Method for producing derivatives of hexahydroazepine,or piperidine,or pyrrolidine (versions)

专利摘要:
2-Oxo-hexahydroazepine, -piperidine and -pyrrolidine derivatives of general formula (I) …<CHEM>… where n is 2, 3 or 4, R is hydrogen, lower alkyl or aryl(lower)alkyl and R<1> is hydrogen or lower alkyl are novel intermediates for their aromatised derivatives of formula (II) …<CHEM>… where n and R<1> are as defined above, R<2> is hydrogen, lower alkyl or aryl(lower)alkyl and R<3> is hydrogen, lower alkyl, aryl(lower)alkyl, lower alkenyl or lower alkynyl. The aromatised derivatives (of which those in which R<1> is hydrogen are novel) can be converted into 3,3-disubstituted-hexahydroazepine, -piperidine and -pyrrolidine derivatives having pharmacological activity, particularly analgesic activity.
公开号:SU1301311A3
申请号:SU782699100
申请日:1978-12-20
公开日:1987-03-30
发明作者:Фредерик Кавалла Джон；Чапмэн Вайт Алан；Джеральд Шеферд Робин
申请人:Джон Вайс Энд Бразер Лимитед (Фирма)；
IPC主号:

专利说明:

conducting stages a
b,
those. without C-alkylation. It is advisable to carry out in the presence of CuBr and LiBr in an acetonitrile medium, followed by its removal in vacuum and suspending the precipitate in alkali. After separating the precipitate, the ChS1 filtrate is acidified and the precipitate of the aromatic compound is separated;
b be carried out in the medium of NaOH solution with dimethyl sulfate; a carried out with sodium amide in toluene at boiling; g is carried out in the medium of ether with lithium aluminum hydride at boiling. Output 1 increased to 38-40% versus 23% and reduced the number of stages to 4-5 versus 7 in the known. 2 sp.f-ly.
one
This invention relates to an improved process for the preparation of hexahydroazepine or piperidine or pyrrolidine derivatives of the general formula:
(UWB
where n 2,3 or 4;
R, is hydrogen, lower alkyl, aryl (lower) alkyl, lower alkenyl or lower alkynyl; R, is lower alkyl; RJ is hydrogen or lower alkyl with analgesic action
The goal is invented and - simplifying the process and increasing the yield of the target products.
Example I. Hexahydro-1-methyl-3- (3-oxocyclohexen-1-yl) 2H-azo-2-one.
12.14 g (17.0 ml) of diisopropylamine in 20 ml of dry tetrahydrofuran (THF) was added dropwise to a stirred (-10 ° C) butyl lithium solution (86 ml of a 1.4 M solution in hexane) stirred in a stream of nitrogen . After 10 minutes, the Gilman test gave a negative result. Also, at -10 ° C, 14.19 g of 1-methylcaprolactam in 20 ml of THF was added. The reaction mixture was stirred for 10 minutes, at 0 ° C., and 12.6 g (0.1 mol) of 3-methoxy-2-cyclohexanone in 20 ml of THF were added to it. The mixture was then allowed to warm to room temperature.
. temperature for 1.5 h., after
Q
which was cooled to -10 ° C and decomposition was carried out by adding 125 ml of 2N. hydrochloric acid, which was introduced rapidly, but at the same time did not allow the temperature to exceed 0 ° C. The mixture was stirred at room temperature for 30 minutes. The aqueous layer was separated and extracted
O dichloromethane. United Organized. The ches extracts were dried over anhydrous magnesium sulphate and evaporated to. oil formation, which was crystallized from a mixture of toluene and petroleum
5 with ether (with so-called boiling point. BO-ZO C, as a result of which 18,99 g of the indicated compound of the designation of the compound with T. 109-PO ° C were obtained.
Found,%: C 70.65; H 8.6, N 6.1.
0 С „Н„ 1Ю2
Calculated,%: C 70.6; H 8.65, N 6.3.
Example 2: Hexahydro-3- (35 hydroxyphenyl) - -methyl-2H-azepin-2-one.
11.1 g of hexahydro -} - metsh1-3 (-OK-siciclohexen-1-yl) -2H-azepin-2-one in 250 ml of acetonitrile was stirred overnight in combination with the mixture
0 22.3 g of copper (II) bromide and 4.3 g
lithium bromide. Then acetonitrile was removed under reduced pressure, and the resulting dark precipitate was suspended in 200 ml of 2N. solution of hydrag ta sodium oxide. The solution was filtered, the precipitate was washed with water and the filtrate was acidified with concentrated hydrochloric acid. Included in the sediment specified in the title of the example phenol
0 was filtered and washed with water to give 8.62 g of an off-white powder with mp. 1 85-1. The second portion of the product in the amount of 900 mg with so pl. 188-191 ° C was obtained by extraction treatment of the mother solutions with chloroform. The resulting product was purified by recrystallization from ethyl acetate or a mixture of ethyl acetate with methanol, resulting in a pure substance with so pl. 192-193 C.
Found,%: C 71.0; H 3.0; N 6.4.
C ,, H ,, NO ,.
Calculated,%: C 71.2; H 7.8; N 6.4
PRI me R 3. Hexahydro-3- (3-methoxyphenyl) - -methyl-2H-azepin-2-one
21.9 g of hexahydro-3- (3-hydroxyphenyl) -1-methyl-2H-azepin-2-one was dissolved in 100 ml of 2M sodium hydroxide solution and 18-, 3 g (14.5 ml) were added to this solution dimethyl sulfate. The reaction mixture was stirred at room temperature for 10 minutes and then seeded. After keeping the mixture at 0 ° C for 3 hours in a calm state, the product precipitated as crystals in the sediment.
Then the crystals were filtered, washed with water and dried to obtain 16.99 g of the title compound as an off-white powder with mp. 83-84 ° C.
Subsequently, 1.69 g of the desired product was obtained by treating aqueous solutions with 50 ml of a 2M solution of sodium hydroxide and 7.25 ml of dimethyl sulfate.
EXAMPLE 4: 3-ethylhexahydro-3- (3-methoxyphenyl) -1-methyl-2H-aze-pin-2-OH.
4.66 g of hexahydro-3- (3-methoxyphenyl) -1-methyl-2H-azepin-2-one in 25 ml of dry toluene was added dropwise to a stirred suspension 1.0 g of sodium amide in 50 ml of dry toluene . The reaction mixture was then heated to reflux, ammonia volatilized, and the reaction mixture turned red. After refluxing for 2 hours, 20 ml of tetrahydrofuran were added, the mixture was cooled and 3.7 g of ethyl iodite was added to it. A white precipitate formed and the red color quickly disappeared. The reaction mixture was refluxed for 2 hours, cooled and decomposed by adding water. The aqueous phase was separated and the organic layer was washed with sat.
50
five
0
five
Q Q. five
It was dried over anhydrous magnesium sulphate and evaporated to give an oil-like product, which was crystallized from diisopropyl ether to give the title compound (3.29 g) with m.p. 62-64 ° C.

