FI94236B - Process for preparing 5, 8, 11-eicosatriynoic acid - Google Patents

Description

94236

Process for the preparation of 5,8,11-eicosatriynoic acid For the preparation of 5,8,11-eicosatriynoic acid

The present invention relates to a process for the preparation of 5,8,11-eiko-5 satrynic acid.

5,8,11-eicosatriynoic acid has long been known (see A. VAN DORP et Coll., Rep. 85, 1966, p. 1233). The following reaction scheme A describes a known method for its preparation. 14C can be used as a label in the synthesis, as well as the syntheses of numerous homologues of this acid are described in particular in the dissertation "ULLMAN MYRON, 1970, Ohio State University, Ph. D., Biochemistry".

15 The synthesis of this acid is described e.g. in U.S. Patent 3,033,884.

Applicants have now discovered a new process for the preparation of 5,8,11-eicosatricinoic acid which allows the preparation of the esters and amides of this invention in good yields and at the most advantageous cost (Formula B).

This method is essentially characterized by synthesizing 1-halo-2,5-tetradecadiene (3) in a single step by reacting 1-decyne (1) with ϊ: 1,4-dihalo-2-butyne (2) to give a strong base. such as in the presence of an organomagnesium base. During this reaction, decyne (1) acetyl is formed in an exchange reaction with a strong base after being reacted with an excess of dihalide (2) to give a surprisingly good yield of compound (3). The result is particularly surprising, since it is known that the synthesis of this halide has hitherto been possible by carrying out the reaction using a propargyl alcohol derivative, the yields being relatively low.

94236

Reaction formula A

a) Synthesis of 1-bromo-2,5-tetradecadine

O

hc = c-ch2oh -> hc = c-ch2-o-thp h3o + 10 (1) NaNH2 -> c8h17-c = c-ch2-o-thp (2) C8H17Br 15 h2o -> c8h17-c = c-ch2oh 20 H30 +> C8H17-CsC-CH2Br 25 PBr3 (1) BrMg-C = C-CH2OMgBr

‘* 3 * 0 -> C8H17-CsC-CH2-CaC-CH2OH

(2) H30 + 35 PBr3 -> C8H71-C = C-CH2-C = C-CH2Br pyridine 40 94236 3 b) Synthesis of the compound 5-hexynecarboxylic acid 5

NaO-CH

Br (CH2) 3Cl -> H-C = C- (CH2) 3Cl

NaCN

-> H-C = C- (CH2) 3CN

15

(1) KOH

-> H-CsC- (CH2) 3CO2H

(2) H30 + 20 c) Field reaction 25 C8H17 “C“ C_CH2’C * C'CH2Br + H_C * C ~ (CH2) 3CO2H (1) 2 eq. -C2H5 MgBr ** 30 J '(2) Cu2 (CN) 2 c8h17- (c = c-ch2) 3 (ch2) 2-co2h.

4,94236

Reaction formula B

5 a) Synthesis of 1-halogen-2,5-tetradecadine (a) strong base c8h17-c = ch -> c8h17-c = c-ch2-c = c-ch2-x 10 (b) xch2c = c-ch2x ( 1) (2) (3) 15 b) Synthesis of 5-hexynecarboxylic acid

KCN

H-C * C- (CH2) 3X -> H-CsC- (CH2) 3-CN

20 (4) (5)

(a) KOH

-> H-CsC- (CH2) 3-CO2H

<b) HCl 25 (6) c) Field reaction:: 3? 0 c8h17-c = c-ch2-c = c-ch2x + H-C = C- (CH2) 3 co2h (3) (6) 35 2 eq. -C2H5 MgBr

THF

The synthesis of Cu2 (CN) 2 c8h17- (c = c-ch2) 3- (ch2) 2-co2h40 5-hexynecarboxylic acid (6) by reaction with 1-halo-2,5-tetra-decadyne (3) is in itself 5,94236 and in a first step potassium cyanide is reacted with 1-halobentyn (4). 5-Hexynitrile (5) is also formed to the corresponding acid (6) by potassium carbonate, followed by acidification in the reaction mixture.

Acetyl of acid (6) is prepared by reaction with two equivalents of an organomagnesium compound. The dianion is also coupled with 1-halotetradecadyne in ether 10 such as tetrahydrofuran. This reaction may optionally be carried out in the presence of an aprotic solvent such as hexamethylphosphoramide (HMPA). Thus a good result is obtained with 5.8.11-eicosatriynoic acid (7).

15 EXAMPLES 5.8.11- Process for the preparation of eicosatrivnoic acid a) Process for the preparation of 1-chloro-2,5-tetradecadine 20

A two-liter beaker equipped with a stirrer and an argon feed tube is charged with 19.35 g of magnesium (0.79 g atom) followed by anhydrous tetra-. . . hydrofuran (THF) 750 cm 3. Then add dropwise>. <· 25 ethyl bromide 90.25 g (1.15 equivalents) keeping T.H.F. under the vertical condenser. At the end of the addition, the latter is maintained until the total conversion of magnesium has taken place. Then, this temperature is added dropwise to 100 g of 1-dekyyniä (0.72 mole) to about 30 during the half-hour and the mixture is kept under reflux further one and a half hours at the end of the addition. 5.20 g of copper cyanide are then added and cooking is continued for a further hour. To the acetyl of 1-decyne thus formed, 250 g of 1,4-dichloro-2-butyne, corresponding to 6,94236 2.8 equivalents relative to decine, are added at a temperature maintained in the range of 35-40 to 50 ° C. Cooking is continued for 5 hours. The solvent is evaporated on a rotary evaporator. The oily mass thus obtained is cooled and mixed with 350 cm3 of water saturated with ammonium chloride, after which the mixture is extracted 3 times with ether. The ether phase is washed twice with water, dried over magnesium sulphate, then concentrated at atmospheric pressure and then the final ether is removed at 2.6 x 102 Pa. The crude 1-chlorotetradecadiin is distilled at a temperature of 118 to 125 ° C at a pressure of 2.6 Pa. In the final fractions at temperatures of 125 to 130 ° C at a pressure of 4 Pa, the remainder is distilled from the product obtained with 1-bromo-2,5-tetradecadiin, which is formed by an exchange reaction in which chlorine is exchanged for bromine. 100 g of 1-chloro-15 2,5-tetradecadiin are obtained, containing about 3-5% of 1-bromo-2,5-tetradecadiin as determined by the RMN of the proton, which is also used in the last step of the coupling reaction.

