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Патент USA US3099672

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United States Patent 0 "ice
Patented July 30, 1963
solids were triturated several times with ethyl ether and
the combined ethereal extracts were washed with water
and evaporated to dryness to give an oily product. Dis
tillation of this oil afforded 136.5 g. of 2,2-dimethallyl
Burton K. Wasson, Valois, Quebec, and John M. Parker,
Montreal, Quebec, Canada, assignors to Charles E.
Frosst 8: Co., Montreal, Quebec, Canada, a corpora
tion of Quebec, Canada
No Drawing. Filed May 4, 1962, Ser. No. 192,338
1,3-propanediol, B.P. 162.5—l72.0° C./15~20 mm. Infra
red: 7\ max. 3.0 (hydroxyl), 3.25, 6.1 (unsaturation),
9.6-9.8 (hydroxyl), 1125p. (methallyl).
(b) 2,2-dimethally-l-1,3-propanediol (83.9 g.) was dis
5 Claims. (Cl. 260-3459)
solved in 59.5 ml. of tetrahydrofuran and treated with
This invention relates to novel dioxaspiro ‘derivatives, 10 1.9 ml. of concentrated hydrochloric acid. The internal
temperature of the solution rose spontaneously to 60° C.
and a process .for the ‘manufacture thereof. More par
ticularly, this invention relates to dioxaspiro compounds
of the formula:
‘and was cooled brie?y, left 1 hour at room temperature,
and refluxed ‘for a period of two hours. The tetrahydro
furan was removed by distillation. The residue was dis
15 solved in ethyl ether, washed with small amounts of
dilute alkali to remove any acid, washed with water,
dried, and evaporated to give 73.7 ‘g. of a pale yellow
liquid. Distillation of this product afforded 68.3 g. of
3,3,8,8-tetramethyl-2,7-dioxaspiro(4.4)nonane, B.P. 115
20 121° C./21
wherein n represents either 1 or 2, and R, R1, R2, and
R3 represent ‘hydrogen or a ‘lower alkyl radical from 1 to
An analytical sample of 3,3,8,8-tetra
methyl-2,7edioxaspiro(4.4)nonane was obtained by re
distillat-ion through a. spinning band column having B.P.
109—110° C./3=0-31 mm, nD25 1.41404. Another speci
3 carbon atoms. Those skilled in the art will appreciate
men had a B.P. of 207.5—208° C./760 rnrn.
that when n is 1 the product will be a dioxaspirononane, 25
Analysis.——Calc. for CHI-12002: C, 71.69; H, 10.94.
and when n is 1 and 2 the product will be a dioxaspiro
Found: C, 72.05, 72.13; H, 11.43, 11.19‘.
decane and when n is 2 the product will be dioxaspiro
The infrared spectrum of 3,3,8,8-tetramethyl-2,7-di
oxaspir0(4.4)nonane indicated the absence of unsatura
The products of this invention are prepared by the re
tion and of hydroxyl groups and the appearance of an
duction of a suitable di-uns'aturated malonate with lithium
additional band in the methyl region.
aluminum hydride to give the corresponding di-unsatu
rated 1,3-propanediol, followed by cyclization of the diol
using catalytic amounts of a mineral acid to ‘give the
corresponding dioxaspiro derivative. For example, re
duction of diethyl dimethallylmalonate with lithium alu 35
2,2-dimethyl - 4 - allyl-4hydroxymethyltetrahydrofuran
minum hydride followed by cyclization of the 2,2~di
(25 g.) was treated dropwise with 6.5 ml. of concentrated
methallyl-1,3-propanediol gave the product 3,3,8,8-tetra
hydrochloric acid. The internal temperature of the solu
methyl-2,74dioxaspiro( 4.4) nonane.
tion rose from 25° ‘C. to 35° C. accompanied by faint
.On the other hand, a similar reduction of diethyl meth
allyl-3-methyl-2-butenyl)malonate followed by cycliza
tion of the 2-methally-l-2(3-methyl-2-lbutenyl)-1,3-pro
panediol gave 3,3,8,8-tetramethyl - 2,7 - dioxaspiro(4.5)
vdecane. Likewise, the above mentioned reaction sequence
when applied to diethyl di4(3-methyl-2-butenyl)malonate
can give 3,3,9,9-tetrarnethyl-2,8-dioxaspiro(5.5)undecane.
