Process for producing derivatives of tetrahydropyridinylindole or their acid salts

专利摘要:

公开号:SU936812A3
申请号:SU792707603
申请日:1979-01-15
公开日:1982-06-15
发明作者:Неделек Люсьен；Гийом Жак；Дюмон Клод
申请人:Руссель-Юклаф (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing new derivatives of tetrahydropyridinylindole of the general formula:
where R ¹ is a hydrogen atom, chlorine, C. -alkoxy; 'are the same or different and • mean a hydrogen atom, -alkyl,
X ¹ * - C ^ -alkyl, C ^ -d-alkenyl, cyclo-Cd, -alkyl, ap-C-jug-alkyl, and if x ^ is methyl, then at least one of the substituents R * , R ^ or Rj has more than one carbon atom; if X * is benzyl, then at least one of the substituents R *, R ₄ or R ^ is not hydrogen, or their salts with acids, which may find application in the pharmaceutical industry.
The interaction of 1,2,3,6- .. -tetrahydropyridine with halide alkyls is known when heated in the presence of a base G1].
The purpose of the invention is the development on the basis of the well-known method of method no ^J radiation of new compounds with valuable pharmaceutical properties. · The goal is achieved tei, "
10. that according to the method for producing tetrahydropyridinylindole derivatives of their salts with acids of the general formula I, a compound of the general formula:
where Rt, Poison and R ₄ have the above meanings, are subjected to interactions with X-Hat, where On - chlorine, bromine or iodine, and X ⁴ has the above meanings and the target product is isolated in free form or in the form of a salt with acid.
The acids used for salt formation can be organic ₅ and inorganic acids, such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, formic, benzoic, maleic, fumaric, succinic, juiceric, citric, oxalic, oxalic, oxalic, oxalic, glyoxal, or arylsulfonic acid, for example benzenesulfonic acid. The interaction of the compounds of general formula II with X ^ -HaE is carried out in is medium of an organic solvent, for example acetone, in the presence of silver oxide or sodium carbonate. The reaction "can be carried out in a medium of triethyl · amine 'in the presence of hexamethanol. ₂ 0 Starting compounds of general formula II are prepared by reacting compounds of general formula:
where R ⁴ , R. and R „are given above,
I 3Q with h-piperidone hydrochloride in acetic acid in the presence or absence of a strong acid or in an alkaline medium, for example, in methanolic potassium hydroxide solution.
Prima p 1 .Neytralny fumarate 5- ³⁵ methoxy-3 "(1-propyl-1,2,3,6-tetrahydropyridin-4-yl) 1H-indole.
Stage A: 5-methoxy 3 “(1 ^_ propyl
1,2,3,6-tetrahydropyridin-4-yl) 1H-indole. ⁴⁰
A suspension of 6 g of 5-methoxy 3- (1,2,3, 6-tetrahydropyridin-4-yl) 1H-indole is introduced into a solution containing 60 ml of triethylamine, 6 ml of hexamethylphospho triamide and 3 ml of propyl iodide. ' ⁴⁵ The resulting suspension is heated at 80 ° C for half an hour, 0.5 ml of propyl iodide is added and kept at 80 ° C for 30 minutes. The reaction mass is cooled, ⁵⁰ 10 ml of water and 20 ml of methanol are added. Elute with methylene chloride and decant. Extract amine fractions of 1 N. hydrochloric acid solution and alkalize the acid layer by adding sodium carbonate. Then extraction is carried out with methylene chloride, the organic layer is washed. And dried. Thus, 6 g of product are obtained, which are dissolved in 5 ml of methanol, 15 ml of ethyl acetate are added, the crystals formed are filtered off, washed with ethyl acetate and dried. Get the target product, melting at 164 ° C ·
Stage B: Neutral fumart 5-methoxy and-3 “(1-propyl-1,2,3,6-tetra hydropyridin-4-yl) 1H-indole.
3.1 g of the product obtained in stage A are dissolved in 15 ml of methanol, poured into a solution containing 15 ml of methanol and 0.68 g of fumaric acid. Methanol is distilled off under reduced pressure and 20 ml of isopropanol are added. Stand with stirring for 30 min at room temperature and for 3θ min at 0 ° C. filtered off, washed with isopropanol and dried. 3.5 g of crude are obtained. product that is purified by crystallization. Thus, 2.13 g of the expected product is obtained, melting at 200 ° C.
Calculated, ^: C, 69.49; H 7.37; N, 8.53;
^Μ · ^β · 656,836.
Found,%: C 69.7; H 7.7; N, 8.6.
5-Methoxy 3 “(1,2,3,6-tetrahydropyridin-4-yl) 1H ~ indole used as the starting material can be obtained as follows.
