CA1053686A - Furane derivatives and production thereof - Google Patents
Furane derivatives and production thereofInfo
- Publication number
- CA1053686A CA1053686A CA202,704A CA202704A CA1053686A CA 1053686 A CA1053686 A CA 1053686A CA 202704 A CA202704 A CA 202704A CA 1053686 A CA1053686 A CA 1053686A
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- carbon atoms
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
This invention relates to therapeutically active 2,5-furane derivatives, wherein the substituent in the 2-position is a lower alkyl group or a group ROOC-(CH2)7-, in which R is hydrogen or lower alkyl, the 5-substituent being an alkyl or alkenyl group of 4 to 13 carbon atoms, which may be substituted with an oxygen atom or a hydroxy group and/or a lower alkyl group at the third carbon atom, counted from the furane ring, and to the production thereof.
This invention relates to therapeutically active 2,5-furane derivatives, wherein the substituent in the 2-position is a lower alkyl group or a group ROOC-(CH2)7-, in which R is hydrogen or lower alkyl, the 5-substituent being an alkyl or alkenyl group of 4 to 13 carbon atoms, which may be substituted with an oxygen atom or a hydroxy group and/or a lower alkyl group at the third carbon atom, counted from the furane ring, and to the production thereof.
Description
The present invention relates to 2,5-furane derivatives and their production and to intermediates in the said production.
The furane derivatives of the invention are represented by the following formula R1~3L CR - CH -- C - R
wherein R represents a lower alkyl group, or a group of the formula ROOC-(CH2)7, wherein R represen~s hydrogen or a lower -. 10 alkyl group, each of R2 and R3 represents hydrogen, or R2 and R3 `:.
together represent a further bond between the two carbon atoms, R4 represents hydrogen, or a lower alkyl group, and R5 represents :
hydroxy, or R4 and R5 together represent an oxygen atom, and R6 .
represents agroup C5Hll,provided that:..~hen-R represents methyl at least one of R2, R and R is other than hydrogen, and when l represents methyl, and R4 and R5 together represent an oxygen atom, R2 and R3 are hydrogen.
The lower alkyl groups of the present compounds are preferably those having 1-4 carbon atoms, i.e., methyl, ethyl, . 20 propyl, isopropyl, butyl, isobutyl, and tert.butyl. The R6 group . is preferably an n-pentyl group.
The compounds of the invention have useful biological . ~ ~ properties combined ~ith a relatively low toxicity. Thus, they .~ have a controlling effect upon the hormone production of corpus .
. .~ .
. ~ ; ..luteum, and are ln that respect almost as effective as the - ~ prostaglandin PGF2~ without however, showing any side effects. : :
. ~ The following schemes of reaction illustrate the . ~ production:~of the compounds of the invention $`~ `
r i: :
~ ( 2)7 ~ O ~ CHO + C5HllCOCH3 NaOH
., O
l~O-C-(CH2)7 _ ~0 ~ _ CH=CHCOC5H11 3( 2 5)2 CH O-C-(CH ) ~ CH=CHCOC5H
III
I + CH3(CH2)4-RC-cH2 n (0CH3)2 > III
O O
II + C2H5H 3 2 4)2 ~
~ NaBH
C2H40-C-(CH2)7 ~ 0 ~ CH C 2 5 11 .' IV
'` C2H50-C-(CH2)7 ~ CH=CH2CHOHC5H
~ IVa ,' H2, Raney-Cu C2H50-C(CH2)7 ~ CH2CH2COC5H 4 >
~: V
C2H50-C- (CH2) ~CH2CH2CHOHC5H
~: VI
VI 2 3 > HO-C-(CH2~7 ~ CH2CH2CHOHC5H
VIa ~, .
. ~ .
, ~ .
.
K2C3 HO-C- (Cl~2) 7 ~CH2CH2COC5Hll O
VII
CH3 ~L CHO + C5HllCOCH3 - ~
VIII
CN3~LCH=CH-COC5H H4 IX
.
CH InL CH--C
3 o -- H--CHOHC5Hl 1 V
VII THCS,HMDS ,~ [CH3~5iOOC-(CH2)~CH2)2cOc5Hll]
XI
1. CH3MgBr ~ I H3
The furane derivatives of the invention are represented by the following formula R1~3L CR - CH -- C - R
wherein R represents a lower alkyl group, or a group of the formula ROOC-(CH2)7, wherein R represen~s hydrogen or a lower -. 10 alkyl group, each of R2 and R3 represents hydrogen, or R2 and R3 `:.
together represent a further bond between the two carbon atoms, R4 represents hydrogen, or a lower alkyl group, and R5 represents :
hydroxy, or R4 and R5 together represent an oxygen atom, and R6 .
represents agroup C5Hll,provided that:..~hen-R represents methyl at least one of R2, R and R is other than hydrogen, and when l represents methyl, and R4 and R5 together represent an oxygen atom, R2 and R3 are hydrogen.
The lower alkyl groups of the present compounds are preferably those having 1-4 carbon atoms, i.e., methyl, ethyl, . 20 propyl, isopropyl, butyl, isobutyl, and tert.butyl. The R6 group . is preferably an n-pentyl group.
The compounds of the invention have useful biological . ~ ~ properties combined ~ith a relatively low toxicity. Thus, they .~ have a controlling effect upon the hormone production of corpus .
. .~ .
. ~ ; ..luteum, and are ln that respect almost as effective as the - ~ prostaglandin PGF2~ without however, showing any side effects. : :
. ~ The following schemes of reaction illustrate the . ~ production:~of the compounds of the invention $`~ `
r i: :
~ ( 2)7 ~ O ~ CHO + C5HllCOCH3 NaOH
., O
l~O-C-(CH2)7 _ ~0 ~ _ CH=CHCOC5H11 3( 2 5)2 CH O-C-(CH ) ~ CH=CHCOC5H
III
I + CH3(CH2)4-RC-cH2 n (0CH3)2 > III
O O
II + C2H5H 3 2 4)2 ~
~ NaBH
C2H40-C-(CH2)7 ~ 0 ~ CH C 2 5 11 .' IV
'` C2H50-C-(CH2)7 ~ CH=CH2CHOHC5H
~ IVa ,' H2, Raney-Cu C2H50-C(CH2)7 ~ CH2CH2COC5H 4 >
~: V
C2H50-C- (CH2) ~CH2CH2CHOHC5H
~: VI
VI 2 3 > HO-C-(CH2~7 ~ CH2CH2CHOHC5H
VIa ~, .
. ~ .
, ~ .
.
K2C3 HO-C- (Cl~2) 7 ~CH2CH2COC5Hll O
VII
CH3 ~L CHO + C5HllCOCH3 - ~
VIII
CN3~LCH=CH-COC5H H4 IX
.
CH InL CH--C
3 o -- H--CHOHC5Hl 1 V
VII THCS,HMDS ,~ [CH3~5iOOC-(CH2)~CH2)2cOc5Hll]
XI
1. CH3MgBr ~ I H3
2~ H30 `: ~ HOOC (CH2) 7 ~ y_ ~CH2) 2- ~ - C5Hll `: OH `~
` ` XII ~-, ~`H~ BF3(C2H5)20 ~ ~ ~ CH30C~(CH2)~7 (CH2)2 - C - C5Hll - :
. ~ ~ o : OH
. , ~ : XIII
R ~CII--CHCOC5H
2 `~ C2H5 ` XVII
H ~ CH ~ ) ~ XV I I 1 . ~
-`- 1053686 H2, Raney Ni R ~ (CH2)2COCs~ll -CH3 XIX ~
C2~5 XX
-CH ( CH 3 ) 2 XXI
b I
NaBH4 . ~ R ~, O ~(CH2) 2CHOHC5H
R:
c --CH3 XXI
, -CH (CH 3 ) 2 XXIV
j~ The starting material for the production of the ¦`~ compounds of the invention are furane derivatives of the formula .:. ~ - :
~ ~ R ~CHO
.~ . , wherein Rl is as hereinbefore defined, which can be produced from known compounds of the formula R ~ -or oxample by formylating according to Vilsmeyer.
The starting aldehydes are condensed with the appropriate àlka~n-2-one, e.g. 2-heptanone, or a 2-oxoalkyl-phosphonic acid dimethyl~ ester~to estab1ish a 3-oxo-l~alkenyl group at the 5-~position~of the furane ring and optionally hydrogenating at the --double bond in l-positionof said side chain catalytically, and educing the keto group with sodlum horohydride or subjecting O~ the-keto group to a Grignardation using an alkyImagnesium halide as~the Grignard reagent.