Found,%: C 73.5; H 9.0; N 5.15.
With eH „HU ,.
Num,%: C 73.5; H 8, 9; N 5.4.
EXAMPLE 5 3-ethylhexahydro-3- (3-methoxyphenyl) -1-methyl-1H-azepine.
5.52 g of 3-ethylhexahydro-3- (3-methoxyphenyl) -1-methyl-2H-azepin-2-one in 100 ml of anhydrous diethyl ether was added dropwise to a stirred suspension of 1.5 g of aluminum lithium hydride in 50 ml of anhydrous diethyl ether. The reaction mixture was maintained at reflux for 3 h.
An additional portion (1.0 g) of lithium aluminum hydride was then added and heating was continued for 2 hours. After cooling, the reaction mixture was decomposed by adding 3 ml of water, 3 ml of 15% sodium hydroxide solution and 6 ml of water to it. The granulated precipitate was filtered and washed with diethyl ether. The combined filtrate and ethereal extracts were subjected to extraction treatment in 3 portions of 25 ml of 2M hydrochloric acid solution. The combined acid washings were basified by the addition of 15M aqueous ammonium hydroxide solution and extracted with diethyl ether. After drying over anhydrous magnesium sulphate, the solvent was removed, leaving 3.98 in the title of the example as a colorless, oil-like product, 98% pure, previously purified by gas-liquid chromatography, identical to that obtained by the usual method. The product is converted to 3-ethyl 1-hexa-hydro-3- (3-hydroxy-phenyl) -1-methyl-1H-azepine by treatment with hydrobromic acid in accordance with the method described in UK patent No. 1285025.
51
P p and m e p 6. 3-ethylhexahydro-3- (3-hydroxyphenyl) -i-methyl-2H-aeepin-2-2-one.
77 MP 1.4 M solution of butyl lithium in hexane was added to solution 1A, 8 ml of diisopropylamine in 20 ml of dry tetrahydrofuran at -10 ° C in a stream of nitrogen. The mixture was stirred at -10 ° C for 10 minutes and Ig was added to it in finely dispersed hexahydro-3- (3-hydroxyphenyl) -1-methyl-2H-azepin-2-one powder. Then, 500 ml of tetrahydrofuran was added to the mixture and the whole mass was refluxed for 3 hours. After cooling, 8.2 g of ethyl iodide was added and the entire mixture was again boiled under reflux for 3 hours. 20 ml of water was carefully poured into the cooled solution and the mixture was evaporated to a brown residue. After dissolving in water, the mixture was in turn extracted with a 2M solution of sodium hydroxide. The washing water and the sodium hydroxide solution were combined and acidified with concentrated hydrochloric acid. The dry residue was filtered, washed with water, dried and recrystallized from ethyl acetate to give 8.72 of the title example compound as white crystals, m.p. 178-180 ° C.
Found,%: C 72.55; H 8.6; N 5.3.
C, 5H2, N02.
Calculated,%: C, 72.8; H 8.6; N5.7
Example 7. 3-ethylhexahydro-3- (3-hydroxyphenyl) -1-methyl-2H-azepine.
A solution of 1.5 g of 3-ethylhexahydro-3- (3-hydroxyphenyl) -1-methyl-2H-azepin-2-one in dry tetragnroflurane was added H stirred suspension of lithium-aluminum hydride (0.48 g) and boiled under reflux within 5 hours. The reaction mixture was cooled and decomposed by adding 1 ° s, and the precipitate was filtered. This precipitate was then washed with tetrahydrofuran, the filtrate was combined with a flush liquid and added to dryness. The dry residue was dissolved in water and ammonium chloride was added. The maslob-like product precipitated was taken up with dichloromethane, dried over anhydrous magnesium sulphate and evaporated to give a solid product, which was recrystallized from acetonitrile.
five
0
five
3
0
five
0
five
0
five
I6
to give 0.91 g of the title compound, with an mp. 127.5-133 ° C, identical to a product obtained in another way, as described in UK patent No. 1285025.
PRI me R 8. 120 ml (1.4 mol) of n-butyl lithium were treated at 20 ° C in a stream of dry: th nitrogen 27 ml (19.2 g) of diisopropylamine in 25 ml of dry diethyl ether. The mixture was stirred for 10 minutes at 20 ° C after completion of the addition operation, and then 20 g of 1-methyl-2-tiperidone in 25 ml of diethyl ether was added dropwise over 10 minutes. This mixture was stirred for an additional 10 minutes, and then 19.4 g of 3-isopropoxy-2-cyclohexenone in 25 ml of diethyl ether was added dropwise to it within 10 minutes. This mixture was stirred for an additional 2 hours, at 20 ° C, and then hydrolyzed by adding (at the beginning dropwise) a mixture of 50 ml of concentrated hydrochloric acid with 50 ml of water. In the acidification process, this mixture was cooled in a water bath in order to reduce the reaction rate to a moderate one. Next, the mixture was cooled to room temperature (from 35 ° C) and the organic phase was separated, and then dried over magnesium sulfate. After removal of the solvent, a mobile yellow oil was obtained in an amount of 0.63 g. The aqueous phase was extracted thoroughly using 10 portions of chloroform, 40 ml each; the combined extracts were washed with 100 ml of water and 100 ml of a saturated aqueous solution of sodium chloride and dried over sulfate magni. Evaporation gave 25.79 g of pale green oil. Two fractions were combined and distilled to obtain two fractions: A — boiling point below 120 ° C with a residual pressure of 1 mm Hg. (4.6 g), colorless. fluid; B - boiling point from 150 to 164 ° C at a residual pressure of 0.07 mm Hg. (14.46 g), yellow oil, solidifying to form a light yellow mass with a melting point of 41 - 62 C. Fraction A was identified by IR spectrometric analysis as somewhat unclean 1-methyl-2-piperidone (23% recovery)
7
while fraction B identified infrared spectrometry and 5GMP spectrometric analyzes as indicated in the title of the example compound.
PRI me R 9, 3- (3-hydroxyphenyl) - 1-methyl-2-piperidone.
3.5 g of 1-methyl-3- (3-oxycyclohexane-1-pc) -2-piperidone with boiling under reflux in 100 ml of acetonitrile in the presence of 1.4 g of lithium bromide and 7.6 g of copper bromide (II ) for 0.5 h. Acetonitrile was evaporated to give a gum, to which 100 ml of 2n was added. sodium hydroxide solution, the solution was filtered, 30 ml of hydrochloric acid was added to the filtrate, water was extracted with chloroform, dried