Is dissolved at 100 ° C 12.6 g 5 ^_ ~ toksiindola IU in 240 ml of acetic acid was added 44 g of 4-piperidone hydrochloride (mono-hydrated) and kept under heating for 30 minutes at 100®S.
After cooling, the reaction mass was poured into ice water containing 400 ml of concentrated ammonium oxide hydrate, extracted with ethyl acetate and the organic layer was washed with salt water. It is dried over magnesium sulfate and evaporated to dryness. 20 g of crude product are obtained, which is purified by chromatography on silica, 1 eluting with a mixture of chloroform-methanol-triethylamine (7-2-1).
5.26 g of 5-methoxy 3 - (1, 2,3,6-tetrahydropyridin-4-yl) 1H-indole are obtained in the form of a gum. .
PRI me R 2. Chlorohydrate 3 ^_ (1-propyl 1,2,3,6-tetrahydropyridin-4-yl) 1H-indole.
EO
Stage A: 3 -. (1-Propyl 1,2,3,6-tetrahydropyridin-4-yl) -1 N.-indole.
Dissolve 4.5 g of 3- (1,2,3,6-tetragtsdropiridin-4-yl) 1H-indole 90 ⁴⁰ acetone. To the resulting solution was added 3 × 15 g of silver oxide and 2.22 ml of propyl iodide. Heated for 3 hours at 50 * C, cooled, filtered and distilled to dryness in vacuo. The resulting crude product was chromatographed on Na * ® silica, eluting with a mixture of chloroform-acetone-triethylamine (6-3-1). The solvent is distilled off and the residue is dissolved in 200. ml of y- - ethyl ester. acetic acid under reflux with heating, the solution is filtered and concentrated to 150 ml. _w Oh lazh- 'give up to 20 ° C,' cause crystallization and cool one night. The crystals are filtered off with suction, washed with ethyl acetate and dried. In this way, 3.9 g of the expected product are obtained, melting at 210 ° C.
Step B: 3 (1-Propyl-1,2,3,6-tetrahydropyridin-4-yl) 1H-indole hydrochloride
3.9 g of the product obtained in stage A are dissolved in 250 ml of isoprop ** nol under reflux and a solution of hydrochloric acid gas in isopropanol is added dropwise until an acidic pH is obtained. The reaction mass is cooled for 2 hours, the crystals are suctioned off, washed with isopropanol and dried under reduced pressure. 4.15 g of crude product are obtained, which are purified by crystallization. In this way get 3.55 g of the target product, melting at 230-232 ° C. ,
Calculated. C 69.42; H, 7.65; fl 12.81; N, 10.12;
I.v. 276.821.
Found D: C, 69.5; H 7.7; N 9.9. 3- (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole used as starting material can be prepared as follows. _
Dissolve 10 g of indole in 200 ml of ⁵⁰ acetic acid was heated at 95 ^_ 10 (G while stirring and under a nitrogen atmosphere. 50 ml of 1 · n.vodnogo tensile thief phosphoric acid monohydrate and 39.3 g of 4-piperidone hydrochloride. The reaction mixture heated at 100 C for 1 h, allowed to cool, poured onto ice, adding 350 ml of concentCi 12.8; '
936812 6 hydrated ammonium oxide and extracted with ethyl acetate. The extracts are washed with water, salt water, dried over magnesium sulfate and evaporated to dryness. T5.7 g of crude product is obtained, it is concentrated in a nitrogen atmosphere and 75 ml of methanol are added, the crystals are filtered off in vacuo, washed with methanol, and ether. 1.4 g of 3- (1,2,3,6-tetrahydropyridin-4-πϊι) 1H-indole are obtained. Mp. 185-186 ° C.
The mother liquors are evaporated and the resulting crude product is chromatographed on silica chromatography, eluting with a mixture of chloroform-triethylamine (6-3 * 1). 4.55 g of product Rf = 0.15 are collected, which are triturated with ether. 4.295 g of 3 ~ (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole are obtained, with a yield of 5.715 g. The product obtained is purified by recrystallization from isopropanol 'and I get ^ 3.56 g. 3 “ <
- (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole. Mp 190-191 ° C
PRI me R 3. Chlorohydrate 3 "(1" pentyl 1,2,3,6-tetrahydropyridin-4-yl) 1H-indole.
Stage A: 3 ^J (1-pentyl-1,2,3,6-tetrahydride ropyridin-4-yl) IH-indole.
10 g of 3- (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole are added in 100 ml of acetone, 5.1δ g of silver oxide and then 20 ml of pentyl iodide are added. After 4 hours of stirring at room temperature, another 2.5 ml of pentyl iodide is added and stirring is continued for 1 hour. The precipitate formed is filtered off, ₄ "О is washed with a mixture of methylene chloride" methanol <50'.50) and the solvents are removed under reduced pressure at 40 ° C. The crude product is purified chrome- <
chromatographically on silica gel, eluting with a mixture of chloroform-methanol-triethylamine (7-2-1). After the eluent was distilled off, the resulting dry extract was dissolved in 250 ml of ethanol at the boil, the solution was filtered and allowed to crystallize at 0-5 ° C. Get 7.9 g of the target product, melting about 180 C.
