Патент USA US3099672код для вставки
United States Patent 0 "ice 3,099,662 Patented July 30, 1963 2 1 solids were triturated several times with ethyl ether and the combined ethereal extracts were washed with water 3,099,662 and evaporated to dryness to give an oily product. Dis tillation of this oil afforded 136.5 g. of 2,2-dimethallyl DIOXASPIRO DERIVATIVES 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: R u 1 R2 Rs ‘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 undecane. 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 EXAMPLE 2 using catalytic amounts of a mineral acid to ‘give the 3,3,8-Trim‘ethyl-2J-Di0xaspir0(4.4)Nonane 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 product. 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 KEXAMPLE 3 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 EXAMPLE 1 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. 3,099,662 3 A1. EXAMPLE 4 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., The infrared 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. 30 (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 R 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. Dis 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. 0 (CH2) n——! R: 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 1.A51.