12.3 g of 2-bromopropane was added to a suspension of 2.43 g of magnesium in 50 ml of di
current over magnesium sulfate and evaporated
the organic phase to produce oil, 20 ethyl ether at that rate.
which kept the mass boiling using a reflux condenser, and the mixture was stirred for 30 minutes after
which, upon standing overnight at 0 ° C in hexane, gave the same solid. This latter was collected, washed with diethyl ether and then with acetone to obtain the title compound of the example as a quarter of its hydrate, which is a colorless solid product (o, 50 g) with mp 1P-114 ° C.
Found.%: C 69.1, H 7., 27; N 7.11.
C ,, H, 5NO.
Calculated,%: C 68.7; H 7.45; N 6.68.
which allowed to maintain a gentle mass boil using a reflux condenser, and the mixture was stirred for 30 minutes after
25 of this add operation. Then, 14 ml of diisopropylamine was added dropwise and the mixture was stirred until a negative result was obtained in the Gilman test (approximately for 1 hour. Then, dropwise (exothermic reaction), 12.7 g of N-methylcaprolactam was added. After completion the operations of adding N-methylcaprolactam by mixing — Example 3. 3-etkhexahydro-35 became difficult due to
1-methyl-3- (3-oxocyclohexan-1-yl) -2H-azepin-2-one.
A 2 M solution of isopropyl magnesium bromide in diethyl ether (70 ml) was treated with 21.7 g of 3-methyl hexahydro-1-methyl-2H-azepin-2-one in 20 ml of THF and this mixture was treated by adding dropwise 19.6 ml of diisopropylamine (exothermic reaction). The reaction mixture was stirred for 2 hours and then treated by adding dropwise 12.6 g of 3-methoxy-2-cyclohexenone in 20 ml of THF. After stirring for 2 hours, the reaction mixture was poured into 250 ml of cold 2N. Noah acid. After 10 minutes, the mixture was extracted with 2 portions of 300 ml of dichloromethane, the combined organic phases were washed with saturated aqueous sodium bicarbonate and dried over magnesium sulfate. Removal of the solvents I under reduced pressure followed by distillation gave the following
in the presence of a sticky solid, which, however, was re-dissolved by the addition of 50 ml of THF. After completing this add operation
40, the entire reaction mixture was stirred for 30 minutes and then treated by adding dropwise 16.4 g of 3-isopropoxy-2-cyclohexenone (an exothermic reaction and stirring again
45 li overnight. The reaction mixture was poured into 250 ml of 2N hydrochloric acid and stirred for 30 minutes. 300 ml of dichloromethane was added and the layers were separated. The aqueous layer was subjected to an extrusion treatment with 2 portions of dichloromethane, 300 ml each, and the combined organic phases were dried over magnesium sulfate. Removal of the solvents under reduced pressure, followed by recrystallization of the residue from ethyl acetate, gave 13.2 g of the title compound an example identical to the product of Example 1.
in the title of the example, the compound is in the form of a viscous oil (at a residual pressure of 0.1 mm Hg with a boiling point of 155-160 ° C) (13 g). As a result of repeated distillation (temperature 154-158 C at a residual pressure of 0.07 mm Hg), an analytical pure product was obtained.
ten
Found,%: C 72.4; H 9.6; N 5.4.
A5 23 ZCalculated,%: C 72.25; H 9.3; N 5.6.
Example 11. Hexahydro-1-methyl-15-3- / 3-oxocyclohexen-1-yl / -2H-, azopin-2-one.
12.3 g of 2-bromopropane was added to a suspension of 2.43 g of magnesium in 50 ml of di-20 ethyl ether at this rate.
which allowed for a gentle mass boiling using a reflux condenser, and the mixture was stirred for 30 minutes after completing this addition operation. Then, 14 ml of diisopropylamine was added dropwise and the mixture was stirred until a negative result was obtained in the Gilman test (approximately for 1 hour. Then, dropwise (exothermic reaction), 12.7 g of N-methylcaprolactam was added. After completion of the operation the addition of a gap of a sticky solid, which, however, was re-dissolved upon the addition of 50 ml of THF.
40, the entire reaction mixture was stirred for 30 minutes and then treated by adding dropwise 16.4 g of 3-isopropoxy-2-cyclohexenone (an exothermic reaction and stirring again overnight. The reaction mixture was poured into 250 ml of 2N saline 300 ml of dichloromethane was added and the layers were separated. The aqueous layer was subjected to extractive treatment with 2 portions of dichloromethane 300 ml each and the combined organic phases were dried over magnesium sulfate. Removal of the solvents under reduced pressure followed by 55 SCHEDES By allyzing the residue from ethyl acetate, 13.2 g of the title compound are obtained, identical to the product of Example 1.
91
Example 12. 1-methyl-3- {3-oxocyclohexan-1-yl) -2pyrrole1adone. I
190 ml of a 1.4 M solution of n-butyl lithium in hexane in a stream of dry nitrogen were treated by adding dropwise 30.3 g of diisopropylamine in 50 ml of dry diethyl ether for 10 minutes with external water cooling to maintain the reaction temperature. The temperature was below 25 C. After a further 10 minutes, 27.72 g of freshly distilled I-methyl-2-pyrrolidone in 25 ml of dry diethyl ether was added dropwise to the reaction mixture over 15 minutes, and then the suspension was stirred for further 20 min at 20 ° C. Next, 15 g of 3-isopropoxy-2-cyclohexanone in 25 ml of diethyl ether was added to the reaction mixture over 15 minutes, the solution was suspended solid material during this addition operation. This mixture was stirred for an additional 2 hours at 20 ° C, and then cooled in ice and treated by addition (first dropwise of the mixture with 100 ml of concentrated hydrochloric acid with 100 ml of water. After a further 10 minutes, the phases were separated and the organic phase was discarded. the same phase was subjected to extraction with 10 portions of 50 ml of chloroform, and then the combined extracts were washed with 100 ml of water and 00 ml of a saturated aqueous sodium chloride solution and dried over magnesium sulfate. Evaporation of the solvent gave at first a colorless oil, to The second one darkened in air to a light red color (37.82 g). Distillation of the oil allowed to obtain the title compound as a pale yellow liquid, which solidified after adding seed to form a yellow mass (32.75 g), t Boil at residual pressure of 0.035 mm and 165 C at residual pressure of 0.07 mm, mp 42-46 ° C.
PRI me R 13. 3- (3-hydroxyphenyl) -1 methyl 2-pyrrolidone.
9.24 g of 1-methyl-3-O-oxocyclohex-) -2-pyrrolchzone, 21.39 g of copper (II) bromide and 4.16 g of lithium bromide were heated under reflux in 50 ml of acetonitrile for 1 h. The resulting dark solution was evaporated to dryness, and
ABOUT
5 Q 0

