NO742234L - - Google Patents

Description

Process for the production of 2,5-furan derivatives.

</>• ..i

The invention relates to a method for production

of new 2,5-furan derivatives with the formula

in which R means an alkyl group or a group of formula ROOC-(CH?)7-, where R means hydrogen or an alkyl group, R and R means hydrogen

il c or together a further bond between two carbon atoms, R and RJ are both hydrogen, or one is hydrogen and the other a hydroxyl-4 5 6 group or an alkyl group, or R and R together are oxygen and R

is a group~CnH2n+^, where n is an integer between 1 and 10. :

Alkyl groups are to be understood here as those with up to

6 carbon atoms, for example methyl, ethyl, isopropyl, butyl and hexyl groups.

The preferred compounds are those where is an n-pent<y>l<g>ru<p>pe..

The compounds in question here have useful biological properties associated with low toxicity. They have thus been shown to

have a regulatory effect on hormone production in the Corpus luteum,

in which respect they are about as effective as prostaglandin PGP2a, but without the side effects.

The following reaction schemes show their production

new connections.

The starting materials for the preparation are furan derivatives with the formula where R" has the above-mentioned meaning and these starting materials can be produced from known substances of the formula

rfTéKsT] by formylation according to Vilsmeyer.

The aldehyde used as starting material is condensed according to the invention with the 2-oxoalkanes or 2-oxoalkyl esters suitable for the formation of the desired double bond containing a side chain in the 5-position, after which, if desired, the double tinning of the side chain is catalytically hydrogenated and/or the keto group is reduced to a secondary alcohol group or eratated with an alkyl group by Grignarding.

If R<1> in the end product is the group H00C(CH2)7-, an esterification can be carried out at the end or conversely an end product in the form of an ester can be saponified into the corresponding acid.

The establishment of the side chain in the 5-position takes place preferably at room temperature in a solution in an alkanol, e.g. methanol or ethanol.

Suitable catalysts for the hydrogenation of the double bond are Raney nickel or copper or a noble metal catalyst such as palladium.

Of the known reducing agents for selective reduction of

the keto group is preferably sodium borohydride.

The invention will be explained in more detail with the help of some examples, the various compounds being identified by the numbering in the reaction schemes listed above.

Example 1.

8-[5-(3-oxo-1-octenyl)-2-furyl7-octanoic acid (II)

I (9.17 g, 0.0364 mol), which is prepared by formylation of furyl-2-octanoic acid, is dissolved in methanol (60 ml) and the solution is cooled to -5°C. 20% aqueous NaOH (9.1 g) is added in a

portion while stirring. 2-heptanone is added to the resulting mixture with stirring at a temperature of 18-20°C over the course of 10 minutes. Stirring is continued for one hour at the same temperature and then for 16 hours at room temperature. The reaction mixture is then poured into water (130 ml) and the pH is adjusted to 7.2 with 3 N acetic acid (9.2 ml). The precipitated yellow crystals are filtered off and washed with

water (30 ml). The filtrate (F) is collected. The wet crystal plate is suspended in a mixture of water (80 ml) and ether (80 ml). The emulsion formed is neutralized to pH 7 with 3 N acetic acid. The ether layer is separated and the aqueous layer is extracted with ether (50 ml). The combined ether extracts are washed with water (50 ml) and dried over magnesium sulfate, after which it is evaporated to dryness on a water bath (60 C), finally at a pressure below 15 mm Hg. Thereby, 6.21 g of crude product of substance II is obtained in form. of a yellow oil which solidifies at room temperature.

The above-mentioned filtrate (F) is stirred with ether (50 ml) and the pH of the emulsion is adjusted to 7 with 3 N acetic acid. • The ether layer is separated and the aqueous layer is extracted with ether (50 ml). The Eterek stretches are united and worked up as above. Chromatography of the yellow, oily residue produced (5.30 g) on silica gel (150 g, sieve 60<-120 mesh) and elution with increasing concentration of acetone in n-hexane gave 2.20 g of crude II.

The combined crude products were crystallized from n-hexane (250 mL). Thereby 7.45 g (6l#) of II as pale yellow crystals with melting point 58-5$°C.

Example 2.

