DERIVES DE TETRAHYDROFURANE ET LEUR PRODUCTION

TETRAHYDROFURANE DERIVATIVES AND PRODUCTION THEREOF

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
This invention relates to therapeutically active
2,5-tetrahydrofurane derivatives, wherein the substituent in the
2-position is a group ROOC-(CH2)7, in which R is hydrogen or
lower alkyl, the 5-substituent being an alkyl of 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.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of 2,5-tetrahydrofurane
derivatives of the formula
I
<IMG>
wherein R1 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 carbon atoms, R4 represents hydrogen,
or a lower alkyl group, R5 is hydroxy or R4 and R5 together
represent an oxygen atom, and R6 represents a C5H11 group
which comprises condensing an aldehyde of the formula
<IMG> II
wherein R1 is as above defined, with the appropriate 2-oxoalkane
of the formula R6-COCH3 wherein R6 is as above or 2-oxo-alkylphos-
phonate of the formula
<IMG>
where R6 is as above and Alk is alkyl to establish a 3-oxo-1-
alkenyl group in 5-position at the tetrahydrofurane ring, in the
resulting compound, 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 hydroxy
converting the keto group into a lower alkyl group by a Grignard
reaction.
14

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 R1 is required to be lower
alkyl esterifying the product obtained.
4. A 2,5-tetrahydrofurane derivative of formula I given
in claim 1 where R1,R2,R3,R4, R5 and R6 areas 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 which comprises
reacting 8-(5-formyl-tetrahydro-2-furyl)-octanoic acid methyl
ester in 1,2-dimethoxy ethane with a reaction mixture prepared by
admixing a sodium hydride in mineral oil suspended in 1,2-dimethoxy
ethane and (2-oxoheptyl)-phosphonic acid dimethyl ester.
6. 8-[5-(3-Oxo-1-octenyl)-tetrahydro-2-furyl]-octanoic
acid methyl ester when prepared by the process as claimed in
claim 5 or an obvious chemical equivalent thereof.
7. A process as claimed in claim 5 in which the product
obtained is treated with sodium tetrahydroborate in methanol.
8. 8[5-(3-Hydroxy-1-octenyl)-tetrahydro-2-furyl]-octanoic
acid methyl ester when prepared by the process as claimed in claim
7 or an obvious chemical equivalent thereof.
9. A process as claimed in claim 7 in which the
product obtained is refluxed in methanol with aqueous potassium
carbonate.
10. 8-[5-(3-Hydroxy-1-octenyl)-tetrahydro-2-furyl]-
octanoic acid when prepared by the process as claimed in claim 9
or an obvious chemical equivalent thereof.
11. A process as claimed in claim 7 in which the product
obtained is hydrogenated in methanol in the presence of Raney nickel.
12. 8-[5-(3-Hydroxyoctyl)-tetrahydro-2-furyl]-octanoic
acid methyl ester when prepared by the process as claimed in
claim 11 or an obvious chemical equivalent thereof.

13. A process as claimed in claim 11 in which the
product obtained is refluxed in methanol with aqueous potassium
carbonate.
14. 8-[5-(3-Hydroxyoctyl)-tetrahydro-2-furyl]-octanoic
acid when prepared by the process as claimed in claim 13 or an
obvious chemical equivalent thereof.
lS. A process as claimed in claim 5 in which the product
obtained is hydrogenated in methanol in the presence of Raney
nickel.
16. 8-[5-(3-Oxooctyl)-tetrahydro-2-furyl]-octanoic acid
methyl ester when prepared by the process as claimed in claim 15
or an obvious chemical equivalent thereof.
17. A process as claimed in claim 15 in which the
product obtained is refluxed in methanol with aqueous potassium
carbonate.
18. 8?5-(3-Oxooctyl)-tetrahydro-2-furyl]-octanoic acid
when prepared by the process as claimed in claim 17 or an obvious
chemical equivalent thereof.
19. A process as claimed in claim 17 in which the product
obtained is mixed with hexamethyldisilazane and trichloromethylchloro
silane a pyridine and the mixture treated with methyl magnesium
bromide in ether.
20. 8?5-(3-Hydroxy-3-methyloctyl)-tetrahydro-2-furyl]-
octanoic acid when prepared by the process as claimed in claim 19
or an obvious chemical equivalent thereof.
21. A process as claimed in claim 19 in which the
product obtained is refluxed in methanol with an ethyl ether
boron trifluoride complex.
22. 8?5-(3-Hydroxy-3-methyloctyl)-tetrahydro-2-furyl]-
octanoic acid methyl ester when prepared by the process as claimed
in claim 21 or an obvious chemical equivalent thereof.
16

