:

wherein b has the hitherto given significance, by converting same into an imino-ether hydrochlorideby treatment with a calculated amount of ethanol and hydrogen chloride at low temperature, reacting the imino-ether hydrochloride with dry ethanol at about or withethanol" and ether under reflux to give the corresponding ethyl orthoester, reacting the ethyl orthoester in ethanol or methanol in the presence of boron trifluoride etherate or of hydrogen chloride with cis-l,3,5-trihydroxy-cyclohexane to give the hindered orthoester and, where a hindered orthoester containing further acetylenic groups is required, condensing the said orthoester in a Grignard reaction with a propargyl halide and then repeating this condensation until the desired chain length is achieved.

The unsaturated acids provided by the invention are essential fatty acids. A deficiency of such acids may cause functional disorders, which may be cured by the addition of said acids to foods and feedstufls. They can also be used in the therapy of pathologic, inflammatory or scaly skin disorders and for the treatment of arterioscelerosis.

The invention is further disclosed in the following examples, which are illustrative but not limitative thereof. All temperatures are stated in degrees centigrade.

Example 1 To a standard ethereal solution of 116.6 ml. (0.11 mole) of 0.9435 N ethyl magnesium bromide were added 80 ml. of dry peroxide free tetrahydrofuran. Ether was distilled off until the temperature reached 46. The mixture was cooled to 0 and 8.4 g. (0.05 mole) of decyn- (9)-oic-(l) acid in tetrahydrofuran added over /2 hour. The mixture was stirred at room temperature for 3 hours when evolution of ethane appeared complete. 0.7 g. of cuprous chloride was added and the mixture stirred for /2 hour. 9.45 g. (0.05 mole) of l-bromo-octyne-(Z) was added dropwise over /2 hour, the mixture stirred at room temperature for 2 hours, and then heated under reflux in an atmosphere of nitrogen for 24 hours. A further amount of cuprous chloride (0.3 g.) was added and the heating under reflux continued for a further 16 hours. The reaction mixture was poured into a mixture of ice and dilute hydrochloric acid and extracted three times with ether. The ether solutions were extracted four times with 2 N potassium carbonate solution and the aqueous extracts acidified with concentrated hydro- 2 Alkyl-Mg-X chloric acid (with the addition of ice) and extracted twice with ether. The ether extracts were washed with water and dried over'sulfuric acid.. Evaporation of the ether gave 12.34 g. of a brown oil. To this crude octadecadiyn- (9,12)-oicacid' was added a solution of absolute ethanol and 5 m1. of concentrated sulfuric acid at 0. The so lution was set aside at room temperature for 45 hours, under nitrogen. The ethanolic ester solution was poured into water and extracted three times with petrol (40-60) washed twice with 2 N sodium carbonate solution twice with water, then dried over sodium sulfate. Evaporation of the ether, followed by distillation of the residue gave 7.23 g. of octadecadiyne-(9,12) oic-(1) acid ethylester; yield 47.5%; B.P. 124-126/ 0.00014 mm. Redistillation gave a sample which boiled at 106-108/0.00021 mm.; It =1.4692.

6.29 g. of the product thus obtained were dissolved in 100 ml. of petrol [40-60 (purified)]. 0.5 g. of Lindlar catalyst was added and the ester hydrogenated at room temperature and atmospheric pressure until the hydrogen uptake began to subside. The catalyst was filtered oflf, the petroleum evaporated and the residue distilled, yielding 5.4 g. (84.8%) of ethyl linoleate; B.P. 150154/ 0.05 mm; n =1.4582.

5.02 g. of ethyl linol'eate were added to aqueous ethanolic sodium hydroxide (2.8 g. sodium hydroxide, 7 ml. water and 63 ml. ethanol) and set aside overnight at room temperature under a nitrogen atmosphere. Aqueous sulfuric acid (1:1) was added, the mixture diluted with water and'extracted three times with petrol (40-60). The extract was dried and the petrol evaporated under nitrogen; The residue was crystallized from 100 ml. of

petrol (40-60") at 20 to remove traces of saturated acid. On further cooling to 60 in a carbon dioxide/ethanol bath, the crystalline acid separated and was filtered ofl. First crop: 1.73 g. M.P. 10 to -8. Distillation of this first crop gave 1.26 g. of an oily product, linoleic acid; B.P. 148152./0.0011 mm.; n =1.4660,

The l-bromo-octyne-(Z) used as starting material can be produced according to the following procedure:

6 litres of liquid ammonia were saturated with acetylene by passage of acetylene gas into the liquid for30 minutes.