~ When Rl represents the group ROOC-(CH2)7-, wherein R is : ~ ~ --5--~, " , . ' ., ' . ' ' i ~ , . -:. , ' , hydrogen, the carboxyl group may subsequently be esterified to yield esters of the invention or, if the resultin~ compound is an ester, it may be saponified to yield the corresponding acid.
The introduction of the side chain in 5-position is preferably carried out at room temperature in solution in an alkanol, e.g. methanol or ethanol.
Suitable catalysts for the hydrogenation are Raney nickel, Raney copper, and noble metal catalysts, e.g. palladium.
The following examples are illustrative of the production of the present compounds, the various compounds being identified by the numbering in the above schemes of reaction.
Example 1 8-[5-(3-Oxo-l-octenyl)-2-furyl]-octanoic acid (II) I (9.17 g, 0.0364 mole), produced by formylating iuryl-- 2-octanoic acid, was dissolved in methanol (60 ml), and the solution was cooled to -5C. Aqueous 20% sodium hydroxide (9.1 g) was added in one portion with stirring. To the resulting mixture, 2-heptanone t5.05 g, 0.0444 mole) was added with stirring over a " period of 10 minutes at a temperature of 18-20C. The stirring . 20 was continued for one hour at the same temperature, and then for additional 16 hours at room temperature. The reactlon mixture was poured into water (130 ml) and adjusted to pH 7.2 with 3N acetic acid (9.2 ml). The resulting yellow crystals`were isolated by .~. ~ .
filtration and washed with water (30 ml). The filtrate (F) was -collected. The wet cake of crystals was suspended in a mixture of water (80 ml) and ether (80 ml) and stirred. The resulting . ~ emulsion was neutralized to pH 7 with 3N acetic acid. The ethereal layer was separated. The aqueous layer was extracted A ~. . .
~- ~ with ether (50 ml). The combined ethereal extracts were washed with water (50 ml) and then dried over magnesium sulfate. The dried ethereal solution was evaporated to dryness from a water bath (60DC), at last under 15 mm Hg. 6.21 g of crude II were ; :
~.
. . , . - , .
hereby obtained as a yellGw oil, which solidified at room temp-erature.
The above filtrate (~) was stirred with ether (50 ml) and the pH of the emulsion was adjusted to 7 with 3N acetic acid.
The ethereal layer was separated, and the aqueous layer extracted with ether (50 ml). The combined ethereal extracts were washed with water (50 ml), dried over magnesium sulfate, and the ether removed ~y distillation from a water bath (60~C), at last under ~ -15 mm Hg. Chromatography of the yellow, oily residue (5.30 g) on silica gel (150 g, 60-120 mesh, from sDH Chemicals Ltd.) 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). 7.45 g (61%) of II were hereby obtained as pale, yellow crystals, m.p. 58-59C.
Calculated for C20H30O4 (334.4): C 71.8~ H 9.0 Found : C 71.7, H 9.0 Example 2 8-[5-(3-Oxo-l-octenyl)-2-furyl]-octanoic acid methyl ester (III) A. II (2.52 g, 0.00755 mole), methanol (30 ml), and ethyl ether-~
~- borontrifluoride complex (0.24 g) were stirred and heated under ref-lux for 1 hour. After cooling, the reaction mixture was poured into ice-water (150 ml) and extracted with two 80-ml portions of ethcr. The combined ethereal extracts were washed with cold 10%
sodium oarbonate ~50 ml) and then with two 50-ml portions of cold -~ater. The ethereal solution was dried over magnesium sulfate and e~aporatèd to-dryness from-a water bath (60C),-at last under 15 Hg. Distillation under nitrogen of the residual oil (2.46 g) gave 2.07 g (79%) of III, bo;3 202~204C, nD 1.5262.
~-~; 3Q C,alculated for C21H32O4 (348.5): C 72.4, H 9.3 one OCH3 8.9 Found : C 72.5, H 9.2 OCH3 8.9 ~, -l~ ~ B. 50% sodium hydride in mineral oil (0.96 g, 0.02 mole) was-i :
~:
; -7-_.. , . . .. . . . -. - .... . . ~ .. :
... . . . .
suspended in dry 1,2-dimethoxyethane (200 ml), The slurry was cooled to 15C and stirred vigorously with a mechanical stirrer.
(2-Oxoheptyl)-phosphonic acid dimethyl ester (Wadsworth et al:
J.A.C.S. 83 (1961) 1733) (4.44 g, 0.02 mole) was added dropwise over a period of 30 minutes, the reaction temperature being kept at 15-20C. After the addition, the suspension of a white, voluminous precipitate was stirred for 1 hour at room temperature.
A solution of I (5.04 g, 0.02 mole) in 1,2-dimethoxyethane (30 ml) was added dropwise over a period of 30 minutes to the stirred suspension, maintained below 25C. The resulting turbid, yellow solution was stirred at room temperature for 1.5 hours. The solvent (200 ml) was distilled off from a water bath (70C) 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 ethereal extracts were washed with two 100-ml portions of water and then dried over magnesium ` sulfate. The dried ethereal solution was evaporated to dryness from a water bath (60C), at last under 15 mm. The residual yellow oil was purified by distillation under nitrogen. 6.34 g ;
~91%) of III was hereby obtained as a yellow liquid, bo 1194-200C, 1.5256. In tlc it had the same Rf values in different solvents as the compound obtained by method A.
Example 3 8-15-~3-Oxo-l-octenyl)-2-furyl]-octanoic acid ethyl ester ~IV) ,: .
A mixture of II (9.94 g, 0.0298 mole), ethanol (190 ml), ;and ethyl ether-borontrifluoride complex (0.97 g) was stirred and heated: under-reflux-for 1.5 hours.- After cooling, the reaction mixture-was poured into ice-water (600 ml) and extracted with three 300-ml portions of ether. The combined ethereal extracts -h ~ ; .
~ 30 were washed with cold 10% sodium carbonate (100 ml~ and then with ; 200-ml portions of cold water. The ethereal solution was dried -~
~ ~ over magnesium sulfate and evaporated to dryness from a water bath ~ ~ ' ~; -8-1~53686 (60C), at last under 15 mm Hg. The resid~al yellow oil (9.84 g) was purified by distillation under nitrogen from a potassium acetate coated flask giving 8.57 g (79%) of IV, b 2 198-201~C, n25 1.5217.
Calculated for ~22H344 (362.5): C 72.9, H 9.5, OC2H5 12.4 Found : C 73.0, H 9.5, OC2H5 12.3 Example 4 8-[5-(3-Oxooctylj-2-furyl]-octanoic acid ethyl ester (V) IV (1.74 g, 0.0048 mole), ethanol (25 ml), and Raney 10 cooper (Ponomarev et al., J. Gen. Chem. USSR 30 (1960) 584) (0.75 g) were shaken under 80 atmospheres of hydrogen for 6 hours at 30C. After filtration, the ethanol was distilled under reduced pressure form a water bath (60C). Ether (30 ml) was added to the residue, and the turbid solution was filtered (G4, Celite a trademark). The ethereal solution was evaporated to dryness from a water bath (50C) under reduced pressure, at last under 15 mm Hg. The residual oil was purified by distillation under nitrogen.
1.51 g t86%) of V was hereby obtained as an almost colorless oil, bo 2 178-181C, nD 1.4700.
i~ 20 Calculated for C22H36O4 (364.5): C 72.5, H 10.0, OC2H5 12.4 Found : C 72.3, H 10.0, OC2H5 12.4 Example 5 8-~5-(3-Hydroxyoctyl)-2-furyl]-octanoic acid ethyl ester (VI) V (1.25 g, 0.003~3 mole) was dissolved in absolute ethanol ~70 ml), and the solution was cooled to -5C. Sodium '~ tetrah~droborate ~O.50 g, 0.0132 mole) was added portionwise during ~ minutes with stirring.- The--turbi-d solution was stirred at~0-5~C--for 15 minutes, then at room temperature for 1 hour. The colorless solution was poured into ice-water (250 ml). 1.5 N
30 sodium hydroxide (10 ml) was added with stirring to the resulting ~
emulsion. The stirring was continued for 15 minutes. The white emulsion was extracted with three 100-ml portions of ether. The _ g _ : . . , : , . , combined ethereal extracts were washed with cold water (100 ml), dried over magnesium sulfate, and the solvent was removed by distillation from a water bath (60C), at last u~der 15 mm Hg.