five
The preparation was treated with 100 ml of 2N sodium hydroxide solution. The obtained orange precipitate was removed by filtration and washed with 10 ml of 2N. sodium hydroxide solution and 25 ml of water. The alkaline filtrate and washings were combined and subjected to extraction with 3 portions of 50 ml of dichloromethane each to remove unreacted starting material. Then, the aqueous phase of the dark color was acidified by adding 25 ml of concentrated hydrochloric acid and subjected to extraction treatment with 4 portions of chloroform in 50 ml. The extracts combined and dried over magnesium sulphate were evaporated to give a dark gum (8.85 g), which was crystallized by the addition of seed crystals and split with a small amount of ethyl acetate to give 7.8 g (86.1%) of a brown crystalline mass with mp. 95-11 5 s. This material was crystallized from a mixture of ethyl acetate and a petroleum product with a m.p. 123-124 ° C (with fold).
I
EXAMPLE 14. 3- (3-Oxyfensh1) - I-methyl-3/1-propyl / -2-pyrrolidone.
Lithium diisopropylamide was obtained in a stream of nitrogen at room temperature from 16 ml of a 1.4 M solution of n-butyl lithium in hexane and 2.8 ml (2.02 g) of diisopropylamine. Then a solution of 1.71 g H- (3-hydroxyphenyl ) -1-methyl-2-pyrrolidone in 50 ml of THF and the final suspension was stirred for
1h at room temperature. Then, 0.95 ml (1.63 g) of 1-iodopropane was added in one portion, whereby the solid material immediately dissolved. This mixture is for
The mixture was heated to boiling for 2 hours using a reflux condenser and kept at reflux for 30 minutes, cooled and treated by adding 20 ml of water. The organic layer was removed under reduced pressure, and the residual aqueous phase was diluted by adding 20 ml of water and extracted with 2 portions of 50 ml of dichloromethane. The lower emulsion phase was separated, combined and subjected to back extraction extraction
3 portions of water, 10 ml each. Dichlorme1113
The tanovan phase was dried over anhydrous magnesium sulphate and evaporated to give the impure title compound as a brown gum which partially crystallized (0.3 g). The aqueous phases were combined with the initial aqueous phases and the pH value was exceeded 12} and acidified with concentrated hydrochloric acid to a pH value of less than 1. The precipitated yellow resin was extracted with 4 portions of 25 ml of dichloromethane and the combined extracts were dried over anhydrous magnesium sulphate and evaporated to give a brown gum, which crystallized upon trituration with a small amount of ethyl acetate (2.04 g). This material was crystallized after treating with a ethyl acetate and removing the solvent from a mixture of cyclohexene and toluene (in a volume ratio of approximately 1: 1), resulting in 0.91 g of 3- (3-hydroxyphenyl) -1-methyl-3- (1 -propyl -2-pyrrolidone in the form of pale brownish-yellow crystals with mp 75.5-76.5 C.
Found,%: C 72.7; H 8.4; N 6.2
.
Calculated,%: C 72.1; H 8.2; N, 6.0
Example 15. Hexahydro-3- (3-oxocyclohexen-1-yl) -2H-azepin-2-one.
Lithium diisopropylamide was obtained. by treating 45.3 ml of diisopropylamine with 231 ml of I, 4 M solution of butyl lithium in hexane in a stream of nitrogen, after which the product was treated at -60 ° C with 63.7 g of 1-trimethylsilylhexa-hydro-2H-azepine in 50 ml of dry THF. After 20 minutes, the white suspension was treated with a solution of 40.8 g of 3-methoxy-2-cyclohexanone in 50 ml of THF. The resulting solution was allowed to warm to ambient temperature. After 3 hours, the cooled solution was treated. 120 ml of concentrated hydrochloric acid and mixed for 18 hours. The THF layer was combined with several chloroform extracts from the aqueous layer. Evaporation of the solvent gave a yellow solid which was recrystallized from ethyl acetate to give hexahydro-3- (3-oxocyclohexen-1-yl) -2H-azepin-2-one (45.5 g) in a not-white form.
th solid substances with so pl.159165 ° C.
Found,%: C 68.9; H 8.74; N 6.7
C, 2 H, NOj.
Calculated,%: C 69.54; H 8.27; N 6.75.
Example 16. 3- (3-hydroxyphenyl) - hexahydro-2H-azepin-2-one.
A mixture of 20.73 g of hexahydro-3- (3-oxocyclohexan-1-yl) -2H-azepin-2-one, 44.9 g of copper (II) bromide, and 8.8 g of lithium bromide and boiling in a cooler of 1000 ml of acetonitrile for 1 hour. After the solvent had been injected, a black resin remained, which was dissolved in an excess of 2% sodium hydroxide solution. The resulting orange suspension was filtered through kieselguhr and the filtrate was acidified (with concentrated hydrochloric acid). The white suspension was extracted several times with chloroform, and the residue which was obtained after evaporation of the organic layers was crystallized from ethyl acetate to obtain 11.18 g H- (3-hydroxyphenyl hexahydro-2H-azepin-2-one with mp. 175-178 sec.
Found,%: C 70.1; H 7.6; N 6,6.
WITH,, , ,
Calculated,%: C, 70.22; H 7.37; N 6.82.
EXAMPLE 17 3- (3-benzyloxaphenyl) -hexahydro-2H-azepin-2-one. : I
A solution of 2.05 g of 3- (3-hydroxyphenyl) -hexahydro-2H-azepin-2-one (2.05 g) in dry DMF was added dropwise to a suspension of 0.3% sodium hydride. After 30 minutes at room temperature, 1.3 benzyl chloride was added. This mixture was stirred for 2 hours and then cooled and treated with water. The resulting solution was extracted several times with toluene, and the combined toluene layers were thoroughly washed with water. The solvent was evaporated to give an oil, which was crystallized from ethyl acetate to obtain 1.4 g of the title product of the product in the form of a solid with mp 119-122 C.
Found,%: C 77.42, H 7.37; N 4.64.
C ,, H2, N02,
Calculated,%: C 77.26; H 7.17; N 4.74.
31
PRI me R 18. 3-ethylhexahydro-3- (3-methoxyphenyl) -2H-azepin-2-one.
Lithium diisopropylamide, obtained by adding 15.7 ml of a 15% solution of butyl lithium in hexane in 3.15 ml of diisopropylamine at -10 ° C in a stream of nitrogen, was treated with a solution of hexahydro-3- (3-methoxyphenyl) -2H-azepin-2-one in THF. After 30 minutes, 0 ml of ethyl bromide was added. This mixture was allowed to warm to room temperature. After 2 hours, the reaction was abruptly stopped with water. The organic layer was scorched to give an oil which crystallized during scraping. The solid was recrystallized from ethyl acetate to give 1.68 g of the above in the title of the example of the compound, mp 85-87 s.
Found,%: C 72.88; H 8.91; N 5.39.
C, 5H ,, NO ,.
Calculated,%: C, 72.84; H 8.56;
N 5.66.
I
And p and meer 19. Hexahydro-3 - (. 3-hydroxyphenyl) - -phenylmethyl-2H-azepin-2-one
A solution of 5.68 g of hexahydro-1-phenylmethyl-2H-azepin-2-one in THF was added at -10 ° C in 0.032 mol of lithium diisopropylamide, prepared from 4.4 ml of diisopropylamine and 22.9 ml of 1.4M solution of butyl lithium in hexane. This mixture was stirred for 30 minutes and then treated with a solution of 2.53 g of 3-methoxy-2-cyclohexanone in THF. After a 5-hour lacter at room temperature, the mixture was poured into 100 m of ice-cold concentrated hydrochloric acid. After stirring vigorously for 12 hours, the solution was shaken with several successive chlorine forms. The combined floroform layers were evaporated to give an orange oil. This last prokiptili with 8.95 g of copper (II) bromide and 1.74 g of lithium bromide (0.02 mol) in acetonitrile for 1 hour. After removing the solvent, black resin remained, which was crushed with an excess of 2 k. sodium hydroxide solution. After removing the orange precipitate, the filtrate was extracted with methylene chloride. The organic layer was acidified with concentrated hydrochloric acid and