Step B: The hydrochloride of 3 "(1 ^_ pentyl-1,2,3,6-tetrahydropyridin-4-yl) 1H-indole.
A suspension of 7.9 g of the product obtained in stage A is prepared in 100 ml of absolute ethanol, and then, at 0-5 * C, 30 ml of an aqueous solution of hydrochloric acid->
lots in ethanol. The reaction mass is left for one hour with stirring, the crystals are filtered off, washed with ether, and then dried in vacuum at 4050 ° C. 8.45 g of the expected chloro _s hydrate are obtained in the form of a yellow product, melting at 210 ° C, and then at 240 ° C.
Calculated, C 70.9; H 8.3; N, 9.2; C1 11.6.
C ^ gHggNgCl. M.V. 304.866. to
Found D: C, 70.7; H 8.3; N 9, "2; C1 1.1.6.
Example 4. 3 “Hydrochloride (1-ethyl 1,2,3,6-tetrahydropyridin-4-yl) 1Н- € | ndol. is
Stage A: 3 ^- (1-ethyl 1,2,3,6-tetrahydropyridin-4-yl) 1H-indole.
Is reacted at 30-35 C for 5 hours under an inert atmosphere and 9.91 g of 3 ~ f1,2.3.6-tetragid- _w ropiridin-4-yl) 1H-indole with 10.6 g of sodium carbonate, 150 ml dimethylformamide and 4.5 ml of ethyl bromide, and then the reaction mass is poured; in 1.5 l of water and the product precipitates. The mixture pe- ₂₅ remeshivayut 1 hour, filtered, washed with water and the precipitate was dried overnight in an oven at 70 ° C in vacuo in the presence of a dehydrating sredst ^va _'n ³⁰
In this way, 8.95 g of crude target product is obtained, melting at 205 ° C, which is redissolved in 400 ml of ethyl acetate, heated to reflux, concentrated to 250 ml, crystallized, allowed to stand for 1 hour, filtered crystals were washed with ethyl ether acetic acid to give ₄₀ 6.28 g of yellow; crystals, melting at 205 ° C.
The mother liquors are concentrated to one third and 1.76 g of the expected product are obtained by crystallization, i.e. total yield 8.04 g.
Stage B: 3 * (1ethyl 1,2,3,6-tetrahydropyridin-4-yl) 1H-indole hydrochloride
8.04 g of the product obtained in stage A are added to a suspension of 80 ml of ⁵⁰ ethanol, cooled, ethanol hydrochloric acid solution is added to acidic pH and it is allowed to settle. After 1 h 30 min, the crystals are filtered off, washed with ethanol, ⁵³ dried at room temperature (in vacuo, 8.67 g of the desired crude hydrochloride are obtained, which are purified by recrystallization in two doses in ethanol and 6.21 g of pure target product is obtained, melting at 232233 ° C.
Calculated D: C 69.42; H, 7.65;
C1 12.81; N, 10.12.
C H, C1N *. M.V. 262,789.
Found D: C, 69.5; H 7.7; C1 12.8; N, 9.9.
PRI me R 5 "Chlorohydrate 3" (1 ^_ -isopropyl 1, g / b-tetrahydropyridin D-yl) 1H-indole.
Stage A: 3 “¢ 1-methylethyl 1,2,3,6-tetrahydropyridin-4-yl) 1H-indole.
In an inert atmosphere, g 3 (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole, 50 ml of dimethylformamide, 5.25 g of sodium carbonate and 2.7 ml, added dropwise, of iodide, isopropyl, are mixed with after 20 hours, the mixture is poured into 400 ml of water, stirred for 30 minutes, crystallized, the crystals are suctioned off, washed, dried at 50 ° C in vacuo, and 5.8 g of the expected product is obtained, melting at 178 ° C.
Stage B: 3 “hydrochloride (1-methylethyl 1,2,3,6-tetrahydropyridin-4-yl) 1H-indole.
In 150 ml of isopropane c. hot, dissolve the product obtained in stage A, add a solution of gaseous HC1 in isopropanol dropwise to acidic pH, crystallize, cool overnight, suction off the crystals, wash isopropanol, dry in vacuum, and obtain 6 g of the expected product, melting at 2 bO ° C.
Analysis (after recrystallization in ethanol).
Calculated D: C, 69.42; H, 7.65;
C1 12.81; N, 10.12.
M.V. 276.821.