Methyl- f -/~ 5-( 3- oxpl- l- octenyl)- 2- furyl7- octanoate ( III)

A. II (2.52 g, 0.00755 mol), methanol (30 mL) and ethyl ether-boron trifluoride complex (0.24 g) were stirred and refluxed for one hour. After cooling, the reaction mixture was poured into ice water

(150 mL) and extracted with two 80 mL portions of ether. The combined ether extracts are washed with cold 1055 µg aqueous sodium carbonate and then with two 50 ml portions of cold water. The ether solution was dried over magnesium sulfate and evaporated to dryness on a water bath (60°C) finally at a pressure below 15 mm Hg. Distillation under nitrogen of the remaining oil (2.46 g) gave 2.07 g (79/0 of III, .

bp 0.3 mm Hg, 202-204°C, n^<5>1.5262.

Calculated for C21E32°1* (348.5): C 72.4 H 9.3 en 0CH 38.9.; Found C 72.5 H 9.2 OCHj 8.9. B. 50% sodium hydride in mineral oil (0.96 g, 0.02 mol); was suspended in dry 1,2-dimethoxyethane (200 mL). The suspension was cooled at 15°C and, with vigorous stirring, (2-oxoheptyl)-phosphoric acid dimethyl ester (Wadsworth et al: JACS 83; (1961) 1733) (-4.44 g, 0.02 mol) was added dropwise during 30 minutes, the reaction temperature being kept at 15-20°C. After the addition, which formed a white voluminous precipitate, it was stirred for one hour at room temperature, whereby the precipitate was suspended in the liquid. ;A solution of I (5.04 g, 0.02 mol) in 1,2-dimethoxyethane (30 mL);was added dropwise over 30 minutes to the stirred suspension, ;which was maintained at a temperature below 25° C. The cloudy, yellow solution formed was stirred for 1 hour at room temperature, after which the solvent was distilled off on a water bath (70°e) under reduced pressure (40 mm Hg). After cooling, the oily residue was diluted with cold water (300 ml) and extracted with two 200 ml portions of ether. The combined ether extracts were washed with two 100 ml portions of water and dried over magnesium sulfate, after which it was evaporated to dryness on a water bath (60°C), finally at a pressure of 15 mm Hg. The remaining yellow oil was purified by distillation under nitrogen. 6.34 g (91?) of III" was obtained as a yellow liquid, bp. 0.1 mm Hg 194-200°C, nD 25 1.5256. By thin layer chromatography it showed the same R^ values in various solvents as the product according to the method mentioned under A. ;Example 3. ;Ethyl 8-[5-(3-oxo-1-octenyl)-2-furyl 7-octanoate (IV);A mixture of II (9.94 g, 0.0298 mol), ethanol (190 mL); and ethyl ether boron trifluoride complex (0.97 g) were stirred and refluxed for 1£ hour. After cooling, the reaction mixture was poured into ice water (600 mL) and extracted with three portions of ether. The combined ether extracts were washed with cold 10% aqueous sodium carbonate (100 mL) and then with two 200 mL portions of cold water. The ether solution was dried over magnesium sulfate and evaporated to dryness on a water bath (60°C) finally at a pressure of 15 mm Hg. The remaining yellow oil (9.84 g) was purified by distillation under nitrogen from a flask internally coated with potassium acetate, yielding 8.57 g t) of IV, b.p. 0.2 mm Hg 198 -2 01°C, n^<5>1.5217.; ; Example 4.;Ethyl 8-[5-(3-oxooctyl)-2-furyl 7-octanoate (V)<:>;IV (1.74 g, 0.0048 mol), ethanol (25 ml) and Raney -copper (0.75 g) was shaken with hydrogen under 80. atmospheric pressure for 6 hours at 30°C. After filtration, the ethanol was distilled off on water (60°C) under reduced pressure* To the distillation residue was added ether (30 ml) and the cloudy solution was filtered. The ether solution was evaporated to dryness on a water bath (50°C) under reduced pressure, finally below 15 mm Hg. The remaining oil was purified by distillation under nitrogen to give 1.51 g (86?) of V as an almost colorless oil with a boiling point of 0.2 mm. Hg, 178-l8l°C and nj?5 1.4700.

Example 5.