14
The white suspension was shaken with several successive portions of chloroform and then evaporated to give a dark red oil (1.2 g), which was crystallized from ethyl acetate to give 0.35 g of the title compound. -166 S.
Found,%: C 75.31; H 7.48; N 4.36.
n hj,
Calculated,%: C, 74.97; H 7.28; N 4.6.
PRI me R 20. Hexahydro-3- (3-hydroxyphenyl) -1-methyl-2H-azepin-2-one.
A solution of 150 g of hexahydro-1-methyl-3- (3-oxocyclohexan-1-yl) -2H-azepine-2-oi; a in 750 ml of dichloromethane was heated to 25 C. During 40 minutes, 97.5 g of bromine was added at 25-32 ° C (with occasional cooling with water) and the mixture was stirred for 2 hours at a temperature of about 25 seconds. Then 200 ml of water was added and the dichloromethane layer was washed with 100 ml of water. The aqueous phases were collected and extracted with 2 portions of dichloromethane, 100 ml each. The dichloromethane extracts were combined and the solvent was distilled off and replaced with ethyl acetate while maintaining the temperature at 72 ° C. 750 ml of ethyl acetate was added; collected 900 ml of distillate). This mixture was then cooled to room temperature and filtered. The resulting product was washed with 100 ml of ethyl acetate and dried to give 134.3 g of the title compound as a crystalline yellowish brown powder. Mp. 184-189 C, identical to the product of the experiment of example 2.
Example 21 Hexahydro-3- (3- oxocyclohexan-1-yl) -2H-azepin-2-one.
one
143 ml of 1.4 M solution of utility
in hexane, 11.3 g of caprolactam in dry tetrahydrofuran in a stream of nitrogen was added dropwise to the stirred solution. After stirring for 50 minutes at 0 ° C, 12.6 g of 3-methoxy-2-cyclohexenone in tetrahydrofuran was added. After the next 30 minutes, the reaction mass was poured into 5 M hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were dried over magnesium sulphate. After removal of the solvent under reduced pressure
151
15 g of yellow solid remained. This product was recrystallized from ethyl acetate to obtain 2.5 g of the title compound, identical to that described in Example 15.
Example 22. Hexahydro (3-methoxyphenyl) -2H-azepin-2-one.
A suspension of 4.1 g of hexahydro-3- (3-hydroxyphenyl) -2H-azepin-2-one 5.6 g without aqueous potassium carbonate and 2.52 g of dimethyl sulfate prokiptyli with stirring in 50 ml of acetone under reflux. After cooling, the solution was filtered and dried to dryness under reduced pressure. The product was recrystallized from a mixture of diisopropyl ether with ethyl acetate, whereby the title compound was obtained.
Example 23 3-Ethylhexahydro-3- (3-methoxyphenyl) -2H-azepin-2-one.
2.19 g of hexahydro-3- (3-methoxyphenyl) -2H-azepin-2-one in dry tetrahydrofuran was added to a stirred solution of lithium diisopropylamide (prepared from 15.7 ml of a 1.4 M solution of butyl lithium and 3, 15 ml of di-nzopropylamine) and in a stream of nitrogen at 0 C. Then 1 ml of ethyl bromide was added in one portion and the reaction mixture allowed to warm to room temperature. After 2 hours, the reaction mixture was poured into 2 M hydrochloric acid, the organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to an oil, which was crystallized from ethyl acetate to give 1.68 g of the title compound with a mp. 85-87 C.
Found,%: C 72.0; H 8.9; N 5.4.
CijTU, N0
N1,%: C 72.8; H 8.6; N 5.7.
PRI me R 24. Cn-Bu ylhexahydro-3- (3-hydroxyphenyl) -I-methyl-2H-azepin-2-one.
1 g of 3- (3-hydroxyphenyl) -1-methylhexa-hydro-2H-azepin-2-one as a finely dispersed powdery solid was added dropwise to a solution of lithium diisopropylamide (prepared from 14.8 ml of diisopropyl amine and 77 ml 1.4 M solution of butyl lithium) in 500 ml of dry tetrahydrofu
50
O 5 o
five
P
,
116
wound in a stream of nitrogen. The suspension was boiled under reflux for 3 hours and j 5.6 ml (7.14 g) of n-bromobutane was added. The reaction mixture was further held at reflux for a further 6 hours, cooled to 0 ° C and an excess of 5 M hydrochloric acid was slowly added dropwise to it. The organic layer was separated and the aqueous layer was discharged with chloroform. The combined organic extracts were washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulphate and evaporated to an oil. This last was crystallized and recrystallized from ethyl acetate to give 9.5 g of colorless crystals with mp 138-142 ° C.
Found,%: C 74.05; H 9.52; N 4.58.
С „Н„ Ш
Calculated,%: C 74.1; H 9.5; N 5.1.
EXAMPLE 25 3-Ethylhexahydro-3-3-hydroxyphenyl) -1-methyl-2H-azene PIN-2-OH.
A solution of 280.5 g of crude 3-ethyl-hexahydro-1-methyl-3- (3-oxocyclohexen-1-yl) -2H-azepin-2-one in 1.4 methylene chloride was stirred with simultaneous treatment of 180 g of bromine in for 1.5 h at 20–25 ° C with periodic water cooling. The reaction mixture was further stirred at room temperature for
2h, however, thin layer chromatographic analysis showed that a certain amount of starting material was still present in the product. Within 10 minutes, an additional 18 g of bromine was added and the solution was stirred for an additional 1 hour. At this, the thin-layer chromatographic analysis did not show the presence of any amount of starting material, as a result of which 500 ml of water was added with cooling and the methylene chloride layer was washed 500 ml: water. Two aqueous washes were combined, subjected to back extraction with 200 ml of methylene chloride, and the extracts were washed with 100 ml of water. The methylene chloride extracts were combined, evaporated to dryness, and the tan solid was triturated with 250 ml.
17
ethyl acetate, filtered, washed with 50 ml of ethyl acetate, and dried in a dry loaf at 60 ° C to obtain 244 g of the title compound with a mp of 72-175 ° C.
EXAMPLE 26. (A) 3- (3-0 со со со - - - cyclohexenyl-yl) -1-propyl-2-pyrrolidinone.
I-Prop-1-2-pyrrolidinone (25.4 g;) about 0.2 mol) in anhydrous tetrahydrofuran (100 ml) is added dropwise to a stirred solution of lithium diisopropyl amide (0.24 mol) in a mixture of hexane / tetrahydrofuran in atmosphere) 5 nitrogen. After stirring for 10 minutes, 3-methoxy-2-cyclohexenone (26.1 g; 0.21 mol) in tetrahydrofuran is added, maintaining the temperature at .10 ° C by cooling with ice. After stirring at room temperature for 4 hours, the solution is cooled and acidified with a 5 M hydrochloric acid solution. The organic layer is separated, and the aqueous layer 25 is extracted several times with chloroform. After washing with brine, the organic extracts are dried over magnesium sulphate and triturated; an oil remains, which is diet- edized and 29.65 g of the title compound are obtained in the form of an oil with a boiling point of 175-180 ° C under a pressure of 1 mbar.
(c) 3- (3-Oxyfensh1) -1-propyl-2-pyrrolidone.
Bromine (6.2 g) in dichloromethane (40 ml) is added dropwise to a stirred solution of 3- (3-oxo-1-AQ cyclohexen-1-yl) -1-propyl-2-pyrrolidinone (8, 8 g) in dichloromethane (100 ml), cooled to 3 ° C under nitrogen atmosphere. At the end of the addition of bromine, the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, the residue was dissolved in 2m solution sodium hydroxide and extracted with dichloromethane. Ch Organic extracts discarded. the aqueous extracts are cooled and acidified with concentrated hydrochloric acid. The precipitated oil is extracted with dichloromethane, dried over magnesium sulfate and boron; an oil that forms colorless crystals remains, 3.09 g, mp 94-96 ° C from ethyl acetate.
30131118
Examples 27-31. According to the procedure described in Example 7, the following compounds were prepared using the appropriate starting materials: Example 27 — 3- (m-hydroxyphenyl) -1,3-dimethyl hexahydro-1H-azepine, the hydrobromide melts at 174-175 ° C; Example 28 — 3- (m-hydroxyphenyl) -3-propylhexahydro-1H-azepine, hydrobromide melts at 74-78 ° C; Example 29: 1,3-diethyl-3- (m-oxyphenyl) hexahypo-l H-azepine, hydrobromide melts at 205-207 ° C (decomp.); Example 30 - 3-ethyl-1-propyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine; bp 200-240 C / 0.1 mmHg, example 31 - 3-ethyl-1- (pro-2-yn) -3- (m-hydroxyphenol) hexahydroazepine, b.p.240- 260 s / 0.01 mm Hg
PRI me R 32. (a) 3-Ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine.
3-Ethyl-3- (m-methoxyLenyl) hexa-hydro-1H-azepine (2.2 g) is heated under reflux with 50% hydrobromic acid for 1.5 h. The reaction mixture is evaporated to dryness and re-evaporated with three parts of propan-2-ol. The resulting oil is dissolved in propan-2-ole and diluted with ether. The title compound (2.5 g) is obtained as hydrobromide, mp.183-185 ° C. I
Found,%: C 55.9; H 7.43; N 4.35.
C, H, NQ.HBr
Calculated,%: C 56.0; H 7.4; N 4.7.
(c) -All-3-ethyl-3- (m-hydroxyphenyl) hexahydro-3-azepine.
A mixture of 3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine hydrobromide (3.0 g), allyl bromide (1.2 g) and potassium carbonate (3.0 g) in acetone (40 ml) is heated with reflux for 16 h. Excess acetone is distilled off under reduced pressure, acetic anhydride (1 ml) is added, heated for 1 h at 100 ° C and then alkalinized with sodium carbonate solution. The precipitated oil is extracted with dilute hydrochloric acid. The acidic extract is then alkalinized and again extracted with ether. The organic extract is dried over magnesium sulphate and embedded in vacuo to give 2.6 g of crude allylic derivative.
The residue is dissolved in a minimum amount of isopropanol and then 50% hydrobromic acid is added until slightly acidic.
1913
The precipitated brown oil is crystallized from a mixture of ethanol and ether, and a decree is obtained in the title (1.55 g in Btffle hydrobromide, mp 141-142 ° C.
Found,%: C 60.1; H 7.7; N 3.9.
C, H 5 0-NVG
Calculated,%: C 60.15; - H 7.7; N 4.1.
PRI me R 33. 3- (3-Ethyl-1-methyl 3-piperidinyl) phenol.
According to the procedure described in Example 6, 3- (3-hydroxyphenyl) -1-methyl-2-piperidone is treated with lithium diisopropylamide in tetrahydrofuran / hexane and then reacted with ethyl iodide. The product, 3-ethyl-1-methyl-3- (3-hydroxyphenyl) -2-piperidone, is reduced with lithium aluminum hydride, as described in Example 7. 3- (3-ethyl-1-methyl-3-piperidinyl) is obtained. phenol in the form of hydrochloride j mp. 233-225 ° C.
PRI me R 34. Hexahydro-1-methyl-3-n-butyl-3- (3-hydroxyphenyl) -2H-azepine.
3-n-Butylhexahydro-3- (3-hydroxyphenyl) -1-methyl-2H-azepin-2-one (6.5 g) in anhydrous tetrahydrofuran (100 ml is added dropwise to a stirred suspension of lithium aluminum hydride (2.0 d) in tetrahydrofuran (100 ml) at O C. The mixture is heated with reflux for 5 hours, and the cooled suspension is treated with water (2.0 ml); 2 and caustic soda solution (4.0 ml) and water (2.0 ml). The filtrate is evaporated, the residue is dissolved in water and treated with solid ammonium chloride. The resulting resin is extracted with methylene chloride and the solution is dried over magnesium sulfate. After the solvent is distilled off An oil is obtained (5 g), which is crystallized from acetonitrile to give the compound indicated in i title (4.74 g), mp 114-P7 ° C.