Distillation of the residual oil (1.34 g) gave 1.18 g (94%) of VI
as a colorless oil, b 1 172-175C, nD 1.4731.
Calculated for C22H38O4 (366.5): C 72.1, H 10.5, OC2H5 12 3 Found : C 72.2, ~ 10.5, OC2H5 12.4 Example 6 8-[5-(3-Oxooctyl)-2-furyl]-octanoic acid (VII) A mixture of V (5.10 g, 0.014 mole), methanol (180 ml), and 20% potassium carbonate (60 g) was stirred and heated under reflux for 1 hour. The turbid solution was concentrated to 1/4 of the volume by distillation from a water bath (60C) under reduced pressure (50 mm Hg). The residue was diluted with water (300 ml), and the resulting clear solution was acidified to pH 6 with acetic acid. The emulsion was extracted with two 150-ml portions of ~ ether. The combined ethereal extracts were washed with two 100-t ml portions of water, and then dried over magnesium sulfate.
Ether was distilled off from a water bath (60C), at last under 20 15 mm Hg. The yellow, oily residue (4.62 g) solidified at room temperature. Purification by crystallization from n-hexane (40 ~` ml) gave 3.54 g (75%) of VII as slightly yellow crystals, m.p.
`t ~64-65C.
Calculated for C20H32O4 (336.5): C 71-4~ H 9-6 Found - : C 71.2, H 9.6 ~ .
~` ~ Exàmple ?
. , 1-(5-Methyl-2-furyl)-1-octen-3-ol (X) ~- - The starting màterial, 1-(5-methyl-2-furyl)-1-octen-3-one (IX, which is known (Chem.Abstr. 74 (1971) 141,418 g), was 30 prepared from VIII (J.Org.Chem. 22 (1957) 1269) after the direction given in the literaturé (J.A.C.S. 70 (1948) 2695).
` IX (1.65 g, 0.008 mole) was dissolved in absolute ~053686 ethanol (200 ~1), and the solution was cooled to 0C. Sodium tetrahydroborate (0.70 g, 0.0185 mole) was added in one portion with stirring. The turbid solution was stirred at 0-5C for 15 minutes and then at room temperature for 20 hours. The solution was concentrated to 1/4 of the volume by distillation from a water bath (40C) under reduced pressure (50 mm Hg). The residual solution was cooled to 10C, and then cold water (800 ml) and N sodium hydroxide (25 ml) were added successively with stirring. The stirring was continued for 15 minutes at room temperature and then the pH of the emulsion was adjusted to 7.8 by addition of 3N acetic acid. The reaction mixture was extracted with two 150-ml portions of ether. The combined organic extracts were washed with water ~100 ml) and dried over magnesium sultate. The ethereal solution was evaporated to dryness from a water bath (60~C) under reduced pressure, at last under 15 mm Hg.
The residual oil (1.67 g) was purified by distillation under nitrogen. 1.13 g (68%) of X were hereby obtained as a yellow liquid, bo 2 97-99C, nD 1.5166-Example 8 ~, .
8-[5-~3-Hydroxyoctyl)-2-furyl]-octanoic acid (VIa) '~ A mixture of VI (2.73 g, 0.00745 mole), methanol (100 ~:: ml), and 20% aqueous potassium carbonate solution (30 ml) was ,~ stirred and heated under reflux for 1 hour. The turbid solution ~`~ was concentrated to 1/4 of the volume by distillation from a water '-~
i`
`~r~ bath (60C) under reduces pressure (60 mm Hg). The residue was ~ diluted with water (100 ml~ and adjusted to pH 7 with acetic acid `i (2.7 ml3. The,resulting emulsion was extracted with two 80-ml ~ portions of ether. The combined ethereal extracts were washed ,~
~` ` with water (100 ml) and then dried over magnesium sulfate. Ether i `~I 30 was distilled off from a water bath (50C), at last under 15 mm Hg.
i'~ The yellow, oily residue (2.58 g) was purified by crystallization , from petroleum ether (boiling below 50~C) (450 ml). 2.13 g (84~) ~ '` '.
of VIa were herehy obtained as almost white crystals with m.p.
43-45~C.
20 34 4 ( 38.5): C 71.0 H 10.1 Found : C 70.8 H 10.1 Example 9 8-[5-(3-Oxooctyl)-2-furyl]-octanoic acid methyl ester .
- III (11.37 g, 0.0326 mole), methanol (150 ml), and Raney nickel (2.5 g) were stirred at room temperature under 1 atmosphere of hydrogen, until one molequivalent of hydrogen had reacted. After filtration, the solvent was removed by distilla-tion from a water bath (60C) under reduced pressure, at last under 15 mm Hg. The residual, light yellow oil (11.4 g) was ; purified by preparativetlc (thin layer chromatography) on silica gel (mixture of petroleum ether (b.<50C) and ether ~2:1) as eluent). 7.25 g of the title compound were obtained as a yellowish oil. Further purification by distillation under nitrogen gave ` 7.05 ~ (62%) of the title compound as an almost colourless oil, bo o7 172-180C, nD 1.4723.
Calculated for C21H34O4 (350.5): C 72.0, H 9.8, OCH3 8.8 20 Found : C 71.8, H 9.9, OCH3 9.0 c Example 10 ;i'~ ' ~ 8-~5-(3-Hydroxyoctyl)-2-furyl]-octanoic acid methyl ester -~
~ .
,~.; - .
The ester of Example 9 (1.61 g, 0.0046 mole) was dl-solved in methanol (30 ml), and sodium tetrahydroborate (0.80 g, 0.021 mole) was added at -10C with stirring. The stirring was ; ~contlnued for 90 minutes, the temperature of the reaction mixture ~ -increasing to 22-25C. The resulting solution was poured into ice-water (200 ml). 1.5N aqueous sodium hydroxide solution ~10 ` ml~ ~as then added, and the emulsion was stirred for 15 minutes.
~`~30 The reaction mixture was extracted with three 100-ml portions of ~ether. The combined organic extracts were washed with two 100-ml portions of water and dried over magnesium sulfate. The ethereal .
~ -12-.~ .
solution ~as evaporated to dryness from a water bath ~60C) under reduced pressure (15 mm Hg). The residual oil (1.59 g) was purified by distillation under nitrogen. 1.50 g (93%) of the title compound were obtained as a colourless oil, bo o7 176-178C, n D 1.4759.
21H36O4 (352.5): C 71.6, H 10 3 OCH 8 8 Found : C 71.7, H 10.5, OCH3 8.7 Example 11 8-15-(3-~ydroxyoctyl)-2-furyl]-octanoic acid A mixture of the ester of Example 10 (2.73 g, 0.0077 ; mole), methanol (100 ml), and 20% potassium carbonate (30 ml) was stirred and heated under reflux for one hour. The colourless solution was concentrated to one fourth of the original volume by distillation from a water bath (60~C) under reduced pressure (60 mm Hg). The residue was diluted with water (100 ml), and the resulting turbid solution was acidified to pH 6 with acetic acid.
The emulsion was extracted with two 100-ml portions of ether. The combined ethereal extracts were washed with two 100-ml portions of water and then dried over magnesium sulfate. Ether was distilled off on a water bath (60C), at last under 15 mm Hg. The yellow, oily residue (2.58 g) solidified at 10C. Purification by crystallization from petroleum ether (b.<50C) (450 ml) gave 2.13 g (81%) of the title compound as white crystals with m.p. 43-45C.
Found : C 70.8, H 10.1 ` Example 12 8-[5-(3-Hydroxy-3-methyloctyl)-2-furyl]-octanoic acid methyl ester (XIII) ~ Vii (4.50 g, 0.0133 mole), pyridine (25 ml), hexa-,~ 30 methyldisilazan (HMDS) (7.2 ml), and trimethyl silylchloride (TMCS) (2.4 ml) were mixed, and the mixture was left overni~ht protected from moisture. The suspension was then filtered in a dry .