Found D: C, 69.2; H 7.9; C1 12.7; N10.1.
PRI me R 6. 6-Methoxy 3- (1-propyl-1,2,3,6-tetrahydropyridin-4-yl) 1H-indole hydrochloride.
Stage A: 6-methoxy 3 “11-propyl”
1,2,3,6 ~ tetrahydropyridin-4-yl) 1H-, indole.
In an inert atmosphere, mix. 10 g of 6-methoxy 3 (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole, 9.28 g of sodium carbonate and 8.93 g of propyl iodide in 200 ml of dimethyformamide, after 5 m the mixture is poured into 1.5 l of water, crystallize, stir for 1 h, the crystals are filtered in vacuo, washed
IS water, dried in vacuo at 50 ^e in the presence of a dehydrating agent to give 9.9 g of the expected product melting at 219-220 ° C.
Step B: 6-methoxy hydrochloride ₅ 3 ~ (1-propyl 1,2,3,6-l-etrahydropyridin-4-yl) 1H-indole.
7.3 g of the product obtained in the previous step are suspended in 105 ml of ethanol, cooled, 7.5 ml of a saturated solution of gaseous hydrochloric acid in ethanol are added to an acid pH, stirred for 1 h 30 min at 05 ° C, the crystals are filtered under vacuum, washed with ethanol, dried in vacuum at 50 ° C, obtain 8.25 g of crude product, which after recrystallization from water gives 6.2 g of pure target product, melting at above 26 ° C.
Calculated,%: C 66.54; H 7.55;
Cl '11, 55 *; N, 9.12. C1Y _g . M.V. 306.843. Found,%: C 66.2; H 7.7; C1 11.7;
N, 9.0. .
The starting 6-methoxy 3 “(1,2,3,6-tetrahydropyridin-4-yl) 1H-indole moψβτ can be prepared as follows. 30.20 g of 6-methoxy 1H-indoLa with 41.75 g of 4-piperidone hydrochloride hydrate in 205 ml of a 2N methanolic solution of potassium hydroxide are heated under reflux and in atmosphere of nitrogen for 8 hours, and then the mixture is stirred one night at room temperature, slowly diluted with water to 1.2 L, crystallized, stirred for 30 minutes, the crystals were filtered, washed thoroughly * with water, dried and 23.05 g of the expected product was obtained, melting at 193 “194 ° C.
Example/. Hydrochloride 3 £ ΐ “- (2-phenylmethyl) 1,2,3,6-tetrahydropyr. Din-4-yl] TH-indole.
Stage A: 3 ~ f1- (2-phenylethyl) 1,2,3,6-tetrahydropyridin-4-yl] 1H-indole.
At 45 ° C, 6.94 g of 3- (1,2,3,6-τ-tetrahydropypyridin-4-yl) 1H-indole dissolved in 105 ml of dimethylformamide was ^stirred with 7.42 g of ^carbo -5J for 5 hours; n sodium natrium and 5.95 ml of phenylethyl bromide, then the mixture is poured into 1 liter of ice water with stirring, crystallized, stirred for 2 hours, the crystals are filtered off ·, washed, washed with water, dried overnight in vacuum in the presence of a dehydrating agent, get 10, 23 g of a yellow product, melting at
936812 10
203 ° C, which is purified by crystallization from ethanol and 7 ”33 g of the expected product are collected, melting at 20b-207 ° C.
Step B: 3- [1t (2-phenyl ethyl) 1,2,3,6-tetrahydropyrididium-4-yl ^ 1H-indole hydrochloride
8.24 g of the product obtained in stage A are suspended in 85 cm ^{3 of} ice-cold ethanol, hydrochloric acid in a solution in ethanol is added to the pH of the acid with stirring, the mixture is stirred for one hour, filtered, washed with ethanol, recrystallized from methanol and obtained in two stages 6.99 g of the target pure product, melting at 28 0 * C.
Calculated,%: C 74.42; H 6.84; C1 8.26; N, 10.46.
C ₂₁ H _{2 >} C1N ₂ . MS 338.888.
Found,%: C 74.4; H 6.9; C1 7.9; N, 10.7.
Example 8. 3 [l - (2-propenyl) 1,2,3,6-tetrahydropyridin-4-yl] IH-indole hydrochloride.
Step A: 3 [1 “(2-propenyl) 1,2,3,6-tetrahydropyridin-4-yl] 1H-indl.
After stirring for 1 h at 32 C ⁱⁿ a solution of 13.86 g of 3 '(1,2,3,6-tetragid ropiridin-4-yl) 1H-indole in 210 ml .. of dimethylformamide, 14.84 g of sodium carbonate and 7 , 3 ml of double-distilled in an inert atmosphere al .-. J libromide, the mixture is poured into 2 l of water, precipitated, the crystals are filtered after another 1 h of stirring, washed, dried in vacuum in the presence of a dehydrating agent, 16.61 g of light yellow are collected product, melting at 177179 ° C, which is purified by recrystallization in ethyl acetate, and in three doses 9.72 g of the desired product, melting I'm at 177 "179 ° C.