Description

1(~5'~
'rhiS i nVeJl~ ll rC~ es to ~,5 tct-r,~hy(lrorlJr~3r!e
derivatives and to -their pro~Juction.
~rhe tetrahydrofllrane deriva-tives of the invcnt;on are
represented by the formula:
1! 2 ~ ~ o~
wllerein R1 represellts hydrogen or a lower alkyl group, each of
R2 alld R3 represents hydrogen, or R2 and R together represent
a urther bond between the two carbon atoms, R4 represents hydrogen
or a lower alkyl group and R5 is hydroxy or R4 and R5 together
represent an oxygen atom, and R represents a C5Hll groua.
The compounds of the invention have useful biological
properties combined with low toxicity. Thus, they have a
controlling effect upon the activity of the sympathetic nervous
system, giving new possibilities for the treatment of hyperpiesis.
Further, they have a luteolytic effect which is of interest in
controlling the rut, or as abortives, in mammals.
The following schemes of reaction illustrate the
production of the compounds of the invention:
(CH3)2CO,p-toluenesolufonic acid
CH300C(CH2)7 ~ ~ C~H 3 78
\OCH3
CH3ooc(cH2) ~ ~CHO
~ '

llDS'~
1l
Cl-13 (Cl~2) 4CC 2 3 2 __ Cl~3()(~(, (( il2) 7- t ~-~J~ 5 11
81~ fJ om I _
III
NaBH
Cll 300C ( Cll 2 ) 7~ ~ CH--ClICllOHC51il 1
91%
IV
`IV OH 7~ l100C ( CH 2 ) 7~--Cll=CllCllOllC 5H 11
IV 112, F~aNi CH300C (C~I2) 7~ CH2Cl~2cllOHcsHI
95%
VI
VI 95%~ HOOC (CH2) 7~ CH2CH2CHOHC5H
VII
III H2 ~ 8aNi CH300C (CH2) 7~CH2CH2cOc5H11
VIII
V1II ~ HOOC (CH2) 7~cH

105;~8~
TMCS, IIMDS ~1~ 3--~ i OOC ( CH ~ ) 7 CH ~C~ (JC 5~
I X ~ ~ LC H 3~ r ~ ~
1- CH3MgBr OH
X 2 . H30 I~OOC (CH2) 7 CH2CH2-1-C5
82% fi^om IX ~ 1~ CH
XI 3
OH
BF3~ (C2H5) 20,CH30H CH300C (CH2) 7 CH2CH
XI 98~ ~ CH3
XII
~0
The starting materials for the production of the
compounds of the invention are tetrahydrofurane derivatives of
the formula:
Rl--O~C- (CH2)~ CHO
wherein Rl is as hereinbefore defined.
The said starting materials are new compounds, which
can be produced e.g. from the 8- (5-dimethoxymethyl-tetrahydro-2-
furyl)-octanoic acid methyl ester known from our copending
application No. 166,252 filed March 16, 1973.
The starting aldehydes are condensed with the appro-
priate alkane-2-one, e.g. 2-heptanone, possibly in the form of
its dimethylphosphonic acid dimethyl ester, resulting in the
formation of a 3-oxo-1-alkenyl group at the 5-position of the
tetrahydrofurane ring, and optionally hydrogenating

1[)5~8~1
the double bond, re(lucing ~ k(to (~ro1~p to a hydro~.y ~roup, or
transforming the keto ~roup into hydroycn and a 10Wer ~lkyl grolip
by a Grignard reaction.
When Rl represents hydrogen in -the resulting compound,
the carboxyl group may subsequently be esterified to yicld
esters of the invention, or, if ~he resulting 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 illustratives of the pro-
duction of the present compounds, the various compounds being
identified by the numbering in the above schemes of reaction.
Example 1
A. 8-(5-Formyl-tetrahydro-2-furyl)-octanoic acid
methyl ester (II)
8-(5-Dimethoxymethyl-tetrahydro-2-furyl)-octanoic
2Q acid methyl ester (I) (1.51 g, 0.00500 mole), _-toluene-sulfonic
acid (30 mg), and acetone (50 ml) were stirred and heated for
about 6 hours in such a way that every 30 minutes about 30 ml of
the acetone were distilled off, and a similar new portion of
acetone was added to the reaction mixture. The reaction was
followed by thin layer chromatography (tlc). After cooling,
sodium bicarbonate (0.1 g) was added, and the suspension was
stirred for 1