Ethyl 8-[""5-(3-hydroxyoctyl)-2-furyl7-octanoate (VI)

V (1.25 g, 0.00343 mol) was dissolved in anhydrous ethanol

(70 mL) and the solution was cooled to -5°C. Sodium borohydride (0.50 g, 0.0132 mol) was added portionwise with stirring over 3 minutes. The cloudy solution was stirred for 15 minutes at 0-5°C and then at room temperature for one hour. The colorless solution became clear. in ice water (250 mL) and 1.5 N sodium hydroxide was added with stirring to the resulting emulsion. The stirring was continued

for 15 minutes, after which the white emulsion was extracted with three 100 ml portions of ether. The combined ether reactants were washed with cold VRnn (1.00ml ) Offtrfrlmt: nvpr TII Sl O-n f» R ■? tlTTIRnl barrel-. Vcwr>T><a-t-.f-.OT» nnnl ^aninrrq-

the agent was finally distilled on a water bath (60°C) at a pressure of 15 mm Hg. Distillation of the residual oil (1.34 g) gave 118 g (94?) of VI as a colorless oil bp 0.1 mm Hg, 172-175°C and n£5 1.4731.

Example 6.

8-/~<,>5-(3-oxooctyl)-2-furyl7-octanoic acid (VII)

A mixture of V (5.10 g, 0.014 mol), methanol (180 ml) and 20% aqueous potassium carbonate (60 g) was stirred and refluxed for one hour. The cloudy solution was concentrated to 1/4 of its volume by distillation on a water bath (60°C) under reduced pressure. It. the remaining residue was diluted with water (300 ml) and the resulting clear solution acidified to pH 6 with acetic acid. The resulting emulsion was extracted with two 150 ml portions of ether and the combined ether extracts were washed with two 100 ml portions of water and dried over magnesium sulfate. The ether was distilled off on a water bath

(60 C), finally at a pressure below 15 mm Hg. The yellow, oily residue (4.62 g) solidified at room temperature. Reasing by crystallization from n-hexane (40 ml) gave 3.54 g (75%) of VII in the form of slightly yellow crystals with a melting point of 64-65°C.

Example 7»

l^( 5- methyl- 2- furyl)- l- octen- 3-ol ( X)

The starting material, 1-(5-methyl-2-furyl)-1-octen-3-one (IX), which is known (CHEM.ABSTR. 74 (1971) 141, 418 g), was prepared from VIII (J. Org. Chem. 22 (1957) 1269) following instructions given in the literature (JACS 70 (1948) 2695).

IX (1.65 g, 0.008 mol) was dissolved in anhydrous ethanol

(200 mL) and the solution was cooled to 0°C, after which sodium borohydride (0.79 g, 0.0185 mol) was added in one portion with stirring.

The cloudy solution formed was stirred at 0-5°C for 15 minutes and then for 20 hours at room temperature. The solution was concentrated to 1/4 of the volume by distillation on a water bath (40°C) under reduced pressure (50 mm Hg). The remaining solution was cooled to 10°C and then cold water (800 ml) was added first and then . N sodium hydroxide (25 ml) with stirring. This was continued for 15 minutes at room temperature and then the pH was adjusted to 7.8 by the addition of 3 N acetic acid. The reaction mixture was extracted with two 15 µl portions of ether. The combined ether extracts were washed with water (100 ml) and dried over magnesium sulfate, after which the ether solution was evaporated to dryness on a water bath (60°C) under reduced pressure, finally below 15 mm Hg. The remaining oil (1.67 g) was purified by distillation under nitrogen to give 1.13 g (68?) of X as a yellow liquid bp 0.2 mm Hg, 97-99°C and nj^ 1.5166 . Example 8.

8^/f"5-(3-Hydroxyoctyl)-2-furyl7-octanoic acid (Via)

A mixture of VI (2.73 g, 0.00745 mol), methanol (100 mL) and 20 µg aqueous potassium carbonate (30 mL) was stirred and refluxed for one hour. The cloudy solution was concentrated to 1/4 of the volume by distillation on a water bath (60°C) under reduced pressure (60 mm Hg). The evaporation residue was diluted with water (100 ml) and

adjusted to pH 7 with acetic acid (2.7 mL). The resulting emulsion was extracted with two 80 mL portions of ether and the combined ether extracts were washed with water (100 mL) and dried over magnesium sulfate. The ether: was finally distilled off on a water bath (50°C) under a pressure of 15 mm Hg. The yellow oily residue (2.58 g) was purified by crystn.

lysis from petroleum ether (boiling point below 50°C) (450 ml), whereby 2.13 g (84?) of Via appeared as almost white crystals with a melting point of 43-45°C

Example 9.

