Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/18—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon triple bonds as unsaturation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
  • C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
  • C07C29/12—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of mineral acids
  • C07C29/124—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of mineral acids of halides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
  • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton

Definitions

• 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.
• 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).
• 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.
• 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.
• the invention concerns compounds having the general formula wherein h stands for an integer of from 6 to 8, and the alkyl esters thereof.
• the invention relates to heneicosapentaen-(3,6,9,l2,15)-oic-(1) acid and the alkyl esters thereof.
• 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.
• halogeno compound to be used as starting material in the process of the invention the bromides are preferred.
• 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.
• cuprous cyanide it is preferred to use cuprous cyanide as the yields are thereby enhanced.
• 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).
• 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.
• acetylenic halogeno compounds used as initial materials may all be prepared from pentyl bromide and propargyl alcohol.
• 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.
• 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,
• adamantyl compounds i.e'. the hindered orthoesters
• used as initial materials can be prepared from a nitrile of the general formula:
• 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.
• 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.
• the l-bromo-octyne-(Z) used as starting material can be produced according to the following procedure:
• 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;
• 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 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.
• 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,
• 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.
• 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.
• the l-bromo-tetradecatriyne-(2,5,8) used as starting material can be prepared according to the following procedure:
• 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.
• 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.
• 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.
• 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.
• 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 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
• the nonadiyn-(5,8)-oic acid used as starting material can be prepared as follows:
• 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.
• the orthoesters used as starting material may be obtained according to the following procedure:
• Example 12 In the same manner as described in Example 11, the
• the orthoester used as starting material may be obtained according to the following procedure:

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Cited By (13)

Citations (2)

• 1958
  • 1958-07-05 GB GB21618/58A patent/GB859897A/en not_active Expired
• 1959
  • 1959-06-22 CH CH506664A patent/CH414595A/de unknown
  • 1959-06-22 CH CH506764A patent/CH412860A/de unknown
  • 1959-06-24 DE DEH36731A patent/DE1174770B/de active Pending
  • 1959-06-30 US US823844A patent/US3033884A/en not_active Expired - Lifetime
  • 1959-07-04 ES ES0250536A patent/ES250536A1/es not_active Expired

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