105~
hour. After fi]trcltion, t:l-e solv(nt ~.,s r(~ ov(d by he(~ting on ~
~ater bath (60C, 10 mm llg), and -t'ne rcs;dual ye]lc~w oil (1.45 y)
was purified by distillation, giving 1.00 g (78%) of II as a
colourless oil, bo o5 119-122C, nD 1.4603.
Calculated for C14 24 4
Found : C 65.4 H 9.6
B. 8-[5-(3-Oxo-l-octenyl)-tetrahydro-2-furyl]-octanoic acid
metllyl ester
, . . , .. .. ,, , . _ ~ .
50QO sodium hydride in mineral oil (1.11 g, n.o230 mole)
lO ~ s suspellded in 1,2-dimethoxyethane (115 ml). At 15C and under
~ic~orous stirring (2-oxoheptyl)-phosphonic acid dimethyl ester
(5.11 g, 0.0230 mole) in dimethoxyethane (23 ml) was added drop-
wise over a period of 15 minutes. The reaction mixture contain-
ing a ~hite, voluminous precipitate was stirred for 1 hour at
room temperature. A solution of crude II (7.20 g), prepared from
I (7.55 g, 0.0250 mole), in 1,2-dimethoxyethane (46 ml) was
added dropwise over a period of 15 minutes to the stirred reaction
mixture, maintained below 25DC. The resulting turbid, yellow
solution was stirred at room temperature for 2 hours. The solvent
was distilled off from a water bath (40C, 10 mm Hg). The oily
residue was dissolved in ether (230 ml), washed with cold 10%
aqueous sodium chloride (60 + 60 + 60 ml) and cold water (60 +
60 ml), and dried over sodium sulfate. After filtration, the
solvent was removed from a water bath (60C, 10 mm Hg). The
residual light tea-coloured oil (9.60 g) was distilled under
nitrogen to give 7.15 g (81%) of III as a light yellowish oil,
bo o5 160-190C, nD 1.4712.
For analysis 1.00 g of III (bo o5 160-190C) was pu-

105'~
rified by chrolnal-o~ral~hy on sil;r-a gel (ether - l;yro;ne (b
50~C) 1:1 as eluent) to givc 0.80 y of a lighl ye]]ow oil.
Distillation (185-l90~C, 0.03 nun 7ig) yielded 0.62 g of III as a
light yellowish oil, nD 1.4756.
Calcul~ted for C21l~36 4 (
Found : C 71.8 H 10.2
E~ample 2
8-[5-(3-l~ydroxy-1-octenyl)-tetrahydro-2-furyl]-octanoic
ac~d metllyl ester
III (3.17 g, O.Q0900 mole) was dissolved in methanol
(75 ml) and sodium tetrahydroborate (1.7 g, 0.045 mole) was
added at 0C with stirring. The stirring was continued for 1
hour. During this time the temperature was slowly raised to
room temperature. The colourless solution was poured into ice-
water (250 ml) and extracted with ether (100 + 50 + 50 ml). The
com~ined ethereal extracts were washed with water (50 + 25 + 25
ml), dried over magnesium sulfate, and evaporated from a water
bath (50C, 10 mm Hg). The obtained light yellowish oil (3.38 g)
was distilled under reduced pressure to give 2.90 g (91~) of IV
as a colourless oil, bo o5 175-188C, -D 1.4699.
For analysis 0.72 g of IV (bc o5 175-188C) was
purified by chromatography on silica gel (ether-ligroine(b.<50C)
1:1 as eluent) to give 0.65 g of a colourless oil. Distillation
(185-190C, 0.05 mm Hg) yielded 0.55 g of IV as a colourless
oil, nD 1.4711.
Calculated for C21H38O4 (354.5):C 71-1 H 10-8
Found :C 71.3 H 10.8