3,3,8-trimethyl-2,7-dioxaspiro(4.4)nonane was prepared
by treatment of 2,2-dirnethyl-4-allyl-4~hydroxymethyltet
rahydrofuran heated on the steam bath in the presence
discoloration. The solution was left 30 minutes at room
temperature and then warmed overnight on a steam bath.
Concentrated sodium hydroxide (containing 4 g. of so
dium hydroxide) was added to the solution maintained
at 15—25° C. and the mixture was extracted with ethyl
ether. The ethereal solution was washed with water and
45 the ether distilled to give 23 g. of a liquid. This liquid
was distilled to afford 20.8 g. of 3,3,8-trimethyl-2,7-di
oxaspiro(4.4)nonane, B.P. 68-74° C./6—8 mm., 111,25
1.4439. The analytical specimen obtained by iiractional
of 10% (by weight) concentrated hydrochloric acid.
distillation on a spinning band column had B.P. 70.5
These conditions were also effective in the ring closure 50 71.0° C./6 mm., 111325 1.4436.
of '2-allyl-2-methallyl-1,3-propanediol to give the same
The compounds to which the invention relates are
useful because of their valuable pharmacological prop
Analysis.—Calc. for CmHlgOzz C, 70.55; H, 10.66.
Found: C, 70.29; H, 10.64.
The infrared spectrum of 3,3,8-trimethyl-2,7-dioxaspiro
(4.4)nonane showed the appearance of a second band in
erties. Thus, for example, they exhibit anti-.convulsant 55 the methyl region and the disappearance of bands asso
properties when tested by audiogenic seizures using a
ciated with unsaturation and hydroxyl groups,
strain of susceptible mice. For example, it has been
‘found that the anti-convulsant dose of 3,3,8-trimethyl
2,7-dioxaspiro(4.4)nonane is substantially lower than the
3 ,3 ,8 -Trimethyl-Z,7-D‘i0xaspir0( 4 .4 ) Nonane
lethal dose, and that the LD50 is 340‘ rug/kg. and that 60
2-allyl-2-methallyl-1,3-propanediol (25 g.) was treated
the anti-convulsant D50 is 75 mgJkg.
at room temperature with 6.5 m1. of concentrated hydro
chloric acid. The internal temperature rose rapidly and
reached 80° C. even with external cooling. The material
3,3,8,8-Tetramethyl-2,7—Di0xaspiro(4.4 ) Nonane
(a) A solution of 214.5 g. of diethyl dimethallyl 65 was warmed 7 hours on the steam bath, made basic by
the addition of 6 N sodium hydroxide, and extracted with
malonate in 500 ml. of anhydrous ethyl ether was added
dropwise over a 4 hour period to a vigorously stirred mix
ture of 45.6 -g. of lithium aluminum hydride and 1250 ml.
of anhydrous ethyl ether maintained at 5-20° C. The
reaction mixture was stirred for 2 hours. The mixture
was cooled, and decomposed by successive addition of
methanol-ethyl ether, methanol-water, and water. The
ethyl ether.
The ether was removed and the residue dis
tilled to give 20.2 g. of 3,3,8-trimethyl—2,7-dioxaspiro
(4.4)-nonane, B.P. 77~83° C./8—10 mm., r1925 1.4438.
The infrared spectrum of this product was identical with
in experimental error with that of the product from Ex
ample 2.
Analysis.-Calc. for C12H22O2: C, 72.68, H, 11.18.
Found: C, 72.74, H, 11.22.
3,3 ,8,8-Tetramethyl-2,7-D ioxaspiro (4 .5 ) Decane
(a) Diethyl methallylmalonate (110.2 g.) was added
Infrared: )\ max. 3.0 (hydroxyl), 3.22, 6.1 (unsatura
tion), 6.9 (CH2), 7.25 (methyl), 9.5-9.8 (hydroxyl),
during 5-10 minutes to a solution of sodium ethoxide
(from 11.9 g. of sodium in 300 ml. of ethanol). The
mixture was stirred for 30 minutes and 76.7 g. of 3-methyl
11.25,“ (methallyl). By proceeding in a similar manner
diethyl di-(3-methyl-2-butenyl)malonate would give 2,2
di-'(3-methyl-2-bu-tenyl) -1,3~propanediol.