ther 6 hours. The ammonia was allowed to evaporate until the volume was considerablyreduced (eg to 2.5 1.) when 1500 ml. of dilute ammonium hydroxide solution were added slowly, followed by 1500 ml. of water. The

aqueous phase was separated and the crude product" washed with 150 ml. of water, 120' m1. of '6 N hydrochloric acid and 150 mhof 2 N sodium carbonate so- 5.1. 130150 /0.0028 mm.; 11 1.4682. (Redistillation gave n ='1.4675). Fom a similar preparation, the crude acid was distilled .to give a colourless liquid of 'boiling point 165l84/0.0001 which solidified to lution. After drying over potassium carbonate/sodium sulfate, heptyne-(l) was distilled at atmospheric pressure;

yield 573.6 g. (85.5%); B.P. 984059; n =1.4095..

of 786 g. (7.2 moles) of ethyl bromide in 600 ml. of'dry ether to 174 g. of magnesium turnings under 1200 ml. of

dry ether dropwise over 7 hours with stirring, so that gentle reflux was maintained. The solution was decanted from excess-magnesium turnings. 690 g. (7.2 moles) ofheptyne-(l) were added dropwise to the ethyl magnesium bromide solution over 2 hours, then stirred for a further hour. and finally heated under reflux for 2 hours. 330g. of paraformaldehyde were heated at ISO-190 and the .10 Ethyl magnesium bromide was prepared by addition give a solid of melting point 33.5-37.5". This was recrystallised from petrol (40-60) at to give a sample of melting point 38-39.

3.45 g. of nonadecadiyn-(l0,13)-oic-(1) acid ethylester were dissolved in 100 ml. of petrol (60-80", purified) and 1.4 g. of Lindlar catalyst were'added. The mixture was hydrogenated at 23 at atmosphericpressure. The byd-rogenation wasstopped when it showed an obvious break in the course of the hydrogen uptake and the catalyst was filtered off and petrol removed. The residue was distilled to yield 2.83 g. of ethyl homolinoleate; B.P. 115-l16/ 0.003 mm.; n =l.4580, (81%). r

resulting formaldehyde gas passed into the flask containing the vigorously stirred heptynyl magnesium bromide solution at 0. oThe operation was completed in about 4-hours. The resulting mixture was poured onto 1900 of 4N'sulfuric acid and ice,- the acid mixture extracted twice with 1 litre of ether and the extracts dried over potassium carbonate. "The ether was evaporated ofi and- ;the. residue distilled through a short Vigreux column;

yield of octyn-(2)-ol-(1) 711.3 g. (78.6%); B.P. 95'

ily/3543 mm; n =1.45 45..

T0 6975 g. (5.54 moles) of a stirred solution of octynj (2')-ol-(1) 'in 900 ml. of dry ether and 112 ml, of dry "pyridine were added dropwise; with cooling, 210.3 g. (2.21- moles) of phosphorusltribrom-ide over 50 minutes. The mixture was heated under reflux for 3. hours, cooled and added 150 225. litres of ice water with stirring. The

mixturewas extracted three timm with 700 ml. of ether,

thejcombinedextracts weredried over calcium chloride and filtered, and the ether was removed by distillation. 1 The residue was distilled to give 820 g. of l-bromo-octyne 2 (yield: 78.4% Br; 48.56/0.15 mm-., 1.488 7.

' i V V ExantplZ f 80 ml. of dry peroxide-free tetrahydrofuran was added to 57 ml. (0.11 mole) of a stirred 1.928 N ethereal solutionbf ethyl magnesium bromide and most of the ether distilled off. The solution was then cooled and some solid;

Example 3 and the ether removed (20 ml.) when most of the complex was in solution. T hesolution was cooled and 0.5 g. of cuprous chloride added and stirring was continued for V2 hour. 11.35 g. (0.05 mole) of l-bromo-undecadiyne- (2,5) were added dropwise over /2 hour and the mixture heatedunder reflux under nitrogen for 16 hours. 0.39 .g. of cuprous chloride was added and the heating under reflux continued for 32 hours. The reaction mixture was cooled and poured onto ice and an excess of sulfuric acid. The mixture was. extracted three times with ether and the extracts washed with water. The ether extract (I) was extracted .four times with 2N sodium carbonate and the ethereal mixture dried over sodium sulfate. The carbonate extract was acidified with hydrochloric acid and extracted with ether. The ether extract (II) was then washed with water and dried over sodium suliate; 'Evaporation of extract (H) gave 9.61 g. of an acidic fraction. Evaporation of extract (I) gave 7.1 g. of a neutral fraction The acidic material was added to a solution of 100ml. of methanol and .4 ml. of concenseparated. 7 9.1'g.'(0.05 mole) of undecyn-(l0)-oic-(1)1 acid in20,ml. of'tetrahydrofuran were added dropwise over /2 hour at 0. The mixture was stirred at room temperature for ,3 hours, by which time the evolution of ethane; appeared complete. 0.7 g. of cuprous chloride was added and the mixture allowed to stand for M4 hour.