. ~ ~
. -, . .
atmosphere, and the filtrate was evaporated on a water bath (80C) under reduced pressure (10 mm Hg). The residue was mixed with dry ether (50 ml), and the mi~ture was filtered to remove a small amount of insoluble material. The filtrate was cooled to 2C in a dry nitrogen atmosphere, and a 3.7M ethereal solution of methyl magnesium bromide (7.8 ml, 0.0289 mole) was added dropwise with stirring over a period of 25 minutes at about 10C. The resulting suspension was stirred overnight at room temperature. It was then added to a mixture of N HCl (32 ml) and water (120 ml), the temperature of which was 5C, and the resulting mixture was stirred for 90 minutes. The ethereal layer was then separated, and the aqueous phase was extracted with ether (30 ml). The combined ethereal extracts were extracted with 0.5N aqueous sodium hydroxide (40 ml). The aqueous extract was made acidic with 0,5N hydrochloric acid (42 ml) and extracted with two 25-ml portions of ether. The combined ethereal extracts were dried with magnesium sulfate and evaporated to dryness from a water bath (70C), at last under lS mm Hg. The residual crude acid XII
(4.23 g) was esterified in a mixture of methanol (50 ml) and ethyl 20 ether - borontrifluoride complex (0.5 ml) as described in Example -2 to give the crude methyl ester XIII (4.2 g). This crude ester was purified by chromatography using a column of silica gel and petxol ether - ether (1:1) as eluent to give 2.1 g of crude oil.
: The distillation under nitrogen of this crude oil gave 1.83 g ~(37S) of XIII, bo 3 178-180C, nD 1.4749.
Calculated for C22H38O4 (366.5): C 72-1, H 10-5~ OCH3 8-5 ` Found : C 71.5, H 10.4, OCH3 8.6 The NMR spectrum was in accordance with the presumed structure for XIII.
~30` Example 13 ~-8-¦5-(3-Hydroxy`-3-methyloctyl)-2-furyl~-octanoic acid (XII) i.:: ' .
mixture of XIII (0.91 g, 0.0025 mole), methanol ` `
, . , ~ . ..
.
(10 ml), and 20~ potassium carbonate (5 ml) was stirred and re~luxed for 90 minutes. The clear yellow solution was mixed with water (15 ml) and acidified to pH 5-6 with acetic acid. The emulsion was extracted with two 15-ml portions of ether. The comhined ethereal extracts were dried over magnesium sulfate.
Ether was distilled off from a water bath (60C), at last under 0.1 mm Hg. The yellow, oily residue (0.86 g) was purified by chromatography on three 20 x 20 cm preparative tlc plates (Merck silica gel 60F254-2 mm layer), and the isolated crude XII herefrom was distilled at 175-185C and 0.03 mm Hg to give 0.63 g XII (71%) as a light yellow oil, nD 1.4844.
Calculated for C21H36O4 (352.5): C 71.~, H 10-3 Found : C 71.7, H 10.3 Example 14 1-_(5-Alkyl-2-furyl)-octen-3-ones (XVII, XVIII) To the stirred solution of a 5-alkylfuraldehyde (0.0666 mole) and 2-heptanone (9.3 ml, 7.58 g 0.0666 mole) in methanol (25 ml) aqueous 20% sodium hydroxide (1.8 ml) was added dropwise at 10-12C over a period of 10 minutes. The clear yellow . 20 solution was stirred at the same temperature for onehour, then for 18 hours at room temperature. The pH of the resulting mixture was adjusted to 7 by addition of acetic acid. The reaction mixture was poured into water ~100 ml) and extracted with two 70-ml portions of ether. The combined organic extracts were washed with -~`~ three 50-ml portions of ether and dried over magnesium sulfate.
i~ The ethereal solution was evaporated to dryness from a water bath t70C) under reduced pressure, at last under 15 mm Hg. The residual oil was purified by distillation under 10 mm Hg.
R 10 mm nD5 m. yield , 30 C C %
CH(CH3)2 174-182 1.5415 57 . . . ~ . . .
. . . .
formula molecular calculated found weiaht C H C H
C2H5 C14H202 220.3 76.3 9.2 76.2 9.2 CH(CH3)2 C15H22O2 234.3 76.9 9.5 76.6 9-4 Example 15 1-(5-Alkyl-2-furyl)-3-octanones ~XIX-XXI) A 1-(5-Alkyl-2-furyl)-1-octen-3-one (0.03 mole), methanol (150 ml), and Raney nickel (10% by weight of the olefin) 10 were stirred at room temperature under 1 atmosphere of hydrogen, until one molequivalent of hydrogen had reacted. After filtration, the solvent was removed by distillation from a water bath (60C) under reduced pressure, at last under 15 mm Hg. The residual light yellow oil was purified by preparative thin layer chromatography.
s Silica gel has been used as adsorbent and a mixture of ether and petroleum ether (b.<50C) (1:8) as developing solvent. The adsorbent was scraped off the glass plates and stirred for 1 hour with ether. After filtration, the solution was evaporated ~ to dryness from a water bath (60C) under reduced pressure, at ;j 20 last under 15 mm Hg. The residual oil was purified by distillation ` under reduced pressure.
~ C nD5 yield .~
~` CH3 140-142 1.4687 ~20DC) 71 C2H5 147-150 1.4675 86 CH(CH3)2 158-159 1.4651 71 - - ~ ---. ..
- R ~ormula molecula~ calculated ~ound ~` weight C H C H
r,~ ~ .
:~ 30 CH3 C13 20 2 208.3 75.0 9.7 74.3 9.8 2 5 C14H22O2 222,3 75.6 10.0 7S.5 10.1 CH(CH ) C15 24 2 236.3 76.2 10.2 76.1 10.3 Example 16 5-Alkyl-~-pentyl-2-furanpropanols (XXII-XXIV) A 1-(5-alkyl-2-furyl)-3-octanone (XIX-XXI) (0.015 mole) was dissolved in ethanol (90 ml), and sodium tetrahydroborate (2.40 g, 0.064 mole) was added at -10C with stirring. The stirring was continued for 90 minutes, the temperature of the reaction mixture increasin~ to 23-25C. The colourless solution was poured into ice-water (300 ml). 1.5N aqueous sodium hydroxide (20 ml) was then added, and the emulsion was stirred for 10 minutes. The reaction mixture was extracted with three 100-ml portions of ether. The combined organic extracts were washed with two 100-ml portions of water and dried over magnesium sulfate.
The ethereal solution was evaporated to dryness from a water bath (60C) under reduced pressure, at last under 15 mmHg. The i~ .
~ residual oil was purified by distillation under reduced pressure.
~`
~"` -l` . .
~''``' .
; . -.:
: -, ~ .
.~, - .
~ -17--~` ^` 1053686 R blCO mm nD5 yield ~.
CH3 148-160 1.4744 (20C) 95 C2H5 152-155 1.4725 93 CH(CH3)2 160 1.4701 91 , R formula molecular calculated found ~eight C H C H
.
CH3 C13H2202 210.3 74.2 10.5 74.1 10.5 C2H5 C14H2402 224.3 75.0 10.8 74.8 10.7 CH(CH3)2¦ C15H2602 238.9 5.6 11.0 75.4 11.2 , ' ., ' .
., .
'i _, , , . ~
.~
.~ .
t ~ '.
- ~ -_ Iy~
` ` XII ~-, ~`H~ BF3(C2H5)20 ~ ~ ~ CH30C~(CH2)~7 (CH2)2 - C - C5Hll - :
. ~ ~ o : OH
. , ~ : XIII
R ~CII--CHCOC5H
2 `~ C2H5 ` XVII
H ~ CH ~ ) ~ XV I I 1 . ~
-`- 1053686 H2, Raney Ni R ~ (CH2)2COCs~ll -CH3 XIX ~
C2~5 XX
-CH ( CH 3 ) 2 XXI
b I
NaBH4 . ~ R ~, O ~(CH2) 2CHOHC5H
R:
c --CH3 XXI
, -CH (CH 3 ) 2 XXIV
j~ The starting material for the production of the ¦`~ compounds of the invention are furane derivatives of the formula .:. ~ - :
~ ~ R ~CHO
.~ . , wherein Rl is as hereinbefore defined, which can be produced from known compounds of the formula R ~ -or oxample by formylating according to Vilsmeyer.
The starting aldehydes are condensed with the appropriate àlka~n-2-one, e.g. 2-heptanone, or a 2-oxoalkyl-phosphonic acid dimethyl~ ester~to estab1ish a 3-oxo-l~alkenyl group at the 5-~position~of the furane ring and optionally hydrogenating at the --double bond in l-positionof said side chain catalytically, and educing the keto group with sodlum horohydride or subjecting O~ the-keto group to a Grignardation using an alkyImagnesium halide as~the Grignard reagent.
~ When Rl represents the group ROOC-(CH2)7-, wherein R is : ~ ~ --5--~, " , . ' ., ' . ' ' i ~ , . -:. , ' , hydrogen, the carboxyl group may subsequently be esterified to yield esters of the invention or, if the resultin~ compound is an ester, it may be saponified to yield the corresponding acid.