(c) 2-methallyl-2-‘( 3-methyl-2-butenyl ) ~1, 3-propauediol
Z-butenyl bromide was added during 20 minutes of stir
ring. The mixture was re?uxed overnight, cooled to
(30 g.) in 110 ml. of tetrahydrofuran was treated drop
room temperature, and treated with water to dissolve the 10 wise during 15 minutes With 28 ml. 6 N hydrochloric acid
sodium chloride. The solution was slightly acidic. The
accompanied by stirring. The internal temperature of
ethanol was removed in vacuo and the residual mixture
the solution rose from 22° to 33° C. The solution was
extracted with ethyl ether. The combined ethereal ex
re?uxed for 3 hours and the tetrahydrofuran distilled at
tracts were washed sparingly with water and the ether
atmospheric pressure to give 31.9 g. of crude 3,3,8,8-tetra
evaporated to give 139.2 g. of oily product. Distillation 15 methyl-2,7-dioxaspiro(4.5)decane.
Distillation of this
of this product afforded 14 g. of forenm, B.P. 72-123°
material through a spinning-band column a?orded an ana
C./11 mm., nD25 1.4495; 121.8 g. of diethyl methallyl(3
lytical sample of 3,3,8,8-tetramethyl-2,7-dioxaspiro'(4.5)‘
methyl-2-butenyl)-malonate, B.P. 121-162° C./11 mm.,
decane, B.P. 94.0-94.5“ C./6 mm., 111325 1.4505.
nD25 1.4566: and 1.8 g. ‘of residue. Further distillation
Analysis.—-Calc. for C12H22O2: ‘C, 72.68, H, 11.18.
a?orded an analytical specimen of diethyl methallyl(3 20 Found:
C, 72.66, 72.72, H, 11.14, 11.24.
methyl-Z-butenyl)malonate, B.P. 149-150° C./14 mm.,
spectrum indicated the absence of unsatu
111325 1.4571.
ration and hydroxyl groups and the presence of methyl
Analysis.-Calc. for ‘0161-12604: C, 68.05: H, 9.28.
groups (7.25, 7.35/1). By proceeding in a similar man
Found: C, 67.67, H, 9.14.
ner 2,2-di-(.3-methyl-2-butenyl)-1,3-propanediol would
Infrared: )\ max. 3.25 (unsaturation), 5.75 (carbonyl), 25 give 3 ,3,9,9-tetramethyl-2,8-dioxaspiro (5.5 ) undecane.
6.1 (unsaturation), 7.25-7.32 (methyl), 8.3-8.5 (ester)
What we claim is:
and 11.15,”. (methallyl). By proceeding in a similar man
ner diethyl‘(3-methyl-2-butenyl)-malonate would give di
ethyl di-(3-methyl-2-butenyl)malonate.
(b) Diethyl methallyl‘(3-methyl-2-butenyl)malonate
. 3,3,8,S-tetramethyl-2,7-dioxaspiro(4.4)nonane.
(99.1 g.) was dissolved‘in 300 ml. of anhydrous ethyl ether
. 3,3 ,8-trimetl1yl-2,7-dioxaspiro ( 4.4) nonane.
. 3,3, 8,S-tetramethyl-2,7-dioxaspiro(4.5 ) decane.
. 3,3,9,9-tetramethyl-2,8-dioxaspiro(5.5)undecane,
and then added ‘dropwise during 2 hours to 20 g. of lith
ium aluminum hydride slurried in 500 ml. anhydrous
ethyl ether maintained at 10-20a C.
The mixture was
stirred during 1 hour with the temperature rising to 25° 35
VC. and left at room temperature overnight. The mixture
Was cooled With an ice-salt bath and decomposed by the
successive addition of methanol-ethyl ether, methanol
water, and water. 'I‘he'solids were collected, washed re
peatedly with ether, the ethereal extracts combined,
washed, and evaporated to give 67.3 g. of ‘an oil.
tillation of this oil at 148-165 ° C./9 mm. afforded 65.6
g. of semipure 2-methallyl-2~(3-methyl-2-butenyl)-1,3
propanediol. The distillate upon standing crystallized
with evolution of heat a?ording white needles, M.P. 54.5 45
55.0° C.
(CH2) n——! R:
wherein R, R1, R2 and R3 are selected from the group
consisting of hydrogen and lower alkyl radicals having
from 1 to 3 carbon atoms, at least one of R, R1, R2 and
R3 is alkyl and n is a positive integer from 1 to 2.
References Cited in the ?le of this patent
Patterson et al.: The Ring Index,‘ 2nd ed., pp. 134 and
222, Amer. Chem. Soc. (1960), QD 291.P3.
Chemical Abstracts, 5th Decennial Index, vols. 41-50,
subject index, Cy-Ey, pp. 4230s-4231s (1947-1956), QD
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