9.45 g. (0.05 mole) of 1-bromo-octyne-(2) in 25 m1. of

' V I tetrahydrofuran were added dropwise over. 20 minutes and stirred for /6 'hourrat room temperature. Themixture was then heated under reflux .for160 hours under nitrogen, 0.3 g. of cuprous chloride being added after the first24 hours. The reaction; mixture was poured onto ice and sulfuric 1 acid and'extracted three times with ether..

The ether solution was extracted four times with 2N so dium carbonate and the aqueous solution acidified with concentrated hydrochloric acid and extracted three times with ether. The ether extract was washed with Walter and dried over sodium sulfate. On evaporation of the ether,

12.18 g. ofa brownsyrup resulted. This syrup was dissolved at 0 in a mixture-of mLof'ethanoland 5 m1. of concentrated sulfuric acid and set aside at room temperature for 48 hours in an'atmosphere of nitrogen. The resulting ethanolic ester solution was poured onto ice and extracted three times with petrol (40-60); washed twice with 2, N sodium'carbonate solution and three times with water, then dried over sodium sulfate. "The petrol was evaporated oif. and the residue distilled; yield 6.41 g. (40%;) of nonadecadiyn-(10,13)f-oic-(1) acid ethyl ester;

trated sulfuric acid at 0, and set aside under a nitrogen atmosphere at room temperature for 48 hours. The

methanolic solution of the ester was poured into 200 ml. water and decanted from'the tar which separated out. The aqueous solution was extracted four times with petrol (40-60) and dried over magnesium sulfate. The petrol was evaporated 0E andthe residue distilled, to yield 3.34 g. (23%) of ootadecatriyn-'(6,9,12)-oic-(1) acid methyl ester; B.P.='140l56/0.0035-0.005 mm; n =1.48 831. 3-1;;17 g..-of octadecatriyne-(6,9,l2) -oic-(1) acid methyl ester were dissolved in 30 ml. of petrol (60-80", purified) and Lindlar" catalyst added. The ester was then hydrogeriated at room temperature and atmospheric pressure. The cat'alyst was filtered 01f, the petrol evaporated and the residue distilled to yield 1.1 g. 93%) of methyl gammalinolenate; Bl. 140 (hath) /0.003 mm,

n j=1.4720. a

"gThe 'I brQm mndecadiyne-(LS) used as starting material can be prepared according to the following procedure:

To 38-9 m1; (0:575 mole) of a 1.928 N standard ethereal solution of ethyl magnesium bromide were added 300 ml.

of dry'peroxide-free tetrahydro-furan and the ether removed by distillation. A solution of 22.4 g. (0.4 mole) of propargyl alcohol in 20 ml. of tetrahydro-furan was added dropwise, with stirring at 0 over 1 hour. The mixture was stirred at room temperature for 2 hours and then heated under reflux for-2 hours; The reaction mixture was cooled, 0.9 g. of cuprous chloride was added and the whole stirred for /2 hour. 47.25 g. (0.25 mole) of 1-bromo-octyne-(2) (obtained according to the procedure described in Example 1) in 20 ml. of tetrahydro-furan were added over /2 hour and the reaction mixture refluxed under nitrogen for 24 hours. Then, 0.4 g. of cuprous chloride was added and refluxing continued for a further 36 hours. The tetrahydro-furan was removed under vacuum, the residue treated with ice and sulfuric acid, and extracted three times with ether; then, the extracts were washed with sodium carbonate solution, water, and dried over sodium sulfate and sodium carbonate. The ether Was evaporated and the residue distilled. There was obtained 33.7 g. of undecadiyn-(2,5)-ol-(1); yield 82%, B.P. 7886/0.0029 mm., n =1.4825.

28.97 g. of the product thus obtained were dissolved in 125 ml. of ether and 0.45 g. of pyridine. To the stirred solution at room temperature were added dropwise, over /2 hour, 17.24 g. of phosphorus tribrornide, the reaction heat just keeping the ether under reflux. The reaction mixture was heated under reflux for 3 hours in an atmosphere of nitrogen. It was then cooled, poured onto ice and extracted three times with ether. The extracts were washed with sodium carbonate solution and water, and dried over sodium sulfate. The ether was evaporated ofl and the residue distilled. Yield: 31 g. (77%) of l-bromoundecadiyne-(2,5); B.P. 8694/ 0.03 mm.; n =l.5 100.