Step B: 3 “f1- (2-propenyl) 1,2,3,6-tetrahydro ropyridin-4-yl 1H-indole hydrochloride
8.79 g of the product obtained in stage A are suspended in 85 ml of ice-cold ethanol, added to acidic pH ^{: a} saturated solution of hydrochloric acid in ethanol, the mixture is stirred for 1 h at 5 ° C, filtered, washed with ethanol, dried in vacuum at $ 0 ° C, 9.36 g of a crystalline product are obtained, which recrystallized from ethanol gives 7.45 g of the target, pure 'hydrochloride, melting at 177 ~ 1784 and at 217-2184.
"And 936812 12
Calculated,%: C 69.93; H 6.96;
N, 10.19; C1 12.90.
With H ^ NjCl. M.V. 274.8.
Found,%: C 69.7; H 7.1; N, 9.9;
C1 13.0. 5
PRI me R 9 · 5-Chloro-3 (1-propyl-1, 2,3,6-tetrahydropyridin-4-yl) 1H-indole hydrochloride.
Stage A: 5-chloro-3 “(1-propyl-1,2,3,6-tetrahydropyridinp4-yl) o 1H-indole.
At room temperature in an inert atmosphere, 9.28 g of 5-chloro 3 ^- (1,2,3,6-15
-tetrahydropyridin-4-yl) 1H-indole with 8.48 g of sodium carbonate and 4.67 ml of propyl iodide, the mixture is poured into 1.4 l of water with stirring, crystals are crystallized, filtered, washed with ₂ q water, dried in vacuum in the presence of dehydrating agents, purified by recrystallization from ethanol and get 6.95 g of the target product, melting at 229 “230 ° C. 25
Stage B: 5-chloro 3 (J “-propyl-1,2,3,6-tetrahydropyridin-4-yl) 1H-indole hydrochloride ’
6.95 g of the product obtained in stage A is suspended in 105 ml of ethanol, _{} 0 is} cooled, a saturated standard solution of HC is added to acidic pH , stirred for 2 hours and 30 minutes at 0 ° C, the crystals were filtered, washed with ethanol, dried in an oven, 7.566 g of crude product was collected, which was recrystallized from ethanol to obtain 5.047 g of light yellow crystals: the desired product, melting at 2 ° from.
Calculated,%: C 61.74; H, 6.47; C1 22.78; N 8.99 M.V. 311,256.
Found,%: C 61.6; H 6.5; C1 22.7; N, 8.8.
The starting 5-chloro 3- (1, 2,3,6-tetrahydropyridin-4-yl) 1H-indole can be obtained by a known method.
PRI me R 10. Hydrochloride 5 ^_ x ^l ° R ^_
3- (1-ethyl-1,2,3,6-tetrahydropyridin-4-th) IH-indole. '. ^fifty
Stage A: 5 “chloro 3“ (1-ethyl-_ -1,2,3,6-tetrahydropyridin-4-yl) IH-indole.
At room temperature, in an inert atmosphere, 12 g of 5 ^- chloro-3- (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole are stirred for ⁵⁵ hours 30 minutes
120 ml of anhydrous dimethylformamide with 10.92 g of sodium carbonate and 5.1 ml • ', -g I of bromoethane, and then 350 ml of distilled water are slowly added, the precipitate is stirred for 1 hour 30 minutes, kept at night, the crystals are filtered in vacuo, washed three times with water and once with 25 ml of a 50% aqueous solution of ethanol, dried in the presence of a dehydrating agent, 9.48 g of a yellow target product are obtained, melting at 208-210 ° C, which is recrystallized twice in ethanol and collected 7.487 g of the target product.
Stage B: hydrochloride 5 ~ chloro 3 “(1“ -ethyl-1,2,3,6-tetrahydropyridin-4-yl) 1H-indole.
7.48 g of the product obtained in stage A Suspended in 40 ml of ethanol, cooled to 0 ° C, add an ethanol solution of HCC to pH 1. The product precipitates, it is stirred for 30 minutes at 0 ° C, left at this temperature for 1 h, filtered, washed with ice-cold ethanol, dried in vacuo at 50 ° C, 7.3 g of the expected product is collected, melting at 225 ° C, which is subjected to recrystallization in ice-cold ethanol, and 5.9 g of pure desired product is obtained, melting at 225 ° C.
Calculated,%: C 60.61; H 6.1; And 23.85; N, 9.42.