B) A process for the preparation of 5-hexynecarboxylic acid

To a solution in an inert atmosphere is added 60.4 g of sodium cyanide (1.23 moles) in 200 cm3 of anhydrous dimethyl sulphoxide (DMSO), a solution of 115 g of 1-chloro-chloro-dichloride is added dropwise at 40-50 ° C. 4-pentyne (1.12 moles) in 100 cm 3 of anhydrous DMSO The reaction is exothermic and it is necessary to cool the reaction mixture to keep the temperature below 70 ° C. After the addition is complete, the mixture is kept at 60-70 ° C for 5 hours, after which it is allowed to stand at 20 ° C overnight. It is then mixed with 1.5 liters of water. The mixture obtained is extracted 4 times with 200 cm3 of ether. The ether phase is removed, then washed twice with 60 cm3 of water and dried over sodium sulfate and concentrated under reduced pressure.

7 94236

Add 200 g of the previous nitrile (2.15 moles) to 2.5 liters of potash (2N). The mixture is stirred continuously for two hours at 90 ° C, then cooled to 0 ° C and hydrochloric acid (5N) is added to the mixture to a pH of about 4. The resulting mixture is extracted four times with 300 ml of ether. The ether fractions are collected, washed twice with aqueous ammonium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure.

230 g of 5-hexynecarboxylic acid are obtained. This is liquid at room temperature and crystallizes at 0 ° C. Spectrum R.M.N. and I.R. correspond to the structure obtained. Elemental analysis: CgHgO2

C H O

15 Calculated: 64.27 7.19 28.54

Found: 64.32 7.21 28.41 c) Process for the preparation of 5,8,11-eicosatriynoic acid in 20,200 cm 3 of T.H.F. 20.05 g of magnesium (0.835 g atoms) are converted into ethylmagnesium bromide as described above by adding 91 g (0.835 moles) of ethyl bromide. To a solution prepared separately and which. contains 46.64 g of 5-hexynecarboxylic acid (0.417 moles)

25,200 cm 3 of anhydrous T.H.F. by stirring at 0 ° C

under an inert atmosphere, a solution of ethylmagnesium bromide prepared as described above is added.

At the end of this addition, 25 cm3 of hex-30 methylmethosphoramide and then 2.5 g of copper cyanide are stirred in. The mixture thus obtained is maintained at 50 ° C for about 1 hour to ensure the total conversion of 5-hexynecarboxylic acid to acetyl, in the form of magnesium carboxylate.

35 94236 8 To this mixture is added dropwise, at a temperature of 40 to 50 ° C, a solution of 0.32 mol of 1-chlorotetradecadiene in 100 cm 3 of T.H.F.

5 Substance T.H.F. the reaction mixture was refluxed for 21 hours. At this point, an additional 1.3 g of copper cyanide is added and refluxing is continued for another 8 hours. The solvent is evaporated off. The thick liquid obtained is acidified by adding 10 100 cm3 of sulfuric acid 4N and then 100 cm3 of sulfuric acid 2N. The heterogeneous mixture obtained is extracted 3 times with 250 cm3 of ether. The ether phases are separated and washed twice with 150 cm3 of saturated aqueous ammonium chloride solution, decanted, dried over sodium sulphate and concentrated. The product obtained is stirred in 100 cm3 of hexane and cooled to 0 ° C.

The crystals are recovered. Wash with cold hexane and dry. 48 g of 5,8,11-eicosatriynoic acid with a melting point of 69-70 ° C are obtained.

Spectrum 1H.R.M.N. and I.R. correspond to the expected structure.

i i

Il IBt III II I I I * 'I

Claims (3)

Process for the preparation of 5,8,11-eicosatriinoic acid, characterized in that 1-decine of the formula C8H17-CsC_H (1) is treated with a strong base to form acetyl which is reacted with 1,4-dihalogen-1-butyne : 10 XCH2CsC-CH2X (2) to prepare 1'-halo-1-tetradeca-2,5-diyne of the formula C8H17-CseC-CH2-OC-CH2X (3) which is reacted with 5-hexynecarboxylic acid: 20 H-CsC (CH2) 3COOH (6) 94236 For the preparation of 5,8,11-eicosatriinoinsyra, the title compound is shown in Figure 1 with the formula 5 c8h17-c = ch (1) is used as a starting material for the preparation of acetyl with the addition of 1,4-dihalo-1-butyn: XCH2C = C-CH2X (2) for the formation of 1'-halo-1-tetradeca-2,5-diine with the formula 15 C8H17-CsC-CH2-C = C-CH2X (3) with 5-hexyncarboxyl: 20 H-CsC (CH2) 3C00H (6) 1 c «