Example 4 117.6 ml. (0.2037 mole) of a 1.732 N standard ethereal solution of ethyl magnesium bromide 'were concentrated by distilling oif the ether (75 ml.). The solution was cooled and 80 ml. of dry peroxide-free tetrahydro-furan were added. 12.18 g. of hexyn-(5)-oic acid in 15 ml, of tetrahydro-furan were added dropwise at over 1 hour. The reaction mixture was stirred at room temperature for 2 hours and heated under reflux for 1 hour, by which time evolution of ethane appeared complete. The reac tion mixture was cooled, 0.98 g. of cuprous chloride added and the mixture stirred for /2 hour. 18 g. of the crude l-bromo-tetradecatriyne-(2,5,8) in 20 ml. of tetrahydro furan were added to the stirred hexyn-()-yl magnesium bromide over /2 hour. The reaction mixture was heated under reflux for a total of 60 hours under nitrogen, 0.4 g. of cuprous chloride being added after the first 24 hours. The reaction mixture was cooled at 0 and poured onto a mixture of ice, dilute sulfuric acid and ether, and extracted twice with ether. The ether extracts were washed three times with 2N sodium carbonate solution; The alkaline extracts were made acid With concentrated hydrochloric acid and extracted three times with ether. The ether extract was washed with water and dried over sodium sulfate. The ether was evaporated under nitrogen and 23.5 g. of a brown syrup resulted. The syrup was treated with petrol (40-60") and ether, and cooled to 0. crystallisation of the acid occurred; it was filtered oil and washed with cold petrol. After drying in a dessicator 7.28 g, of crude eicosatetrayn-(5,8,1l,14)-oic-(1) acid was obtained; yield 36%; M.P. 69-71. Recrystallisation from petrol (4060)/ ether; M.P. 8182.

2.42 g. of pure eicosatetrayn-(5,8,1l,14)-oic-( 1) acid were suspended in 150 ml. of petrol (6080, purified), and 0.8 g, of Lindlar catalyst added. It was then hydrogenated at 21.5 and atmospheric pressure. The hydrogenation was stopped when a break in uptake curve became apparent. The catalyst was filtered 0E and the petrol evaporated off under nitrogen to yield 2.38 g. of eicosatetraen-(5,8,l1,l4)-oic-(1) acid; yield 95%.

i 3.5 g. of eicosatetraen-(5,8,11,14)-oic-(1) acid were dissolved in 140 ml. of methanolic hydrochloric acid and set aside under nitrogen for 48 hours. 50 ml, of methanol were removed under slight vacuum and the residue poured onto ice and extracted three times with ether. The extracts were washed twice with 2N sodium carbonate solution, twice'with water and dried over so- V 10 dium sulfate. The ether Was evaporated and the residue distilled yielding 2.8 g. of eicosatetraen-(5,8,11,14)-oic- (1) acid methyl ester (methyl arachidonate); B.P. 124- 136/0.0036 mm., n =1.4755.

The l-bromo-tetradecatriyne-(2,5,8) used as starting material can be prepared according to the following procedure:

178.6 ml. (0.344 mole) of 1.928 N ethereal ethyl magnesium bromide were concentrated by distilling off 100 ml. of ether. The residue was cooled and 100 ml. of dry peroxide-free tetrahydro-furan was added. 10.29 g. (0.1836 mole) of propargyl alcohol in ml. of tetrahydro-furan were added dropwise over 1 hour to the stirred solution at 0. The reaction mixture was stirred at room temperature for 1 /2 hours and then heated under reflux for 1% hours. Evolution of ethane was slightly less than theoretical. The mixture was cooled, 0.9 g. of

cuprous chloride added and stirred for /2 hour. 26.06 g. of 1-bromo-undecadiyne-(2,5) (obtained according to the procedure described in Example 3) in 20 ml. of tetrahydro-furan were addedover /2 hour with stirring and then heated under reflux for a total of 60 hours under nitrogen, 0.4 g. of cuprous chloride being added after 24 hours. The tetrahydro-furan was removed under vacuum, the" residue added to ice and sulfuric acid, and extracted three times with ether. The ether extract was washed with sodium carbonate solution and water, then dried over sodium sulfate and potassium carbonate. The ether was removed and 27 g. of a brown oil remained. The oil was dissolved in petrol (40-60") and cooled in an acetone/carbon dioxide bath, whereupon tetra'deca triyn-(2,5,8)-ol-(1) crystallised out and was filtered off and dried in a dessicator over paratfin wax; M.P. 27.5- 29.5"; yield 16 g. 1