Example 35. 3- (l-Meth-I-3-propyl pypropyl-3-ShI) phenol.
3- (3-hydroxyphenyl) -1-methyl-3- (l-propyl) -2-pyrrolidone (3.9 g) is added in portions to a stirred suspension of lithium aluminum hydride (0.65 g) in / heterrahydrofuran (7, 5 ml) and heated with reflux for 4 hours. The reaction mixture is allowed to cool and stirred at room temperature for 65 hours, then treated with water (1.4 ml), 4m solution,
five
-
)
) 35 „45
120
thief of caustic soda (0.7 ml) and water (1.4 ml). The precipitate was filtered off and the tetrahydrofuran was distilled off under reduced pressure. The residual oil is dissolved in ether, extracted with 2m hydrochloric acid solution, neutralized with ammonium hydroxide, extracted with chloroform, dried and evaporated to an oil. The oil is dissolved in ethyl acetate, washed with water and saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to an oil (2.2 g). The oil is crystallized from ether / methanol to give the crystalline hydrochloride of the title compound (2.2 g), mp, 147-148 ° C,
Example 36. Hexahydro-1-methyl-3- (3-methoxyphenyl) -2H-azepin-2on, I
Bromine (8.2 g) in benzene (10 ml) is added dropwise to a stirred solution of hexahydro-1methyl-3- (3-hydroxycycloxen-1-yl) -2H-azepin-2-one in benzene (30 ml) and methanol (6.2 ml) at 5-10 s. After 1.25 hours, the mixture was poured into water, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts are washed with 2M sodium hydroxide solution, water and dried over magnesium sulfate, after evaporation, 5.4 g of a pale oil are obtained, which is chromatographed on silica gel with chloroform / meta: NOL eluant (97, h). The resulting crystalline product is identical to the authentic material
Example 37, 3-Ethylhexahydro-3- (3 oxo-1-cyclohexan-1-yl) -1-phenyl-methyl-2H-azepin-2-one.
Diisopropylamine (0.42 ml, 3 mmol) is added with stirring under nitrogen to isopropyl magnesium bromide (from magnesium, 0.72 g; 30 mmol) and 2-bromopropane (3.7 g; 30 mmol) in anhydrous toluene / ether mixture 4: 1 (40 ml). After stirring for 30 minutes at room temperature, 3-ethylhexahydro-1-phenylmethyl-2H-aze-PIN-2-OH (6.2 g; 27 mmol) is added and the mixture is heated with reflux for 2 hours. The reaction mixture is cooled and added 3-isopropoxycyclohexan-2-one (4.62 g; 30 mmol) in toluene (10 ml). After stirring the mixture at room temperature for 30 min.
21
poured into a mixture of ice with concentrated hydrochloric acid. The reaction mixture was stirred at room temperature for 3 hours. The organic layer was separated and extracted with 2M sodium hydroxide solution. After drying over magnesium sulfate, the solvent is removed under reduced pressure to obtain the title compound as an oil (5.2 g), which is used in crude form for flavoring (Example 38).
Example 38. 3-Ethylhexahydro-3- (3-hydroxyphenyl) -1-phenylmethyl-2H-azepin-2-one.
Crude H-ethexahydro-H- (3-oxo-1-cyclohexe-1-yl) -1-phenylmethyl-2H-azepin-2-one (5.2 g) in acetic acid (20 ml) is treated with stirring bromine (1.54 g) in acetic acid (5.5 ml). After stirring at room temperature for 2 hours, the acetic acid is removed under reduced pressure, the research institute, the residue is dissolved in ether and the extractant 2N. sodium hydroxide solution. The alkaline extracts are acidified with 2N hydrochloric acid solution and extracted with ether. After drying over magnesium sulfate, the ether is distilled off and an oil is obtained which is chromatographed on silica gel with eluant hexane ethyl acetate (1: 1). The product is crystallized from hexane and the title compound is obtained as colorless diamonds, mp. 152-154 ° C.
Found,%: C 77.8; H 8.1; N 4.35.
C „K„ KO.
Calculated,%: C 77.9; H 7.8; N 4,3
Example 39 Hexahydro-3- (3-methoxyphenyl) -methyl-2H-azepin-2-one
Hexahydro-methsch1-3- (oxocyclohexene-1-sh:) - 2H-azepin-2-one (3.3 g) is dissolved in carbon tetrachloride (25 ml), methanol (5 ml) and N-bromo cinimide (4.48 g). The reaction mixture is heated and stirred for 4 hours with reflux. The reaction is monitored by gas chromatography. After no further increase in the content of the desired product is detected in the reaction mixture, it is cooled, the aqueous phase is poured into water, extracted with additional portions of carbon tetrachloride. The combined extracts were 2N. sodium hydroxide solution, then with water.
5 0 jf
20 25 30
40
.
 .
45 50 55
0131122
dried over magnesium sulfate and evaporated to an oil, which is chromatographed on silica gel with chloroform / methanol (97: 3) as eluent, to give the title compound, identical to that obtained in Example 3.
Example 40 Hexahydro-3- (3-hydroxyphenyl -1-methyl-2H-azepin-2-one.
Hexahydro-1-methyl-3- (oxocyclohexene-1-yl -2H-azepin-2-one (22.1 g) and 5% palladium on carbon (2.2 g) are heated to 150-160 ° C for 2.5 hours. After cooling, toluene (100 ml) is added, then a dilute solution of sodium hydroxide (80 ml of water with 20 ml of 40% sodium hydroxide solution). The reaction mixture is filtered and the aqueous phase is washed with toluene (100 ml) The toluene extracts are combined and washed with additional water (50 ml). The aqueous phases are combined and added with stirring to methanol (50 ml) and concentrated hydrochloric acid (50 ml) with cooling. , Washed with water (50 mL) and dried to yield indicated. Zannoe the title compound (10.7 g) identical to the compound prepared in Example 2.
Example 41. 3-Ethylhexahydro-3- (3-hydroxyphenyl) -1-metsh1-2H-azepin- .2-one.
A 100 ml conical flask is charged with 25 g of 3-ethylhexahydro-3- (3-oxo-1-cyclohexen-1-yl) -1-methyl-2H-azepin-2-one and 1.25 g of 5% - Palladium on coal. The viscous reaction mixture is then heated to 100 C. Then it is stirred at 200 ° C and maintained at this temperature for 4 hours. After cooling to a temperature of approximately 50 ° C, the reaction mixture is dissolved in methanol with a total amount of 150 ml. The mixture is filtered and the filtrate is evaporated to dryness to give a white solid. It is triturated with 100 ml of ethyl acetate and dried in an air dryer, the title compound is obtained as a white powder (12.8 g), so pl. 172-175 ° C.
Example 42. 3-Ethylhexahydro-3- (3-hydroxyphenyl) -I-phenylmethyl-1H-azepine.
3-Ethylhexahydro-Z- (3-hydroxyphenyl) -1-phenylmethyl-2H-azepin-2-one (described in Example 40) (4.1 g) in anhydrous
2313
tetrahydrofuran (25 ml) is added to a stirred suspension of lithium aluminum hydride (l g) in ether (50 ml). The reaction mixture is heated for 1 h with reflux, cooled overnight, then decomposed by successive addition of water (1 ml), 5m sodium hydroxide solution (1 ml) and water (2 ml). The precipitate is filtered off and washed with hot isopropanol. The solvents are removed under reduced pressure and the complete solution of ammonium chloride is added to the residue. The separated oil is extracted with ether (3x50 ml), dried over magnesium sulphate, evaporated and the title compound (2.1 g) is obtained as colorless glass. The purity of the compound is confirmed by thin layer and gas-liquid chromatography; structure confirmed by the NQR and IR spectroscopy.
Example 43, 3-Ethylhexahydro-3- (3-hydroxy-1) -1-phenyl 1-methyl-2H-azepium-2-one.
Hexahydro-3- (3-hydroxyphenyl) -1-phenylmethyl-2H-azepin-2-one (Example 19) (0.01 mol) in toluene (20 ml) was added dropwise to a stirred solution of diisopropylamide lithium (from 0.02 mol lithium butyl and 0.021 mol diisopropylamine) in a mixture of tetrahydrofuran / hexane (50 ml) while maintaining the reaction medium at ambient temperature (if necessary by cooling) and under nitrogen atmosphere. After stirring at ambient temperature for 1 h, bromoethane (0.012 mol) is added. The reaction mixture is stirred overnight, then injected into a mixture of ice and hydrochloric acid. The organic layer is separated and the aqueous layer is extracted with toluene. The combined organic extracts are washed with water, dried over magnesium sulfate, evaporated and an oil is obtained, which is crystallized from hexane as colorless diamonds, mp, 152-154 ° C, identical to the product described in Example 38,
Example 44, 3-Ethylhexahydro-3- (3-methoxyphenip) - H-azepine,
3-Ehx hexahydro-3- (3-methoxyphenyl) -2H-azepn-2-one (0.01 mol) in tetrahydrofuran (20 ml) is added dropwise to a stirred suspension124.
sy lithium halide hydride (0.01 2 mol) in ether (100 ml). The reaction mixture is heated with reflux for 2 hours, left overnight, then decomposed by successive addition of water, 4m of sodium hydroxide solution and water. The precipitate is filtered off and washed with ether. The combined organic filtrates are dried over magnesium sulphate and evaporated under reduced pressure to give an oil that gives a crystalline hydrobromic salt so pl. 143-146 ° C.
Example 45. 3-Ethylhexahydro-3- (3-methoxyphenyl) -1-methyl-2H-azepin-2-one,
3-Ethylhexahydro-3- (3-methoxyphenyl) -2H-azepin-2-one (0.01 mol) in tetrahydrofuran (50 ml) is added dropwise to a stirred suspension of sodium amide (0.011 mol in toluene (50 ml) .The reaction mixture is heated with reflux for 2 hours, cooled and dimethyl sulfate (0.01 mol) is added. The reaction mixture is heated again with reflux for 1 hour, cooled and washed with water. After drying over magnesium sulfate, the solvent is distilled off and an oil is obtained which is crystallized from diisopropyl ether to obtain a product identical to the product of example 6, mp. 62-64 ° C
Example 46, 3-Ethylhexahydro-3- (3-methoxyphensh1) -1-phenylmethyl-2H-azepin-2-one, I
Using the procedure described in Example 45 above, but replacing dynethyl sulfate (0.01 mol) with phenylmethyl chloride (0.01 mol), the title compound was obtained.
Example 47. 3- (3-Ethylhexa-hydro-1- (2-propinyl) -1H-azepin-3-yl) phenol,
Stir at room temperature for 24 hours 3- (3-ethylhexa-hydro-1H-azepin-3-yl) phenol (5 g), 3-bromopropinyl (3.04 g) and potassium carbonate (3.45 g) in dry dime-type formamide (80 ml). The solid is filtered and the filtrate is evaporated under reduced pressure. The remaining oil is dissolved in a 2N hydrochloric acid solution and extracted with ether. After drying over magnesium sulfate and distilling off the solvent, an oil is obtained, t, bale, 240–260 s at a pressure of 0.1 mm Hg.
Found,%: C 80.0; H 9.1, - N 5.3
СЦН „НО.
Calculated,%: C 79.3; H 9.0; N 5.4