The introduction of the side chain in 5-position is preferably carried out at room temperature in solution in an alkanol, e.g. methanol or ethanol.
Suitable catalysts for the hydrogenation are Raney nickel, Raney copper, and noble metal catalysts, e.g. palladium.
The following examples are illustrative of the production of the present compounds, the various compounds being identified by the numbering in the above schemes of reaction.
Example 1 8-[5-(3-Oxo-l-octenyl)-2-furyl]-octanoic acid (II) I (9.17 g, 0.0364 mole), produced by formylating iuryl-- 2-octanoic acid, was dissolved in methanol (60 ml), and the solution was cooled to -5C. Aqueous 20% sodium hydroxide (9.1 g) was added in one portion with stirring. To the resulting mixture, 2-heptanone t5.05 g, 0.0444 mole) was added with stirring over a " period of 10 minutes at a temperature of 18-20C. The stirring . 20 was continued for one hour at the same temperature, and then for additional 16 hours at room temperature. The reactlon mixture was poured into water (130 ml) and adjusted to pH 7.2 with 3N acetic acid (9.2 ml). The resulting yellow crystals`were isolated by .~. ~ .
filtration and washed with water (30 ml). The filtrate (F) was -collected. The wet cake of crystals was suspended in a mixture of water (80 ml) and ether (80 ml) and stirred. The resulting . ~ emulsion was neutralized to pH 7 with 3N acetic acid. The ethereal layer was separated. The aqueous layer was extracted A ~. . .
~- ~ with ether (50 ml). The combined ethereal extracts were washed with water (50 ml) and then dried over magnesium sulfate. The dried ethereal solution was evaporated to dryness from a water bath (60DC), at last under 15 mm Hg. 6.21 g of crude II were ; :
~.
. . , . - , .
hereby obtained as a yellGw oil, which solidified at room temp-erature.
The above filtrate (~) was stirred with ether (50 ml) and the pH of the emulsion was adjusted to 7 with 3N acetic acid.
The ethereal layer was separated, and the aqueous layer extracted with ether (50 ml). The combined ethereal extracts were washed with water (50 ml), dried over magnesium sulfate, and the ether removed ~y distillation from a water bath (60~C), at last under ~ -15 mm Hg. Chromatography of the yellow, oily residue (5.30 g) on silica gel (150 g, 60-120 mesh, from sDH Chemicals Ltd.) 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). 7.45 g (61%) of II were hereby obtained as pale, yellow crystals, m.p. 58-59C.
Calculated for C20H30O4 (334.4): C 71.8~ H 9.0 Found : C 71.7, H 9.0 Example 2 8-[5-(3-Oxo-l-octenyl)-2-furyl]-octanoic acid methyl ester (III) A. II (2.52 g, 0.00755 mole), methanol (30 ml), and ethyl ether-~
~- borontrifluoride complex (0.24 g) were stirred and heated under ref-lux for 1 hour. After cooling, the reaction mixture was poured into ice-water (150 ml) and extracted with two 80-ml portions of ethcr. The combined ethereal extracts were washed with cold 10%
sodium oarbonate ~50 ml) and then with two 50-ml portions of cold -~ater. The ethereal solution was dried over magnesium sulfate and e~aporatèd to-dryness from-a water bath (60C),-at last under 15 Hg. Distillation under nitrogen of the residual oil (2.46 g) gave 2.07 g (79%) of III, bo;3 202~204C, nD 1.5262.
~-~; 3Q C,alculated for C21H32O4 (348.5): C 72.4, H 9.3 one OCH3 8.9 Found : C 72.5, H 9.2 OCH3 8.9 ~, -l~ ~ B. 50% sodium hydride in mineral oil (0.96 g, 0.02 mole) was-i :
~:
; -7-_.. , . . .. . . . -. - .... . . ~ .. :
... . . . .
suspended in dry 1,2-dimethoxyethane (200 ml), The slurry was cooled to 15C and stirred vigorously with a mechanical stirrer.
(2-Oxoheptyl)-phosphonic acid dimethyl ester (Wadsworth et al:
J.A.C.S. 83 (1961) 1733) (4.44 g, 0.02 mole) was added dropwise over a period of 30 minutes, the reaction temperature being kept at 15-20C. After the addition, the suspension of a white, voluminous precipitate was stirred for 1 hour at room temperature.
A solution of I (5.04 g, 0.02 mole) in 1,2-dimethoxyethane (30 ml) was added dropwise over a period of 30 minutes to the stirred suspension, maintained below 25C. The resulting turbid, yellow solution was stirred at room temperature for 1.5 hours. The solvent (200 ml) was distilled off from a water bath (70C) 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 ethereal extracts were washed with two 100-ml portions of water and then dried over magnesium ` sulfate. The dried ethereal solution was evaporated to dryness from a water bath (60C), at last under 15 mm. The residual yellow oil was purified by distillation under nitrogen. 6.34 g ;
~91%) of III was hereby obtained as a yellow liquid, bo 1194-200C, 1.5256. In tlc it had the same Rf values in different solvents as the compound obtained by method A.
Example 3 8-15-~3-Oxo-l-octenyl)-2-furyl]-octanoic acid ethyl ester ~IV) ,: .
A mixture of II (9.94 g, 0.0298 mole), ethanol (190 ml), ;and ethyl ether-borontrifluoride complex (0.97 g) was stirred and heated: under-reflux-for 1.5 hours.- After cooling, the reaction mixture-was poured into ice-water (600 ml) and extracted with three 300-ml portions of ether. The combined ethereal extracts -h ~ ; .
~ 30 were washed with cold 10% sodium carbonate (100 ml~ and then with ; 200-ml portions of cold water. The ethereal solution was dried -~
~ ~ over magnesium sulfate and evaporated to dryness from a water bath ~ ~ ' ~; -8-1~53686 (60C), at last under 15 mm Hg. The resid~al yellow oil (9.84 g) was purified by distillation under nitrogen from a potassium acetate coated flask giving 8.57 g (79%) of IV, b 2 198-201~C, n25 1.5217.
Calculated for ~22H344 (362.5): C 72.9, H 9.5, OC2H5 12.4 Found : C 73.0, H 9.5, OC2H5 12.3 Example 4 8-[5-(3-Oxooctylj-2-furyl]-octanoic acid ethyl ester (V) IV (1.74 g, 0.0048 mole), ethanol (25 ml), and Raney 10 cooper (Ponomarev et al., J. Gen. Chem. USSR 30 (1960) 584) (0.75 g) were shaken under 80 atmospheres of hydrogen for 6 hours at 30C. After filtration, the ethanol was distilled under reduced pressure form a water bath (60C). Ether (30 ml) was added to the residue, and the turbid solution was filtered (G4, Celite a trademark). The ethereal solution was evaporated to dryness from a water bath (50C) under reduced pressure, at last under 15 mm Hg. The residual oil was purified by distillation under nitrogen.
1.51 g t86%) of V was hereby obtained as an almost colorless oil, bo 2 178-181C, nD 1.4700.
i~ 20 Calculated for C22H36O4 (364.5): C 72.5, H 10.0, OC2H5 12.4 Found : C 72.3, H 10.0, OC2H5 12.4 Example 5 8-~5-(3-Hydroxyoctyl)-2-furyl]-octanoic acid ethyl ester (VI) V (1.25 g, 0.003~3 mole) was dissolved in absolute ethanol ~70 ml), and the solution was cooled to -5C. Sodium '~ tetrah~droborate ~O.50 g, 0.0132 mole) was added portionwise during ~ minutes with stirring.- The--turbi-d solution was stirred at~0-5~C--for 15 minutes, then at room temperature for 1 hour. The colorless solution was poured into ice-water (250 ml). 1.5 N
30 sodium hydroxide (10 ml) was added with stirring to the resulting ~
emulsion. The stirring was continued for 15 minutes. The white emulsion was extracted with three 100-ml portions of ether. The _ g _ : . . , : , . , combined ethereal extracts were washed with cold water (100 ml), dried over magnesium sulfate, and the solvent was removed by distillation from a water bath (60C), at last u~der 15 mm Hg.
Distillation of the residual oil (1.34 g) gave 1.18 g (94%) of VI
as a colorless oil, b 1 172-175C, nD 1.4731.