To 16 g. of the above product in ml. of dry ether and 0.1 g. of pyridine were added dropwise, over /2 hour, 2.72 m1. of phosphorus tribromide in 15 ml. of ether under a stream of nitrogen throughout. The reaction mixture was heated under reflux on a water bath for 3 hours. It was then cooled, poured onto ice and extracted three times with ether. The ether extracts were washed twice with 2N sodium carbonate solution and twice with water. while keeping nitrogen over the solution. The extracts were dried over sodium sulfate, filtered and the ether evaporated off, leaving 18 g. of a brown syrup of crude LbIomO-tetradecatriyne-(2,5,8), which was used without further purification.

Example 5 To 3.18 g.of magnesium under 30 ml. of tetrahydrofuran were added 13.67 g. of ethyl bromide in 30 ml. of tetrahydro-furan dropwise over /2 hour at 0". After stirring at 20 for 2 /2 hours, 6.4 g. of pentyn-(4)-oic acid in 50 ml. of tetrahydro-furan were added over 1 hour at 0 and then stirred at 20 for 2 hours. 0.5 g. of cuprous cyanide was added followed by 6.6 g. of l-bromo-heptadecatetrayne-(2,5,8,l1) in 50 ml. of tetrahydro-fu-ran and the mixture heated under reflux under nitrogen for 20 hours. 7 The mixture Was concentrated, poured onto ice/2 N sulfuric acid and extracted three times with diethyl ether. The acidic material Was extracted three times with 2 N ammonia solution, washed with ether,

acidified with concentrated hydrochloric acid and exe for 1 hour at petrol (40-60).

genffive equivalents=850 ml;), the rate of hydrogenaj tioh almost stopped. The solution was filtered, concentrate dto dryness, dissolved in 50 ml. of ethanol'contai'ning 2.5 g. of hydrogen chloride'and kept at 20 under nitrogen in the dark for 15 hours. .The ethyl esterwas W distilled [B.P. 147-152/0.01 min] as a pale yellow oil;

yield 1.62 g.; n =l.4841. The ultraviolet spectrum was transparent and the infrared spectrum showed the 7 expected bands with only a trace of trans isomer. Alkali ethyl bromide in 100 ml. of tetrahydro-furan dropwise at over 1 /2 hours (after the reaction had been initiated at 20 After stirring at 20 for 17%. hours, the Grignard solution was cooled to 0 and 16.8 g. (0.3 mole) of propargyl alcohol in 40 ml. of jtetrahydro-furan were added over lhour, stirred at 20 for /2 hour'and heated under reflux for 1 /2 hours. 0.5 g. of cuprous chloride was added, followed by 26.5 g. (0.1 mole) of 1-bromo tetradecatriyne-(Liii) inSO ml. of tetrahydro-furan and the mixture heated under reflux for 20 hours in a nitrogen atmosphere. 0.5 g. of cuprous chloride was added after 17 hours. The mixturewas slightly concentrated, cooled, poured on ice, extracted three times with diethyl ether, washed twice with sodium carbonate, three times with water. and dried over sodium sulfate. YThe ether was rebf petrol (4060)..

crystallisation (twice) from petrol (60-80") gave pale cream needles; yield 74%; M.P. 5657. The ultraviolet was transparent, the infrared gave the expected bands.

14.3 g. of the alcohol thus obtained were added to 150 ml. of'diy ether and 0.1 g. of pyridine and treated under nitrogen, with 2.02 ml. of phosphorus tribromide in 25 ml. of diethyl ether over a period ,of minutes at The solution was heated under reflux for 3 hours,'cooled, poured on ice and extracted three times with ether, washed twice with 2N sodium'carbona'te solution, four times with water and dried over sodium sulfate. The ether was removed and the 1-bromo-heptadecatetrayne-(2,5,8,11) after extraction with petrol (4060) to remove explosive insoluble tar, was distilled [B.P. 145l55/ 0.01 mm., n =1.5315] as a pale yellow oil; yield 6.61 g. (36%). Redist'illation' gave an analytical sample; B.P.=160 l62/0.01 mm., n ='1.5281, M.P.=26.5-28.