C ^ HfgCkNz. M.V. 297.239 Found,%: C 60.4; H 6.1; C1 23.6; N, 9.3.
Example p11. Hydrochloride 5 “chloro 3Π (cyclopropylmethyl) 1,2,3,6-tetrahydropyridin-4-yl] 1H-indole.
Stage A: 5-chloro 3 “[l- (cyclopropylmethyl) 1,2,3,6-tetrahydropyridin-4-yl] 1H-indole.
To a solution of 12.5 g of 5 ^_ chloro-3 ~ (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole in 120 ml of anhydrous dimethylformamide was added 11.5 g of sodium carbonate and 6.5 ml of chloromethylcyclopropane, the mixture is stirred for 24 hours at 70 ° C in an inert gas, cooled to 30 ° C, 300 ml of water (distilled) are added, while stirring, it is cooled using an ice-water bath. The precipitate was stirred for 45 minutes, held for 15 minutes, the crystals were filtered in vacuo, washed three times with distilled water, 20 ml of a 50% aqueous solution of ethanol, dried in vacuum at 50 ° C in the presence of a dehydrating agent, 13.54 g of 936812 of a crude product that is re-triturated * steal by heating under reflux in 350 ml of ethanol, filtered, [concentrated to 300 ml, crystallized at room temperature, then left for 1 h 30 min in a refrigerator, filtered under vacuum, washed with ethanol, dried in vacuum and get 7.8 the expected product melting at 205 ° C.
Stage B: Hydrochloride 5 ~ chloro 3 ^_ [l ^_ - (cyclopropylmethyl) -1,2,3,6-tetrahydropyridine 4-ylZ 1H-indole.
To a suspension of 7.8 g of the product obtained in the previous step in 80 ml of ethanol chilled in an ice-water bath, HC8 ethanol was added to pH 1, stirred for 1 h, the resulting precipitate was allowed to stand for 15 min, the crystals were filtered in vacuo, washed with ethanol, dried under reduced pressure, recrystallized from ethanol to obtain 6.9 g of pure target hydrochloride, melting at 242-244 ° C. .
Calculated, C 63 ,. 16; H, 6.23; C1 21.93; N, 8.66.
Q ₇ H _2o Cl _x N _a . M.V. 323,268.
* Found, C 63.3; H 6.2; C1 22.2; N8.6.
PRI me R 12. 6-Methoxy 2-methyl-3- (1-propyl 1,2,3,6-tetrahydropyridin-4-yl) 1H-indole hydrochloride.
Stage A: 6-methoxy 2-methyl-3 ~ (1-propyl 1,2,3,6-tetrahydropyrzidin-4-yl) 1H-indole.
In a nitrogen atmosphere at 40 ° C, 10.3 g of 6-methoxy 2-methyl-3 (1,2,3,6-tetrahydropyridin-4-yl) 1 N-indal hydrochloride are mixed with 11.845 g of sodium carbonate, 103 ml of dimethylformamide and 4.82 ml of propyl iodide, after 4 hours and 30 minutes the reaction mixture was poured into water with stirring, the obtained resin was extracted with ethyl acetate, washed with water and then with salt water, dried, evaporated to dryness, 10.1 g of the obtained resin was diluted with 50 ml of ethanol, the product is crystallized in this way, stirred for 45 minutes at room temperature, cooled for 30 minutes with stirring ii, left alone for 30 minutes, the crystals are sucked off, washed with ethanol and ether, and 7.8 g of the base of the expected product are obtained, melting at 90-95 ° С.
Step B: 5 ~ methoxy-2-methyl-3 ~ (1-propyl-1,2,3,6-tetrahydro ropyridin-4-yl) 1H-indole hydrochloride
9.1 g of the base obtained in the previous step are dissolved in 70 ml of isopropanol, the solution is filtered, cooled, saturated with dry HC & isopropanol are added, the precipitated crystals are stirred for 30 minutes, allowed to stand for 10 minutes, suctioned off under vacuum at room temperature, washed with isopropanol, collected 8.73 g of the desired hydrochloride, melting above 260 ° С, are purified by recrystallization in meta-zero and 4.4 g of the expected pure product are obtained, melting at'2 75 ° С · Calculated, С 67.37; H 7.85;
C1 11.00; N, 8.73 C ^ H ^ ClNjO. M.V. 320.87.
Found,%; C, 67.2; H, 8.00; C1 11.00; N, 8.6.
^d 6-methoxy hydrochloride “2-methyl-3“ “(1,2,3,6 ~ tetrahydropyridin-4-yl) 1H-indole can be obtained as follows25.