Calculated for C22H38O4 (366.5): C 72.1, H 10.5, OC2H5 12 3 Found : C 72.2, ~ 10.5, OC2H5 12.4 Example 6 8-[5-(3-Oxooctyl)-2-furyl]-octanoic acid (VII) A mixture of V (5.10 g, 0.014 mole), methanol (180 ml), and 20% potassium carbonate (60 g) was stirred and heated under reflux for 1 hour. The turbid solution was concentrated to 1/4 of the volume by distillation from a water bath (60C) under reduced pressure (50 mm Hg). The residue was diluted with water (300 ml), and the resulting clear solution was acidified to pH 6 with acetic acid. The emulsion was extracted with two 150-ml portions of ~ ether. The combined ethereal extracts were washed with two 100-t ml portions of water, and then dried over magnesium sulfate.
Ether was distilled off from a water bath (60C), at last under 20 15 mm Hg. The yellow, oily residue (4.62 g) solidified at room temperature. Purification by crystallization from n-hexane (40 ~` ml) gave 3.54 g (75%) of VII as slightly yellow crystals, m.p.
`t ~64-65C.
Calculated for C20H32O4 (336.5): C 71-4~ H 9-6 Found - : C 71.2, H 9.6 ~ .
~` ~ Exàmple ?
. , 1-(5-Methyl-2-furyl)-1-octen-3-ol (X) ~- - The starting màterial, 1-(5-methyl-2-furyl)-1-octen-3-one (IX, which is known (Chem.Abstr. 74 (1971) 141,418 g), was 30 prepared from VIII (J.Org.Chem. 22 (1957) 1269) after the direction given in the literaturé (J.A.C.S. 70 (1948) 2695).
` IX (1.65 g, 0.008 mole) was dissolved in absolute ~053686 ethanol (200 ~1), and the solution was cooled to 0C. Sodium tetrahydroborate (0.70 g, 0.0185 mole) was added in one portion with stirring. The turbid solution was stirred at 0-5C for 15 minutes and then at room temperature for 20 hours. The solution was concentrated to 1/4 of the volume by distillation from a water bath (40C) under reduced pressure (50 mm Hg). The residual solution was cooled to 10C, and then cold water (800 ml) and N sodium hydroxide (25 ml) were added successively with stirring. The stirring was continued for 15 minutes at room temperature and then the pH of the emulsion was adjusted to 7.8 by addition of 3N acetic acid. The reaction mixture was extracted with two 150-ml portions of ether. The combined organic extracts were washed with water ~100 ml) and dried over magnesium sultate. The ethereal solution was evaporated to dryness from a water bath (60~C) under reduced pressure, at last under 15 mm Hg.
The residual oil (1.67 g) was purified by distillation under nitrogen. 1.13 g (68%) of X were hereby obtained as a yellow liquid, bo 2 97-99C, nD 1.5166-Example 8 ~, .
8-[5-~3-Hydroxyoctyl)-2-furyl]-octanoic acid (VIa) '~ A mixture of VI (2.73 g, 0.00745 mole), methanol (100 ~:: ml), and 20% aqueous potassium carbonate solution (30 ml) was ,~ stirred and heated under reflux for 1 hour. The turbid solution ~`~ was concentrated to 1/4 of the volume by distillation from a water '-~
i`
`~r~ bath (60C) under reduces pressure (60 mm Hg). The residue was ~ diluted with water (100 ml~ and adjusted to pH 7 with acetic acid `i (2.7 ml3. The,resulting emulsion was extracted with two 80-ml ~ portions of ether. The combined ethereal extracts were washed ,~
~` ` with water (100 ml) and then dried over magnesium sulfate. Ether i `~I 30 was distilled off from a water bath (50C), at last under 15 mm Hg.
i'~ The yellow, oily residue (2.58 g) was purified by crystallization , from petroleum ether (boiling below 50~C) (450 ml). 2.13 g (84~) ~ '` '.
of VIa were herehy obtained as almost white crystals with m.p.
43-45~C.
20 34 4 ( 38.5): C 71.0 H 10.1 Found : C 70.8 H 10.1 Example 9 8-[5-(3-Oxooctyl)-2-furyl]-octanoic acid methyl ester .
- III (11.37 g, 0.0326 mole), methanol (150 ml), and Raney nickel (2.5 g) were stirred at room temperature under 1 atmosphere of hydrogen, until one molequivalent of hydrogen had reacted. After filtration, the solvent was removed by distilla-tion from a water bath (60C) under reduced pressure, at last under 15 mm Hg. The residual, light yellow oil (11.4 g) was ; purified by preparativetlc (thin layer chromatography) on silica gel (mixture of petroleum ether (b.<50C) and ether ~2:1) as eluent). 7.25 g of the title compound were obtained as a yellowish oil. Further purification by distillation under nitrogen gave ` 7.05 ~ (62%) of the title compound as an almost colourless oil, bo o7 172-180C, nD 1.4723.
Calculated for C21H34O4 (350.5): C 72.0, H 9.8, OCH3 8.8 20 Found : C 71.8, H 9.9, OCH3 9.0 c Example 10 ;i'~ ' ~ 8-~5-(3-Hydroxyoctyl)-2-furyl]-octanoic acid methyl ester -~
~ .
,~.; - .
The ester of Example 9 (1.61 g, 0.0046 mole) was dl-solved in methanol (30 ml), and sodium tetrahydroborate (0.80 g, 0.021 mole) was added at -10C with stirring. The stirring was ; ~contlnued for 90 minutes, the temperature of the reaction mixture ~ -increasing to 22-25C. The resulting solution was poured into ice-water (200 ml). 1.5N aqueous sodium hydroxide solution ~10 ` ml~ ~as then added, and the emulsion was stirred for 15 minutes.
~`~30 The reaction mixture was extracted with three 100-ml portions of ~ether. The combined organic extracts were washed with two 100-ml portions of water and dried over magnesium sulfate. The ethereal .
~ -12-.~ .
solution ~as evaporated to dryness from a water bath ~60C) under reduced pressure (15 mm Hg). The residual oil (1.59 g) was purified by distillation under nitrogen. 1.50 g (93%) of the title compound were obtained as a colourless oil, bo o7 176-178C, n D 1.4759.
21H36O4 (352.5): C 71.6, H 10 3 OCH 8 8 Found : C 71.7, H 10.5, OCH3 8.7 Example 11 8-15-(3-~ydroxyoctyl)-2-furyl]-octanoic acid A mixture of the ester of Example 10 (2.73 g, 0.0077 ; mole), methanol (100 ml), and 20% potassium carbonate (30 ml) was stirred and heated under reflux for one hour. The colourless solution was concentrated to one fourth of the original volume by distillation from a water bath (60~C) under reduced pressure (60 mm Hg). The residue was diluted with water (100 ml), and the resulting turbid solution was acidified to pH 6 with acetic acid.
The emulsion was extracted with two 100-ml portions of ether. The combined ethereal extracts were washed with two 100-ml portions of water and then dried over magnesium sulfate. Ether was distilled off on a water bath (60C), at last under 15 mm Hg. The yellow, oily residue (2.58 g) solidified at 10C. Purification by crystallization from petroleum ether (b.<50C) (450 ml) gave 2.13 g (81%) of the title compound as white crystals with m.p. 43-45C.
Found : C 70.8, H 10.1 ` Example 12 8-[5-(3-Hydroxy-3-methyloctyl)-2-furyl]-octanoic acid methyl ester (XIII) ~ Vii (4.50 g, 0.0133 mole), pyridine (25 ml), hexa-,~ 30 methyldisilazan (HMDS) (7.2 ml), and trimethyl silylchloride (TMCS) (2.4 ml) were mixed, and the mixture was left overni~ht protected from moisture. The suspension was then filtered in a dry .
. ~ ~
. -, . .
atmosphere, and the filtrate was evaporated on a water bath (80C) under reduced pressure (10 mm Hg). The residue was mixed with dry ether (50 ml), and the mi~ture was filtered to remove a small amount of insoluble material. The filtrate was cooled to 2C in a dry nitrogen atmosphere, and a 3.7M ethereal solution of methyl magnesium bromide (7.8 ml, 0.0289 mole) was added dropwise with stirring over a period of 25 minutes at about 10C. The resulting suspension was stirred overnight at room temperature. It was then added to a mixture of N HCl (32 ml) and water (120 ml), the temperature of which was 5C, and the resulting mixture was stirred for 90 minutes. The ethereal layer was then separated, and the aqueous phase was extracted with ether (30 ml). The combined ethereal extracts were extracted with 0.5N aqueous sodium hydroxide (40 ml). The aqueous extract was made acidic with 0,5N hydrochloric acid (42 ml) and extracted with two 25-ml portions of ether. The combined ethereal extracts were dried with magnesium sulfate and evaporated to dryness from a water bath (70C), at last under lS mm Hg. The residual crude acid XII
(4.23 g) was esterified in a mixture of methanol (50 ml) and ethyl 20 ether - borontrifluoride complex (0.5 ml) as described in Example -2 to give the crude methyl ester XIII (4.2 g). This crude ester was purified by chromatography using a column of silica gel and petxol ether - ether (1:1) as eluent to give 2.1 g of crude oil.