Example 6 84.7 ml. (0.16 mole) of an 1.889 N ethereal ethylmagnesium bromide solution was distilled under reduced pressure in order to remove the ether. 100 ml. of tetra- ,hydro-furan were added with stirring at 0 to the resulting syrup, followed by a solution of 10.08 g. (0.08 mole) of heptyn-(6)-oic acid in 20 ml. of tetrahydro-furan over a period of 30 minutes at 5. 7 The solution was stirred 0-5" then for 3 hours at about 20. 0.5 g.

p of copper powder and 11.35 g. (0.05 mole) of l-bromoundecadiyne-(2,5) in 20 ml. of. tetrahydro-furan' were added and the mixture was stirred at about 20 for 4 /2 7 a and the product was extracted with ether, washed with water and dried with sodium'suliate.

The total crude acidic fraction (15.78 g.) was dissolved up in 150 ml. of The solution was decanted from a small amount of gum and then cooled to -5. There -moved and the residual gum crystallised from 200 V 17.8 g.' of heptadecatetrayn- (2,5,8,11),-.ol-(1) separated as brown crystals and redays under an atmosphere of nitrogen. The solution was 'were obtained 9.23 g. of the crystalline octadecatriynhours with copper-powder as thecatalyst and gave a 21% yield of the triynoic acid.

V 7 Example 7 v To a suspension of 4.81 g; (0.198 mole) of magnesium under 30 ml. of tetrahydro-furan were added at 0, 23.98 g. (0.22 mole) of ethyl bromide in 50 ml. of tetrahydrofuran overa period of 35 minutes. The solution was then stirred at about 20 for 1 hour and 11.34 g. (0.09 mole) of heptyn-(6)-oic-(1) acid in '20 ml. of tetrahydro-furau over a period of 20 minutes at 0. The solution was then stirred at about 20 for 3 hours. 0.5 g. of cuprous cyanide and 11.35 g. of l-bromoundec'adiyne (2.5)' were added and the mixture stirred and refluxed for 36 hours under nitrogen. The product was worked up as in Example 6 and the octadecatriyn-(6,9,12)-oic-(1) acid crystallised from petroleumetheras creamy needles; yield 9.97 g. (73%); M.P. 47-51-.

Example 8 furan was added dropwise to the stirred chilled solution over 30 minutesand the resulting suspension allowed to warm to about 20 over 2-3 hours. A slow stream of dry nitrogen was passed 'over the reaction mixture and 0.5 g. of anhydrous cuprous cyanide added to the stirred suspension, followed by a solution of 6.63 g. (0.025 mole) of 1-bromo-tetradecatriyne-(2,5,8) in 20 ml. of dry tetrahydro-furan. The mixture was stirred and heated under reflux for 60 hours and then chilled and poured onto ice/ ml. of 2 N sulfuric acid (fume cupboard) and extracted with diethyl ether. The ether extracts were combined and extracted three times with 2 N ammonium hydroxide (1 X 50 1111.; 2 X 25 m1.) and the ammoniacal extracts acidified to Congo red with 6 N sulfuric acid. The total acid product was extracted with diethyl ether and the extracts dried and evaporated to give 13.07 g. of a crystalline material. This was dissolved in ml. of boiling light petroleum ether 60-80"; and

chilled in ice/salt to give the eicosatetrayn-(5,8,11,14)-

An ethereal solution of. ethyl-magnesium bromide (0.08 mole) was evaporated under reduced pressure and the ether replaced by 70 ml. of dry tetrahydro-furan at 0. A solution of 8.96 g. (0.08 mole) of hexyn-(5)-oic- (1) acid in dry tetrahydro-turan was added at 0 and the experiment continued as in Example 8, but with the use of 0.5 g. of copper powder instead of cuprous cyanide and the heating time reduced to 36 hours. The reaction was worked up by adding 36 g. of ammonium chloride in 150 -rnl.of water at 0 and extracting with diethyl ether. The ether extracts were extracted with ammonia as in Example 8 and the ammoniacal extracts acidified and extracted with ether; These extracts were dried and crystallisation from 150 ml. of light petroleum ether (60-80); yield 41.6%; M.P. 79-81".