~.os~
Example 3
8-[5-(3-liyd~oxy-1-oc~enyl)~tetrahydro--2-fl~ry1]-ocl-.Jn~ic a-;d
_ . _ _ . _ _ . _ . _ . _ _ _ _ . _ ,, , .. _ .., , , , . . , _ . .. . .
IV (1.77 g, 0.00500 mole), meth,lnol(20 ml), ~nd 20%
aqueous potassium carbonate (10 ml) were stirred and heated
under reflux or 90 minutes. The methanol was removed from a
~ater bath (60C, 100 mm Hg). The residue was ~iluted with water
(25 ml) and washed with ether (25 ml). The resulting clear
solution was acidified to pH 5-6 with acetic acid. The
resulting emulsion was extracted with ether (25 + 25 ml). The
com~ined ethereal extracts were dried over sodium sulfate and
evaporated from a water bath (60C, 1 mm Hg) to give 1.60 g (94%)
of V as a colourless oil, -D 1.4778.
For analysis, 1.60 g of V (-D 1.4778) was purified
by chromatography on silica gel (ether - ligroine (b.<50C) 2:1
as eluent) to give 1.30 g of a colourless oil. Distillation
(190-195~C, 0.04 mm Hg) yielded 1.04 g of V as a colourless oil,
nD 1.4790.
Calculated for C20H36O4 (340.5): C 70-5 H 10-7
Found : C 70.3 H 10.7
Example 4
8-l5-(3-Hydroxyoct l)-tetrahydro-2-furyl]-octanoic
Y
acid methyl ester
IV (1.77 g, 0.00500 mole), methanol (50 ml), and
Raney nickel (1 g) were shaken under hydrogen at a pressure of
70 atmospheres for 24 hours at room temperature. After filtra-
tion, the solvent was remo~ed from a water bath (60~C, 10 mm Hg).
Ether (50 ml) was added to the residue, and the turbid, colour-
less solution was filtered. The

lOS'~
ethereal so]ntion was e~<~po~ed to ~lryr,ess from ~ -"<~f-r b~h
(60C, 10 mm l~g). The r-sidual c1ear, colourlcss oi] (1 90 g)
was distilled under reduced pressure to give 1.69 y (95%) of
VI as a colourless oil, b 5 160-172C, nD 1.4625.
For analysis, 1.50 g of VI (bo o5 160-172C) was
pul-ified by chromatography on silica gel (e~her - liyroine (b.<
50C) 1:1 as eluent) to give 1.20 g of a colourless oil. Dis-
tillation under xed~lced pressure gave 1.05 g of VI as a colour-
less oil, bo 1 175-176C, nD 1.4630.
Calclllated for C21H40 4 (
Found : C 70.8 H 11.3
Example 5
8-[5-(3-Hydroxyoctyl)-tetrahydro-2-furyl]-octanoic acid
VI (1.78 g, 0.00500 mole), methanol (20 ml), and 20%
aqueous potassium carbonate (10 ml) were stirred and heated
under reflux for 90 minutes. The methanol was removed from a
water bath (60C, 100 mm Hg). The residue was diluted with
water (25 ml) and washed with ether (25 ml). The resulting
clear solution was acidified to pH 5-6 with acetic acid. An
emulsion was formed, which was extracted with ether (25 + 25 ml).
The combined ethereal extracts were dried over sodium sulfate
and evaporated from a water bath ~60C, 1 mm Hg) to give 1.62 g
(95~) of VII as a light yellowish oil, -D 1.4682.
For analysis, 1.62 g of VII (-D 1.4682) was purified
~y chromatography on silica gel (ether - ligroine (b.<50C) 2:1
as eluent) to give 1.20 g of a light yellowish oil.
Distillation (180-190C, 0.03 mm Hg) yielded 0.85 g of VII

1(~5'~8(~
as a li~ht yellowish oil, which solidif;ed OJl standing
M.p. 32-33C, nD 1.4713.
Calculated for C20 38 4 (
Found : C 69.9 H 11.1
Example 6
8-[5-(3-Oxooctyl)-tetrahydro-2-furyl]-octanoic acid
methyl ester
III (3.52 ~. 0.0100 mole), methanol (50 ml), and Raney
nickel (0.5 g) were stirred under hydrogen at a pressure of 1
a~mosphere, until absorption stopped. After filtration, the
solvent was removed from a water bath (60C, 10 mm Hg). The
residual light yellowish oil (3.60 g) was distilled under
reduced pressure to give 3.01 g (85%) of VIII as a light yellow-
ish oil, bo o3 165-176C~ nD5 1-4608-
For analysis, 3.01 g of VIII (bo o3 165-176C) was
purified by chromatography on silica gel (ether - ligroine
(b.<5C~C) 1:2 as eluent) to give 2.06 g of a colourless oil.
Distillation under reduced pressure gave 1.95 g of VIII as a
colourless oil, bo o3 172-174C, nD 1-4600-
Calculated for C21 38 4 (
Found : C 71.0 H 10.9
Example 7
8-[5-(3-Oxooctyl)-tetrahydro-2-furyl]-octanoic acid
VIII (1.77 g, 0.00500 mole), methanol (20 ml), and
20~ aqueous potassium carbonate (10 ml) were stirred and heated
under reflux for 2,5 hours. The methanol was removed from a
water bath (60C, 100 mm Hg). The residue was diluted with
water (25 ml) and washed with ether (25 ml). The
--10--