Methyl 8-[5-(3-oxooctyl)-2-furyl 7-octanoate

III (11.37 g, 0.0326 mol), methanol (100 mL) and Raney nickel (2.5 g) were stirred at room temperature under hydrogen at one atmosphere until one molar equivalent of hydrogen was taken up. After filtration, the solvent was removed by distillation on a water bath (60°C). under reduced pressure, finally below 15 mm Hg. The remaining pale yellow oil (11.4 g) was purified by preparative thin layer chromatography (tic) on silica gel (mixture of petroleum ether (bp below 50°C) and ether (2:1) as eluent). This resulted in 7.25 g of a faintly yellow oil, which, after further purification by distillation under nitrogen, gave 7.05 g (62?) of the title compound as an almost odorless oil with a boiling point of 0.07 mm Hg, 172- 180<p>C and n^<5>1.4723.

Example, 10. Methyl 8-[5-(3-hydroxyoctyl)-2-furyl-7-octanoate The ester according to example 9 (1.61 g, Q.0046 mol) was dissolved in methanol (30 ml) and sodium borohydride (0.80 g, 0.021 mol) was added at -10° C. with stirring, this was continued for 90 minutes during which the temperature rose to 22-25° C. The resulting solution was poured into ice water (200 mL), 1.5 N aqueous sodium hydroxide (10 mL) was added and the resulting emulsion was stirred for 15 minutes, after which it was extracted with three 100 mL portions of ether. The combined ether extracts were washed with two 100 mL portions of water and dried over magnesium sulfate. The ether solution was evaporated to dryness on water bath (60°C) under reduced pressure (15 mm Hg) The residual oil (1.59 g) was purified by distillation under nitrogen to give 1.50 g ( 93%) of the title compound as a colorless oil with a boiling point of 0.07 mm Hg, 176-178°C and n£<5>1.4759. Example 11. 8-/"~5-(3-Hydroxyoctyl)-2-fury 17-octanoic acid A mixture of the ester from Example 10 (2.73 g, 0.0077 mol), methanol (100 mL) and 20 ?-ig aqueous potassium carbonate (30 ral) was stirred and refluxed for one hour. The colorless solution was evaporated to 1/4 of the volume on a water bath (60°C) under reduced pressure (60 mm Hg). The evaporation residue was diluted with water (100 mL) and the resulting cloudy solution was acidified to pH 6 with acetic acid.The resulting emulsion was extracted with two 100 mL pnions ether. The combined ether extracts were washed with two 100 ml portions of water and dried over magnesium sulfate. The ether was distilled off on a water bath (60°C) while reducing the pressure, finally below 15 mm Hg. It remaining yellow oily residue (2.58 g) solidified at 10°C. Purification by crystallization from petroleum ether (boiling point below 50°C) (450 ml) gave 2.13 g (81?) of the title compound as white crystals, m.p. 43-45°C.

Example 12.

Methyl 8-[5-(3-hydroxy-3-methyloctyl)-2-furyl7-octanoate (XIII)

VII (4.50 g, 0.0133 mol), pyridine (25 mL), hexamethyldisilazane (HMDS) (7.2 mL) and trimethylsilyl chloride (TMCS) (2.4 mL) were mixed and the mixture was set aside for the next day protected from humidity. The resulting suspension was filtered in a dry atmosphere and the filtrate was evaporated on a water bath (8o°C) under reduced pressure (10 mm Hg). The evaporation residue was mixed with dry ether (50 ml) and filtered to remove a small amount of insoluble material. The filtrate was cooled to 2°C in a dry nitrogen atmosphere and 3.7 molar ethereal solution of methylmagnesium bromide (7.8 mL, 0.0289 mol) was added dropwise with stirring at 10°C over 25 minutes.

The resulting suspension was allowed to stir at room temperature until the next day and was then added to a mixture of normal HCl (32 ml) and water (120 ml) at a temperature of 5°C and the resulting mixture was stirred for 90 minutes. The ether phase was then separated and the water phase extracted with ether. The combined ether extracts were extracted with 0.5 N aqueous sodium hydroxide (40 mL). The aqueous extract was acidified with 0.5 N HCl (42 mL) and extracted with two 25 mL portions

ether. The combined ether extracts were dried over magnesium sulfate and evaporated to dryness on steam (70°C) finally below 15 mm Hg.

The remaining crude acid XII (4.23 g) was esterified in a mixture of methanol (50 mL) and ether boron trifluoride complex (0.5 mL) to give the crude methyl ester XIII (4.2 g). The ester was purified by chromatography on a column of silica gel with a mixture (1:1) of petroleum ether and ether as eluent and gave 2.1 g of an oily product which, on distillation under nitrogen, gave 1.83 g (37?) of XIII with boiling point 0.3 mm Hg 178-180°C and n£<5>1.4749.