Example 10 To a suspension of 1.95 g. (0.08 mole) of magnesium under 50 ml. of dry tetrahydro-furan were added 9.59 g. (0.088 mole) of ethyl bromide in 10 ml. of tetrahydrofuran over /1 hours. After the reaction had been initiated, the addition was run at After the addition, the

solution was stirred at about 20 for 2 hours. At 5,

5.99 g. (0.04 mole) of nonadiyn-(5,8)-oic-( 1) acid in 50 ml. of tetrahydro-furan were added, under nitrogen over 1 hour. After stirring at about 20 for 2 hours, 0.5 g. of cuprous cyanide was added, followed minutes later by 4.54 g. (0.02 mole) of 1-bromo-undecadiyne-(2,5) in ml. of tetrahydro-furan, run in over 15 minutes. The solution was then heated under reflux under nitrogen for 17 hours with stirring, cooled and added to excess sulfuric acid and ice. The product was extracted three times with 50 ml. of ether, washed with water and dried with sodium sulfate. The ether was removed and the residue treated with isopropyl ether and, after filtration, the required acid crystallised out at 0 as needles melting at 73-80"; yield 1.27 g. Recrystallisation from methanol gave 0.87 g. of the pure eicosatetrayn-(5,8,11,14)-oic-(1) acid as colourless plates; yield 15%, M.P. 83-84. A mixed melting point with an authentic specimen gave no depression.

1.48 g. (0.005 mole) of eicosatetrayn-(5,8,11,14)-oic- (1) acid in 100 ml. of dry diethyl ether were added dropwise to a stirred suspension of 0.3 g. of lithium aluminuium hydride in 100 ml. of dry diethyl ether and the resulting suspension heated under reflux for 2 hours. The suspension was chilled on ice, 1 ml. of ethyl acetate added, followed by 50 ml. of 2 N dilute sulfuric acid, and the layers separated. The aqueous phase was extracted twice with 100 ml. of diethyl ether and the combined ether solutions washed with 100 ml. of 2 N sodium carbonate solution, water, and then dried and evaporated. The residual crude solid (1.4 g.) was crystallised from 50 ml. of petroleum ether (40-60) containing 8 ml. of ether and charcoal to give 0.54 g. of eicosatetrayn-(5,8,11,14)- ol-(l) as cream coloured plates; yield 38.3%; M.P. =50.551.5.

The nonadiyn-(5,8)-oic acid used as starting material can be prepared as follows:

To a suspension of 10.2 g. (0.42 mole) of magnesium under 50 ml. of dry tetrahydro-furan were added 49.05 g. (0.45 mole) of ethyl bromide in 100 ml. of tetrahydro furan over a period of 1% hours. When the reaction had started, the solution was cooled to 0. After the solution had been stirred at about 20 for 1% hours, 22.4 g. (0.2 mole) of hexyn-(5)-oic acid in 50 ml. of tetrahydro-furan were added at 5 over a period of 1% hours. 150 ml. of tetrahydro-furan were then added and the mixture was stirred at about 20 for 1% hours. 0.5 g. of cuprous cyanide was added followed by 11.9 g. (0.1 mole) of propargyl bromide in 50 ml. of tetrahydro-furan over 15 minutes and the solution was then heated under reflux in a nitrogen atmosphere for 21% hours. The mixture was cooled and poured onto excess 2 N sulfuric acid and ice. The product was extracted three times with 50 ml. of ether, washed with water and dried with sodium sulfate.

The residue, after removing the ether, was distilled to give 9.87 g. or unchanged hexyn-(5)-oic-( 1) acid (B.P. 87/0.35 mm.) and 8.01 g. of nonadiyn-(5,8)-oic acid; yield 53%, B.P. 116-117/0.40 mm. and n =1.4862.

Example 11 To a suspension of 1.27 g. of magnesium under 25 ml. of dry tetrahydro-furan were added 5.99 g. of ethyl bromide in 25 ml. of tetrahydro-furan, first at about 20 and, when the reaction was initiated, at 5 The solution was then stirred for 2 hours when a solution of 10.41 g. of the 5-[2',4',10'-trioxa-adamantyl-(3)J-pentyne-(1) in 20 ml. of tetrahydro-furan was added over 20 minutes at 0. After stirring at about 20 for 3 hours, 0.5 g. of cuprous cyanide and then 6.63 g. of l-bromotetradecatriyne-(2,5,8) in 20 ml. of tetrahydro-furan were added. The mixture was heated under reflux under nitrogen for 20 hours, cooled, added to ice cold ammonium chloride solution and the product extracted into diethyl ether, which was washed with water and dried by means of sodium sulfate. Removal of the diethyl ether gave the crude product. Treatment of this crude material with 40 ml. of 2 N sulfuric acid, 40 ml. of tetrahydro-furan and 20 ml. of ethanol at removed thejcyclohexantrioxy-( 1,3,5) group and separation of theacidic material gave eicosatetrayn-(5,8,11,14)-oic-( 1) acidas colourless crystalline material melting at 8081, after crystallisation from methanol. A mixed melting point with an authentic sample gave no depression.