At 10 ° C, in an inert atmosphere, 2 g of 6-methoxy22-methyl-1H-indole are mixed with 4 g of 4-piperid hydrochloride hydrate in 40 ml of acetic acid. After 30 hours 1 hour, the ZOmin mixture is cooled, poured onto 150 g of ice and 80 ml of pure ammonium hydroxide at 22 ° Be, extracted with ethyl acetate, washed with water, dried over magnesium sulfate ₃₅ , distilled to dryness in vacuo, the residue obtained is taken up in ethyl acetate, heated to boiling, cooled, and precipitated crystals. washed with ethyl acetate, dried in vacuo and oluchayut 2.5 g of a crude 'product.
Getting hydrochloride.
The resulting product was dissolved in ^45-50 ml of hot isopropanol, cooled, a solution of rancose HCl in isopropanol was added dropwise to acid pH, and the seed was crystallized. After one night of 5 °, the crystals are washed with isopropanol, dried in vacuo to give 2.25 g of the expected product, melting at 270 ° C.
Calculated, I: C 64.52; H 6.87;
C1 12.72; N, 10.05.
C ^ H ^ ClN _a O.
Found, C, 64.5; H, 7.0; C1 13.0; N 9, ¾.
The proposed compounds or their salts with acids have antidepressant and antipsychotic properties, ^ also an antiemetic effect.

权利要求:
Claims (1)
[1]
59 Step A: 3- (1-propyl 1,2,3,6-tet rahydropyridin-4-yl) -1H. -indol  A, 5 g of 3- (1t2, 3,6,6-TeTpa hydropyridin-4-yl) 1H-indole is dissolved in 90 ml of acetone.  To the resulting solution was added g of silver oxide and 2.22 ml of propyl iodide.  Heat for 3 hours at, cool, filter and distill, dry under vacuum. The resulting crude product is chromatographed on silica, eluting with chloroform-acetone-triethylamine ().  The solvent is distilled off and the residue is dissolved in 20O, ml of ethyl ether with bar.  the hydrochloric acid is heated to reflux, the solution is filtered, and concentrated to 150 ml. Cool before causing crystallization and cool overnight.  The crystals are sucked off, washed with ethyl acetate and dried.  In this way, 3.9 g of the expected product are obtained, melting at.  Stage B: 3- (1-Propyl-1, 2.3, 6-tetrahydropyridin-4-yl) 1H -indole hydrochloride.  3.9 g of the product obtained in step A is dissolved in 250 ml of isopropanol with heating under reflux and a solution of gaseous hydrochloric acid in isopropanol is added dropwise to obtain an acidic pH.  The reaction mass is cooled for 2 h, the crystals are sucked off, washed with isopropanol and dried under reduced pressure.  4.15 g of crude product are obtained, which are purified by crystallization.  In this way, g of the desired product is obtained, melting at 230-232 C.  Calculated. : C, 69.42; H 7, b5; pi 12.81; N 10.12; C H oNzHCl M. at.  276,821.  Found,%: C b9,5; H 7.7; Cf 12.8; N 9.9.  The 3- (1,2,3,6-tetrahydropyridin-4-yl) 1H-INDOL used as the starting material can be obtained with l 1 in the following way.  10 g of indole is dissolved in 200 ml of acetic acid, heated at 95-1 ° C with stirring and under nitrogen atmosphere.  50 ml of 1N are added. an aqueous solution of phosphoric acid and 39.3 g of 4-piperidone hydrochloride monohydrate.  The reaction mass is heated for 1 h, allowed to cool, poured on ice, adding 350 ml of concentrated ammonium hydroxide and extracted with ethyl acetate.  The extracts are washed with water, salt water, dried over magnesium sulfate and evaporated to dryness.  T5.7 g of crude product is obtained, it is concentrated in a nitrogen atmosphere and 75 ml of methanol are added, the crystals are filtered off under vacuum, washed with methanol, and ether.  Get 1, g of 3- (1,2,3 6-tetrahydropyridine-i-L) 1H-indole.  T. square TVZ-Tvb S.  The mother liquors are evaporated and purified by chromatography on a dioxide.  the resulting crude product was eluted with chloroform-triethylamine (6-3-1).  4.55 g of product Rf 0.15 is collected.  which is triturated with ether.  Get 4,295 g of 3- (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole, with you.  move 5. 715  The resulting product is purified by recrystallization from i-propanol and get,  3- (1,2,3,6-tetrahydr6pyridin-4-yl) 1H-indole.  T. square  190-191 c.  PRI me R 3.  3- (1-pentyl 1,2,3,6-tetrahydropyridin-4-yl) 1H-indole hydrochloride.  Stage A: 3-C-Pentyl-1,2,3,6-tetrahydropyridin-4-yl) 1H-indole.  10 g of 3- (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole are added to 100 ml of acetone, g of silver oxide is added, and then 20 ml of pentyl iodide.  