: The distillation under nitrogen of this crude oil gave 1.83 g ~(37S) of XIII, bo 3 178-180C, nD 1.4749.
Calculated for C22H38O4 (366.5): C 72-1, H 10-5~ OCH3 8-5 ` Found : C 71.5, H 10.4, OCH3 8.6 The NMR spectrum was in accordance with the presumed structure for XIII.
~30` Example 13 ~-8-¦5-(3-Hydroxy`-3-methyloctyl)-2-furyl~-octanoic acid (XII) i.:: ' .
mixture of XIII (0.91 g, 0.0025 mole), methanol ` `
, . , ~ . ..
.
(10 ml), and 20~ potassium carbonate (5 ml) was stirred and re~luxed for 90 minutes. The clear yellow solution was mixed with water (15 ml) and acidified to pH 5-6 with acetic acid. The emulsion was extracted with two 15-ml portions of ether. The comhined ethereal extracts were dried over magnesium sulfate.
Ether was distilled off from a water bath (60C), at last under 0.1 mm Hg. The yellow, oily residue (0.86 g) was purified by chromatography on three 20 x 20 cm preparative tlc plates (Merck silica gel 60F254-2 mm layer), and the isolated crude XII herefrom was distilled at 175-185C and 0.03 mm Hg to give 0.63 g XII (71%) as a light yellow oil, nD 1.4844.
Calculated for C21H36O4 (352.5): C 71.~, H 10-3 Found : C 71.7, H 10.3 Example 14 1-_(5-Alkyl-2-furyl)-octen-3-ones (XVII, XVIII) To the stirred solution of a 5-alkylfuraldehyde (0.0666 mole) and 2-heptanone (9.3 ml, 7.58 g 0.0666 mole) in methanol (25 ml) aqueous 20% sodium hydroxide (1.8 ml) was added dropwise at 10-12C over a period of 10 minutes. The clear yellow . 20 solution was stirred at the same temperature for onehour, then for 18 hours at room temperature. The pH of the resulting mixture was adjusted to 7 by addition of acetic acid. The reaction mixture was poured into water ~100 ml) and extracted with two 70-ml portions of ether. The combined organic extracts were washed with -~`~ three 50-ml portions of ether and dried over magnesium sulfate.
i~ The ethereal solution was evaporated to dryness from a water bath t70C) under reduced pressure, at last under 15 mm Hg. The residual oil was purified by distillation under 10 mm Hg.
R 10 mm nD5 m. yield , 30 C C %
CH(CH3)2 174-182 1.5415 57 . . . ~ . . .
. . . .
formula molecular calculated found weiaht C H C H
C2H5 C14H202 220.3 76.3 9.2 76.2 9.2 CH(CH3)2 C15H22O2 234.3 76.9 9.5 76.6 9-4 Example 15 1-(5-Alkyl-2-furyl)-3-octanones ~XIX-XXI) A 1-(5-Alkyl-2-furyl)-1-octen-3-one (0.03 mole), methanol (150 ml), and Raney nickel (10% by weight of the olefin) 10 were stirred at room temperature under 1 atmosphere of hydrogen, until one molequivalent of hydrogen had reacted. After filtration, the solvent was removed by distillation from a water bath (60C) under reduced pressure, at last under 15 mm Hg. The residual light yellow oil was purified by preparative thin layer chromatography.
s Silica gel has been used as adsorbent and a mixture of ether and petroleum ether (b.<50C) (1:8) as developing solvent. The adsorbent was scraped off the glass plates and stirred for 1 hour with ether. After filtration, the solution was evaporated ~ to dryness from a water bath (60C) under reduced pressure, at ;j 20 last under 15 mm Hg. The residual oil was purified by distillation ` under reduced pressure.
~ C nD5 yield .~
~` CH3 140-142 1.4687 ~20DC) 71 C2H5 147-150 1.4675 86 CH(CH3)2 158-159 1.4651 71 - - ~ ---. ..
- R ~ormula molecula~ calculated ~ound ~` weight C H C H
r,~ ~ .
:~ 30 CH3 C13 20 2 208.3 75.0 9.7 74.3 9.8 2 5 C14H22O2 222,3 75.6 10.0 7S.5 10.1 CH(CH ) C15 24 2 236.3 76.2 10.2 76.1 10.3 Example 16 5-Alkyl-~-pentyl-2-furanpropanols (XXII-XXIV) A 1-(5-alkyl-2-furyl)-3-octanone (XIX-XXI) (0.015 mole) was dissolved in ethanol (90 ml), and sodium tetrahydroborate (2.40 g, 0.064 mole) was added at -10C with stirring. The stirring was continued for 90 minutes, the temperature of the reaction mixture increasin~ to 23-25C. The colourless solution was poured into ice-water (300 ml). 1.5N aqueous sodium hydroxide (20 ml) was then added, and the emulsion was stirred for 10 minutes. The reaction mixture was extracted with three 100-ml portions of ether. The combined organic extracts were washed with two 100-ml portions of water and dried over magnesium sulfate.
The ethereal solution was evaporated to dryness from a water bath (60C) under reduced pressure, at last under 15 mmHg. The i~ .
~ residual oil was purified by distillation under reduced pressure.
~`
~"` -l` . .
~''``' .
; . -.:
: -, ~ .
.~, - .
~ -17--~` ^` 1053686 R blCO mm nD5 yield ~.
CH3 148-160 1.4744 (20C) 95 C2H5 152-155 1.4725 93 CH(CH3)2 160 1.4701 91 , R formula molecular calculated found ~eight C H C H
.
CH3 C13H2202 210.3 74.2 10.5 74.1 10.5 C2H5 C14H2402 224.3 75.0 10.8 74.8 10.7 CH(CH3)2¦ C15H2602 238.9 5.6 11.0 75.4 11.2 , ' ., ' .
., .
'i _, , , . ~
.~
.~ .
t ~ '.
- ~ -_ Iy~
Claims (16)
PROPERTY OR PRIVILGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of 2,5-furane derivatives of the formula I
wherein R1 represents a lower alkyl group, or a group of the formula ROOC-(CH2)7, wherein R represents hydrogen or a lower alkyl group, each of R2 and R3 represents hydrogen, or R2 and R3 together represent a further bond between the two carbon atoms, R4 represents hydrogen, or a lower alkyl group, and R5 represents hydroxy, or R4 and R5 together represent an oxygen atom, and R6 represents a group C5H11 provided that when R1 represents methyl at least one of R2, R3, and R4 is other than hydrogen, and when represents methyl, and R4 and R5 together represent an oxygen atom, R2 and R3 are hydrogen, which comprises condensing an aldehyde of the formula II
wherein R1 is as above defined, with the appropriate 2-oxoalkane of the formula R6 - CO.CH3 where R6 is as above or 2-oxo-alkyl-phosphonate of the formula where R6 is as above and Alk is alkyl to establish the 5-substi-tuent having a double bond between the first and the second carbon atom and when R2 and R3 are required to be hydrogen, catalytically hydrogenating the double bond, when R4 is required to be hydrogen and R5 hydroxy reducing the keto group to a hydroxy group and when R4 is required to be lower alkyl and R5 is hydroxy converting the keto group into a lower alkyl group by a Grignard reaction.
wherein R1 represents a lower alkyl group, or a group of the formula ROOC-(CH2)7, wherein R represents hydrogen or a lower alkyl group, each of R2 and R3 represents hydrogen, or R2 and R3 together represent a further bond between the two carbon atoms, R4 represents hydrogen, or a lower alkyl group, and R5 represents hydroxy, or R4 and R5 together represent an oxygen atom, and R6 represents a group C5H11 provided that when R1 represents methyl at least one of R2, R3, and R4 is other than hydrogen, and when represents methyl, and R4 and R5 together represent an oxygen atom, R2 and R3 are hydrogen, which comprises condensing an aldehyde of the formula II
wherein R1 is as above defined, with the appropriate 2-oxoalkane of the formula R6 - CO.CH3 where R6 is as above or 2-oxo-alkyl-phosphonate of the formula where R6 is as above and Alk is alkyl to establish the 5-substi-tuent having a double bond between the first and the second carbon atom and when R2 and R3 are required to be hydrogen, catalytically hydrogenating the double bond, when R4 is required to be hydrogen and R5 hydroxy reducing the keto group to a hydroxy group and when R4 is required to be lower alkyl and R5 is hydroxy converting the keto group into a lower alkyl group by a Grignard reaction.