权利要求:
Claims (2)
[1]
Formula 5
one . The method of obtaining derivatives of hexahydroazepine or piperidine, or pyrrolidine of General formula I
P
2.3 or hydrogen
lower alkyl, reel (lower) alkyl, lower alkenyl or lower alkynyl; lower alkyl; hydrogen or lower alkyl, lich ayuschiy. with the fact that, due to the simplification of the process and raising of water, to a compound of the general form II
l and
"% DGG °,
41
Where
R:
P
R
hydrogen, lower alkyl or aryl (lower) alkyl;
- has the indicated values;
-hydrogen,
act as a flavoring agent, such as bivalent copper halide, halogen, N-bromosuccinimide, palladium on carbon, and then, if necessary, O - (lower) is alkylated to form 2-oxo-hexa-hydroazepine, or -piperidine or - pyrrolidine derivative of general formula III
where R, is hydrogen, or lower alkyl; R | - hydrogen, lower alkyl or
aryl (lower) alkyl; R and p are the indicated meanings, are C-alkylated in the presence of a strong base, the resulting compound of general formula IV
five
0
five
0
five
where n, R and K have the indicated
value;
Rj (lower) alkyl, and, if necessary, N-alkylated, when R, is hydrogen, obtaining a compound of the general formula IV, where R is lower alkyl, or aryl (lower) alkyl, followed by reduction with a transferring H-compound Compounds of general formula IV, where R ,, R and p have the indicated meanings, R is hydrogen, lower alkyl or aryl (lower alkyl, and the separation of the desired product of general formula I, or, if necessary, ether cleavage, of a compound of general formula I, where Rj is lower alkyl, or N-alkylation of a compound of general formula I, where R is hydrogen, teaching compounds; of where R, - lower alkyl, aryl (lower) alkyl, lower alkenyl or lower alkynyl.
[2]
2. The method of producing hexahydrose pina, or piperidine, or pyrrolidine of general formula I
(CH2b
where n 2,3 or 4;
R is hydrogen, lower alkyl, aryl, (lower) alkyl, lower alkenyl or lower alkynyl,
Rj is lower alkyl;
R-- is hydrogen or lower alkyl, characterized in that, in order to simplify the process and increase the yield, the compound of general formula II
.X
C-v ..
(VDL
I
where R is hydrogen, lower alkyl or aryl (lower) alkyl;
R, j is lower alkyl;
p has the indicated value (act as a flavoring agent such as copper halide, halogen, N-bromosuccinimide, palladium on carbon, and then, if necessary, O- (lower) alkylate the resulting 2-oxo-hexahydroazepigic, or piperidine or pyrrolidine derivative of general formula III
where R is hydrogen, or lower alkyl; R | - hydrogen, lower alkyl or aryl (lower) alkyl; have the indicated meanings.
Priority signs: 22.12.77 when R / is hydrogen, R is hydrogen, lower alkyl, aryl (lower)
alkyl;
„,. ..2 .. ,, „. , 05/30/78 with Rj - lower alkyl,
 K-alkylate, if necessary, - R, is lower alkenyl, lower apkinyl.
n and r
ABOUT
five
0
I28
when R is hydrogen, to obtain a compound
of general formula III, where R is lower alkyl or aryl (lower) alkyl, followed by reduction with a transferring H-compound of a compound of general formula III, where R, R and n have the indicated meanings, R, is hydrogen, lower alkyl or aryl (lower) alkyl, and by separating the desired product of general formula I, or, if necessary, by ether cleavage of a compound of general formula I, where R is a lower alkyl, or by N-alkylation of a compound of general formula I, where RJ is hydrogen, to give a compound where R is lower alkyl, aryl (lower) alkyl, lower alkenyl or lower alkyn silt
Priority signs: 22.12.77 with R / - hydrogen, R Compiled by I. Bocharova Editor V. Kovtun Tehred V, Kadar Proofreader M. Pojo
Order 1163/58 Circulation 372Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing company, Uzhgorod, Prolektna str., 4