The orthoesters used as starting material may be obtained according to the following procedure:

23.28 g. (0.25 mole) of 5cyano-pentyne-( 1) and 12.66 g. (0.275 mole) of absolute ethanol were cooled to 0 and 10.02 g. (0.275 mole) of dry hydrogen chloride were passed into the solution. The mixture was kept at 0-5 for 3 days. The resulting hard cake was ground up with dry diethyl ether, filtered, washed with diethyl ether and dried in a vacuum desiccator. There were obtained 43.4 g. of 1-imino-hexyn-(5)-yl-(1) ethyl ether hydrochloride [M.P. 113 (d)], which was used without further purification. (This reaction when carried out in diethyl ether is considerably slower.)

20.57 g. of the above compound were dissolved in 115 m1. of dry absolute ethanol, 200 ml. of diethyl ether were added and the solution heated under reflux tor 20 hours. The precipitated ammonium chloride (5.9 g.) was filtered off and the ethanol and diethyl ether removed by distillation. The resulting 1,1,1-triethoxy-hexyne-(5) was distilled as a colourless liquid; yield 15.43 g. (61%); B.P. 104106/ 14 mm., n =1.4309.

To a solution of 11.78 g. (0.055 mole) of the above compound in 25 ml. of absolute ethanol were added 6.6 g. (0.05 mole) of cis-1,3,5-trihydroxy-cyclohexane and 17 drops of a 45% solution of boron trifluoride in diethyl ether. The solution was kept at about 20 for 2 days, when most of the cis-1,3,5-trihydroxy-cyclohexane went into solution. 1.0 g. of potassium carbonate was added and the ethanol removed under reduced pressure. The residue was dissolved in diethyl ether and the mixture filtered. The ethereal filtrate was concentrated and the residue crystallised from ml. of petroleum ether (40- 60). The resulting hindered orthoester, 5-[2,4,10'-trioxa-adamantyl-(3)]-pentyne-(1), separated as large colourless prisms, yield 8.75 g. (84%); M.P. 5354. (Instead of boron trifluoride as a catalyst, hydrogen chloride can also be used; however, the reaction is then slow and incomplete.)

Example 12 In the same manner as described in Example 11, the

hexyne-(l) was prepared and reacted with l-bromo-undecadiyne-(2,5 in tetrahydro-furan with cuprous chloride as a catalyst. The condensation product was isolated and distilled; B.P. /0.005 mm., (yield 24%). Acid hydrolysis of this material by the method described in Example 11 gave the required crystalline octa-decatriyn- (6,9,12)oic-( 1) acid which, after recrystallisation from petroleum ether, melted at 52.5-53.5". 7

The orthoester used as starting material may be obtained according to the following procedure:

In a similar manner to the procedure of Example 11, 26.78 g. (0.25 mole) of 6-cyano-hexyne-( 1) were reacted to give 1-imino-heptyn-(6)-yl-(1) ethyl ether hydrochloride; yield 38.0 g. (80%); M.P. 97-98 (d).

56 g. ofthe above hydrochloride were suspended in 200 ml. of dry ethanol and shaken until complete dissolution occurred. The solution was kept at about 20 1 for 4 days and then filtered to remove the ammonium chloride (9.28 g.). After removal of the ethanol, diethyl ether was added and any unchanged imino-heptynyl ethyl ether hydrochloride (16.42 g.) was removed by filtration. Distillation of the filtrate gave 25.54 g. of 1,1,1- triethoxy-heptyne-(fi) (yield 50%, based on removed imino-heptynyl ethyl ether hydrochloride); B1. .103- 1l8/14mm;, n =1.4348. r r

In a similar manner ofpro'cedure to Example 11, the 1,1,1-triethoxy-heptyne (6) .Was reacted with tie-1,3,5- trihydroxy-cyclohexane to give 6- [2,4',10-trioxa-adarnantyl-(3)]hexyne-(1)in 84% yield. :It crystallised from petroleum ether (40- 60?) 'as colourless prisms; MI.- 47-492 Having now particularly described and ascertained the nature of our said invention andin what manner. the

1 t5 same is to be performed,- We declare that What we claim is: Eicosatetrayn-(5;8,1 1,14) -oic:( 1) acid.

References Cited in the file of this patent UNITED sTArEs' PATENTS OTHER REFERENCES Analytical Chem, vol. 25, pp. 953-955, June 1953.

Journal of the Chem. Soc. (London), June 1953, pp. 1785-1793.

Chem. Abstracts, vol. 28, page 1015 6 (1934).

Chem. Abstracts, vol. 38, page 1470 (.1944).