105'~80~
resulting clear solution was acidified 1o pl~ 5~6 with acetic
acid. The emulsion being formed was extrac1:ed with ether ~25 +
25 ml). The combined ethereal extracts were dried over sodium
sulfate and evaporated from a water bath (6CC, 1 rnm Hg). The
yellowish, oily residue of IX (1.60 g, 94%) solidified by
standing. M.p. 26-28C, _~ 1.4673.
For analysis, 1.60 g of IX (m.p. 26-28C) was purified
by chromatography on silica gel (ether - ligroine (b.C50C) 1:1
as eluent) to give 1.30 g of a light yellowish oil. Distillation
under reduced pressure yielded 0.88 g of IX as a light yellowish
oil, which solidified by standing, bo o5 200-202C, m.p. 31-32C,
n2D5 1 4686.
Calculated for C20H36O4 (340.5) : C 70.5 H 10-7
Found : C 70.5 H 10.7
Example 8
_-[5-(3-Hydroxy-3-methyloctyl)-tetrahydro-2-furyl]-
octanoic acid
IX (6.30 g, 0.0185 mole), hexamethyldisilazane (HMDS)
(12 ml), trimethylchlorosilane (TMCS) (6 ml), and pyridine (40
ml) were mixed and kept overnight at room temperature. The
resulting white suspension was evaporated to dryness (50C, 10
mm Hg). Ether (100 ml) was added, and the suspension was
filtered. The resulting clear, yellow solution of X was
cooled to 0C, and methylmagnesium bromide in ether (3.8N, 8.0
ml, 0.030 mole) was added dropwise during 20 minutes. After
stirring for 2 hours at room temperature, the white suspension
being formed was poured into a mixture of cold hydrochloric acid
(0.25N, 140 ml) and ether (50 ml). The ethereal phase was
separated, and

5~
the aqueous layer was extracted with ether (50 + 25 ml~,
The combined ethereal extracts were washed with water
(50 ml) and dried over sodium sulfate. The solvent was
removed ~rom a water bath (60C, 10 mm Hg), and the re-
sidual light yellowish oil (7,40 g) was distilled under
reduced pressure to give 5.40 g (82%) of XI as a light
yellowish oil, bo o8 203-210C, nD5 1.4710,
For analysis, 1.50 g of XI (bo o8 203-210C) ~as pu-
rified by chromatography on silica gel (ether - ligroine
lo (b,< 50C) 1:1 as eluent) to give 1,10 g of a light yel-
lowish oil. Distillation (190-200C, 0.05 mm Hg) yielded
1.00 g of XI as a light yellowish oil, nD5 1,4725,
Calculated for C21H4004 (356,5): C 70,7 H 11-3
Found : C 70.5 H 11.2
Example 9
8-/~-(3-Hydroxy-3-methyloctyl~-tetrahydro-2-furyl7-
octanoic acid methyl ester (XII)
XI (1.78 g, 0.00500 mole), methanol (25 ml), and
ethyl ether-borontrifluoride complex (0.1 ml) were stirred
and heated under reflux for 1 hour. After cooling, the re-
action mixture was poured into ice - water (200 ml) and
extracted with ether (50 + 50 + 25 ml)0 The combined ethe-
real extracts were washed with cold 2% aqueous sodium hy-
drogen carbonate (50 ml) and water (50 ml~. The ethereal
solution was dried over sodium sulfate and evaporated to
dryness from a water bath (60C, 10 mm Hg). The residual
yellowish oil (1.95 g) was distilled under reduced pres-
sure to give 1.82 g (98%) of XII as a colourless oil,
bo o3 160-170C, nD5 1.46250
For analysis, 1.80 g of VII (bo o3 160-170C) was pu-
- 12 -

105'~
rified by chromatoyrdphy on sil;ca yel (ct:hcr-]iyroine (b.<5G~C)
1:1 as eluent) to give 1.00 g of a colourlcss oil. Distill~tiGn
(150-160C, 0.05 mm llg) yielded 0.75 g of XII as a colourless
oil, n2~5 1.4640.
Calculated for C22H42O4 (370.6) : C 71.3 H 11-4
Found : C 71.1 H 11.4.
-13-