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AT373586B|1984-02-10|

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JPS64392B2|1989-01-06|

---

US4197241A|1980-04-08|

---

HK18082A|1982-05-07|

---

KE3206A|1982-05-21|

---

MY8200279A|1982-12-31|

---

US4197239A|1980-04-08|

---

PH14412A|1981-07-09|

---

CS207748B2|1981-08-31|

---

JPS5488286A|1979-07-13|

---

PL211970A1|1980-02-25|

---

DK156302B|1989-07-31|

---

IL55924A|1982-01-31|

---

FI70575C|1986-09-24|

---

CY1144A|1982-09-10|

---

KE3207A|1982-05-21|

---

DD141308A5|1980-04-23|

---

CA1113092A|1981-11-24|

---

AR221710A1|1981-03-13|

---

ATA898578A|1983-06-15|

---

IE47631B1|1984-05-16|

---

MX5628E|1983-11-15|

---

PL126008B1|1983-06-30|

---

CY1145A|1982-09-10|

---

EP0003253A1|1979-08-08|

---

AU4147978A|1979-06-28|

---

FI70575B|1986-06-06|

---

MY8200278A|1982-12-31|

---

ES481125A1|1980-02-01|

---

IT1102761B|1985-10-07|

---

DD149515A5|1981-07-15|

---

GB1593888A|1981-07-22|

---

EG13745A|1983-03-31|

---

FI783922A|1979-06-23|

---

ES476160A1|1979-11-16|

---

AU519653B2|1981-12-17|

---

IE782252L|1979-06-22|

---

ZA786244B|1980-06-25|

---

DE2862139D1|1983-01-27|

---

YU40543B|1986-02-28|

---

GR64029B|1980-01-19|

---

EP0003253B1|1982-12-22|

---

CA1113465A|1981-12-01|

---

PT68962A|1979-01-01|

---

IT7831286D0|1978-12-22|

---

YU299778A|1983-12-31|

---

PH14517A|1981-08-26|

---

DK156302C|1989-12-11|

---

IL55924D0|1979-01-31|

---

HU181997B|1983-11-28|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US2524643A|1947-12-04|1950-10-03|Maltbie Lab Inc|3-phenyl-2-piperidones|

---

US3149123A|1961-01-04|1964-09-15|Parke Davis & Co|1, 3-dialkyl-3-oxyphenylpyrrolidine compounds|

---

FR1181M|1961-06-02|Boehringer Sohn Ingelheim|New 3-phenyl-pyrrolidines and their salts.|

---

FR1337793A|1962-06-19|1963-09-20|Parke Davis & Co|Pyrrolidine compounds and process for the preparation thereof|

---

GB1285025A|1968-08-16|1972-08-09|Wyeth John & Brother Ltd|Hexahydroazepines|

---

CH526534A|1970-02-05|1972-08-15|Sandoz Ag|Pyrrolidine-1-carboxamidine derivs - from pyrrolidine derivs and cyanamides broncholytics|

---

CH526535A|1970-02-05|1972-08-15|Sandoz Ag|Pyrrolidine-1-carboxamidine derivs - from pyrrolidine derivs and guanylpyrazole|

---

CH526536A|1970-02-05|1972-08-15|Sandoz Ag|3-phenylpyrrolidine derivs - with broncholytic activity|

---

US3729465A|1971-02-03|1973-04-24|Wyeth John & Brother Ltd|Hexahydroazepines|

---

JPS4911844A|1972-05-09|1974-02-01|

---

BE850777A|1976-01-28|1977-07-26|Sandoz Sa|NEW DERIVATIVES OF PYRROLIDINE|AT11046T|1979-07-03|1985-01-15|John Wyeth & Brother Limited|METHOD FOR PRODUCING 2-OXO AND 2UNSUBSTITUTED HEXAHYDROAZEPINE DERIVATIVES.|

---

IE54154B1|1981-12-02|1989-07-05|Wyeth John & Brother Ltd|M-hydroxyphenyl substituted compounds|

---

US5665754A|1993-09-20|1997-09-09|Glaxo Wellcome Inc.|Substituted pyrrolidines|

---

SE0001438D0|2000-04-18|2000-04-18|Axon Chemicals Bv|New chemical compounds and their use in therapy|

---

KR100421282B1|2001-08-22|2004-03-09|부광약품 주식회사|Process for preparing 1-methylhexahydro-4-azepinone hydrochloride|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

GB53370/77A|GB1593888A|1977-12-22|1977-12-22|Hexahydroazepine piperidine and pyrrolidine derivatives|

---