2. A process as claimed in Claim 1, in which the reduction is effected with sodium borohydride and the Grignard reagent is a lower alkyl magnesium halide.
3. A process as claimed in Claim 1, in which when in the product obtained R is hydrogen and R is required to be lower alkyl esterifying the product obtained.
4. A compound of formula I given in Claim 1, wherein R1, R2, R3, R4, R5 and R6 are as in Claim 1, when prepared by the process as claimed in Claim 1, 2 or 3 or an obvious chemical equivalent thereof.
5. A process as claimed in Claim 1, in which in the reactants R is an alkyl group of 1 to 4 carbon atoms and R6 is n-pentyl.
6. A compound of formula I given in Claim 1, wherein R1, R2, R3, R4 and R5 are as in Claim 1 and R is an alkyl group of 1-4 carbon atoms, and R6 is the n-pentyl group when prepared by the process as claimed in Claim 5 or an obvious chemical equivalent thereof.
7. A process as claimed in Claim 1, in which in the reactants R1 is the group of the formula ROOC-(CH2)7 where R is hydrogen or alkyl of 1 to 4 carbon atoms and R is n-pentyl.
8. A compound of formula I given in Claim 1, in which R1 is HOOC-(CH2)7-, and R2, R3, R4 and R5 are as in Claim 1 and R6 is the n-pentyl group, and esters thereof with alkanols of 1-4 carbon atoms when prepared by the process as claimed in Claim 7 or an obvious chemical equivalent thereof.
9. A process as claimed in Claim 1, which comprises reducing 1-(5-methyl-2-furyl)-1-octen-3-one in absolute ethanol with sodium tetrahydroborate.
10. A compound of the formula I given in claim 1, in which R1 is methyl, R2 and R3 together is a further bond between the carbon atoms, R4 is hydrogen, R5 is hydroxy, and R6 is n-pentyl when prepared by the process as claimed in claim 9 or an obvious chemical equivalent thereof.
11. A process as claimed in claim 1, which comprises hydrogenating 1-(5-methyl-2-furyl)-1-octen-3-one in methanol in the presence of a Raney nickel catalyst.
12. A compound of formula I given in claim 1, in which R1 is methyl, R2 and R3 are hydrogen, R4 and R5 together are oxygen, and R6 is n-pentyl when prepared by the process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. A process as claimed in claim 1, which comprises treating a compound obtained by formulating furyl-2-octanoic acid in methanol with sodium hydroxide and when required treating the free acid so obtained with a C1-C4 alkanol in the presence of an ethyl ether boron trifluoride complex under reflux.
14. A compound of formula I given in claim 1, in which R1 is HOOC-(CH2)7 -, R2 and R3 together are a further bond between the carbon atoms, R4 and R5 together are oxygen, and R6 is n-pentyl and the esters thereof with C1 -C4 alkanols when prepared by the process as claimed in claim 13 or an obvious chemical equivalent thereof.
15. A process as claimed in claim 1, in which in the reactants R1 is alkyl of 2 to 8 carbon atoms.
16. A compound of formula I given in claim 1, in which R1 is aklyl of 2 to 8 carbon atoms in R2, R3, R4, R5, and R6 are as in claim 1 when ever prepared or produced by the process as claimed in claim 15 , or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2924173A GB1466256A (en) | 1973-06-20 | 1973-06-20 | 2,5-substituted furans and their production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1053686A true CA1053686A (en) | 1979-05-01 |
Family
ID=10288383
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA202,705A Expired CA1052801A (en) | 1973-06-20 | 1974-06-18 | Tetrahydrofurane derivatives and production thereof |
| CA202,704A Expired CA1053686A (en) | 1973-06-20 | 1974-06-18 | Furane derivatives and production thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA202,705A Expired CA1052801A (en) | 1973-06-20 | 1974-06-18 | Tetrahydrofurane derivatives and production thereof |
Country Status (13)
| Country | Link |
|---|---|
| JP (2) | JPS5032165A (en) |
| BE (2) | BE816570A (en) |
| CA (2) | CA1052801A (en) |
| DD (2) | DD113356A5 (en) |
| DE (2) | DE2429248A1 (en) |
| DK (2) | DK329674A (en) |
| FI (2) | FI187474A (en) |
| FR (2) | FR2234302B1 (en) |
| GB (1) | GB1466256A (en) |
| IL (2) | IL45065A (en) |
| NL (2) | NL7408199A (en) |
| NO (2) | NO742235L (en) |
| SE (2) | SE7408097L (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03502882A (en) * | 1987-12-15 | 1991-07-04 | ザ トラスティーズ オブ プリンストン ユニヴァーシティ | Transgenic testing system for mutagens and carcinogens |
-
1973
- 1973-06-20 GB GB2924173A patent/GB1466256A/en not_active Expired
-
1974
- 1974-06-18 CA CA202,705A patent/CA1052801A/en not_active Expired
- 1974-06-18 CA CA202,704A patent/CA1053686A/en not_active Expired
- 1974-06-19 DE DE2429248A patent/DE2429248A1/en active Pending
- 1974-06-19 NL NL7408199A patent/NL7408199A/xx not_active Application Discontinuation
- 1974-06-19 DE DE2429247A patent/DE2429247A1/en active Pending
- 1974-06-19 BE BE145629A patent/BE816570A/en unknown
- 1974-06-19 IL IL45065A patent/IL45065A/en unknown
- 1974-06-19 NO NO742235A patent/NO742235L/no unknown
- 1974-06-19 NL NL7408200A patent/NL7408200A/xx not_active Application Discontinuation
- 1974-06-19 DD DD179283A patent/DD113356A5/xx unknown
- 1974-06-19 JP JP49069267A patent/JPS5032165A/ja active Pending
- 1974-06-19 SE SE7408097A patent/SE7408097L/xx unknown
- 1974-06-19 SE SE7408096A patent/SE7408096L/xx unknown
- 1974-06-19 BE BE145628A patent/BE816569A/en unknown
- 1974-06-19 DD DD179281A patent/DD112755A5/xx unknown
- 1974-06-19 FR FR7421231A patent/FR2234302B1/fr not_active Expired
- 1974-06-19 FI FI1874/74A patent/FI187474A/fi unknown
- 1974-06-19 JP JP49069266A patent/JPS5032164A/ja active Pending
- 1974-06-19 FR FR7421232A patent/FR2234301B1/fr not_active Expired
- 1974-06-19 FI FI1873/74A patent/FI187374A/fi unknown
- 1974-06-19 NO NO742234A patent/NO742234L/no unknown
- 1974-06-19 IL IL45066A patent/IL45066A/en unknown
- 1974-06-20 DK DK329674A patent/DK329674A/da unknown
- 1974-06-20 DK DK329874A patent/DK329874A/da unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5032165A (en) | 1975-03-28 |
| SE7408096L (en) | 1974-12-23 |
| NO742235L (en) | 1975-01-13 |
| NL7408200A (en) | 1974-12-24 |
| FR2234302B1 (en) | 1978-12-01 |
| IL45066A0 (en) | 1974-09-10 |
| BE816569A (en) | 1974-10-16 |
| SE7408097L (en) | 1974-12-23 |
| IL45066A (en) | 1977-07-31 |
| DK329874A (en) | 1975-02-10 |
| DD113356A5 (en) | 1975-06-05 |
| NL7408199A (en) | 1974-12-24 |
| FR2234301A1 (en) | 1975-01-17 |
| BE816570A (en) | 1974-10-16 |
| NO742234L (en) | 1975-01-13 |
| DE2429247A1 (en) | 1975-01-16 |
| DK329674A (en) | 1975-02-10 |
| IL45065A0 (en) | 1974-09-10 |
| GB1466256A (en) | 1977-03-02 |
| CA1052801A (en) | 1979-04-17 |
| IL45065A (en) | 1978-06-15 |
| FR2234301B1 (en) | 1978-09-22 |
| JPS5032164A (en) | 1975-03-28 |
| FI187374A (en) | 1974-12-21 |
| DE2429248A1 (en) | 1975-01-16 |
| FI187474A (en) | 1974-12-21 |
| FR2234302A1 (en) | 1975-01-17 |
| DD112755A5 (en) | 1975-05-05 |
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