The NMR spectrum was found to be consistent with the assumed structure of XIII.

Example 13. 8-/"~5-(3-Hydroxy-3-methyloctyl)-2-furyl7-octanoic acid (XII)

A mixture of XIII (0.91 g, 0.025 mol), methanol (10 mL) and 20 µg aqueous potassium carbonate (5 mL) was stirred and refluxed for 90 minutes. The resulting pale yellow solution was mixed with water (15 ml) and acidified to pH 5-6 with acetic acid. The resulting emulsion was extracted with two 15 mL portions of ether and the combined ether extracts were dried over magnesium sulfate. The ether was finally distilled off on a water bath (60°C) at a pressure of 0.1 mm. Hg. The remaining yellow oily residue (0.86 g) was purified by chromatography and the thus isolated crude compound XII was distilled at 175-185°C and 0.03 mm Hg to give 0.6.3 g of XII (71?) as a pale yellow oil with n£5 1.4844.

Example 14.

l-(5-alkyl-2-furyl)-octen-3-ones ( XVII, XVIII)

To a stirred solution of a 5-alkylfuraldehyde (0.0666 mol) and 2-heptanone (9.3 ml, 7.58 g, 0.0666 mol) in methanol was added 20 µg of aqueous sodium hydroxide (1, 8 ml) drop by drop at 10-12°C. within 10 minutes. The resulting clear yellow solution was stirred at the same temperature for one hour and then for 18 hours at room temperature, after which the pH was adjusted to % by adding acetic acid. The reaction mixture was poured into water (100 ml) and

extracted with two 70 ml portions of ether. The combined extracts were washed with three 50 ml portions of water and dried over magnesium sulfate. The ether solution was evaporated to dryness on a water bath (70°C) under reduced pressure, finally below 15 mm Hg and the remaining oil purified by distillation at 10 mm Hg.

- Example 15 ♦' 1^( 5-alkyl-2-furyl)-3-octanones ( XIX- XXI ) A 1-(5-alkyl-2-furyl)-1-octen-3-one (0.03 mol ), methanol (150 ml) and Raney nickel (10 wt?, of the starting material) stirred at room temperature under hydrogen of atmospheric pressure, until a molar equivalent of hydrogen was occupied. After filtration, the solution was 'the agent removed by distillation on a water bath (60°C) under reduced pressure, finally below 15 mm Hg. The remaining pale yellow oil was purified. by preparative thin-layer chromatography, with silica gel being used as adsorbent and a 1:8 mixture of ether and petroleum ether (boiling point below 50°C) as developing fluid. The adsorbent was removed and stirred for one hour with ether. After filtration, the ether solution was evaporated to dryness on a water bath (60°C) under reduced pressure (15 mm Hg). The remaining oil was purified by distillation under reduced pressure.

Example 16.

5- alkyl- a- pentyl- 2- furan propanols ( XXII- XXIV)

A i-(5-alkyl-2-furyl)-3-octanoh (XIX-XXI) (0.015 mol) was dissolved in ethanol (90 ml) and added with stirring at

-10°C. sodium borohydride (2.40 g, 0.064 mol). The stirring was continued. for 90 minutes, whereby the temperature of the reaction mixture rose to 23-25°C. The colorless solution was poured into ice water (300 ml) and 1.5 N aqueous sodium hydroxide (20 ml) was added, after which it. resulting emulsion was stirred for 10 minutes. The reaction mixture was extracted with three 100 mL portions of ether. The United Etherek stretches were washed with two 100 ml portions of water and dried over magnesium sulfate, after which it was evaporated on a water bath (60°C) under reduced pressure (15 mm Hg). The remaining oil was purified by distillation under reduced pressure.

Claims (1)

Process for the preparation of 2,5-furan derivatives with formula wherein R means an alkyl group or a group 2 of the formula ROOC-(CHP)7-, where R means hydrogen or an alkyl group, R and R .mean hydrogen or together a further bond between the two carbon atoms, R and R means both hydrogen or one is hydrogen and the other one hydroxyL li c f . group or an alkyl group, or R and R^ together mean oxygen and R means a group .Cn H2n+^ , where n is an integer between 1 and 10, is characterized by the fact that an aldehyde with formula is condensed with a suitable 2-oxoalkane or 2-oxoal-kyla=b£r for the formation of the desired, a double bond containing a side chain in the 5-position, after which, if desired, the double bond of the side chain is catalytically hydrogenated and/or the keto group is reduced to a secondary alcohol group or replaced with an alkyl group by Grignarding.