After 4 hours of stirring at room temperature, another 2 to 5 ml of iodide pentyl is added and stirring is continued for 1 hour.  The precipitation is filtered off, washed with a mixture of methylene methanol chloride C50. 50 and remove the solvents under reduced pressure at.  The crude product is purified by chromatography on silica gel, eluting with chloroform-methanol-triethylamine (7-2-1).  After the eluent has been distilled off, it is again dissolved. the obtained dry extract in 250 ml of ethanol at the boil, the solution is filtered and left to crystallize at.  7.9 g of the expected product are obtained, melting at about 180 C.  Stage B: 3- (1-Pentyl 1,2,3 6-tetragsdropyridin-4-yl) 1H-indole hydrochloride.   A suspension of 7.9 g of the product obtained in stage A in 100 ml of absolute ethanol is prepared, and then at 0-5C-30 ml of hydrochloric acid / 9 lots in ethanol are introduced.  The reaction mass was left for one hour with stirring, the crystals were filtered off, washed with ether, and then dried under vacuum at.  8.5 g of the expected hydrochloride are obtained in the form of a yellow product, applied to the nickname at, and then at Calculated,%: C, 70.9; N 9. 2; C1 11.6.  QeH2gf42Cl.  M. at.  , 866.  Found,%: C 70.7; H 8.3; N 9; C1 11.6.  An example.  3-Cl-ethyl hydrochloride 112,3,6-tetrahydropyridin-4-yl 1H-1Ndol.  Step -A: 1,2,3,6-tetrahydropyridin-4-yl) 1H-indole.  9.91 g of 3- (1,2,3,6-1 tetragide ropyridin-yl) 1H-indole with 10.6 g of sodium carbonate, 150 ml of dimethylformamide and under an inert atmosphere are reacted at 30-35fC for 5 hours and in an inert atmosphere. and, 5 ml of ethyl bromide, and then the reaction mass is poured into 1.5 liters of water and the product precipitates.  The mixture is stirred for 1 h, filtered off, the precipitate washed with water and dried one night in a drying cabinet under vacuum in the presence of a dehydrating agent.   In this way, 8.95 g of crude desired product is obtained, melting under which are redissolved in fOO ml of et1 &quot; 1-acetic acid ester with heating under reflux, the solution is filtered off in a hot form, concentrated to 250 W1, crystallized, kept 1 m, the crystals are filtered off, washed with ethyl acetate and 6.28 g of yellow are obtained; the crystals melting at.  The stock solutions are concentrated to one third and another 1.76 g of the desired product is obtained by crystallization, i. e.  total output 8, OA,  Stage B: 3-hydrochloride (1-ethyl 1,2; 3 6-tetrahydropyridin-yl) 1H-indole.  8, OA g of the product obtained in step A is introduced into a suspension in 80 ml of ethanol, cooled, an ethanolic hydrochloric acid solution is added to an acidic pH and allowed to settle.  After 1 h 30 min, the crystals are filtered off, washed with ethanol, dried at room temperature in vacuo, to obtain 8.67 g of the desired crude hydrochloride. one that is purified by ne 2 recrystallization in two steps in ethanol and 6.21 g of the pure desired product are obtained, melting at 232233 ° C.  Calculated: C 69.2; H 7, b5; C1 12.81; N 10.12.  C H CIN.  M. at.  262,789.  Found: C 69.5; H 7.7; C1 12.8; N 9.9.  P Rome p 5.  3- (1-Isopropyl 1,2,3,6-tetrahydropyridin-4-yl) 1H-indryl hydrochloride.  Stage A: 3-C1 methylethyl 1,2,3,6-tetrahydropyridine -yl) F-indole.  In an inert atmosphere is stirred 5 g of 3- (1. 2,3fb-tetrahydropyridine-yl) 1H-indole, 50 ml of dimethylformamide, 5.25 g of sodium carbonate and 2.7 ml, added dropwise, iodide.  isopropyl, after 20 hours the mixture is poured into tOO ml of water, stirred for 30 minutes, crystallized, the crystals are filtered off with suction, washed and dried under vacuum to give 5.8 g of the desired product, melting at 178 ° C.  Stage B: 3- (1 methylethyl 1,2,3,6-tetrahydropyridine - "- yl) 1H-indole hydrochloride.  In 150 ml of isopropane c.  the product obtained in stage A is dissolved in a hot form, a solution of gaseous HCl in isopropanol is added dropwise to an acidic pH, crystallized, cooled overnight, the crystals are sucked off, washed with isopropanol, dried in a vacuum and. 6 g of the expected product are obtained, melting at 260 ° C.  Analysis (after recrystallization in ethanol).  Calculated: С 69, Н 7.65; C1 12.81; N 10.12.   M. at.  276,821.  Found: C 69.2; H 7.9; C1 12.7; N10.1.  PRI me R 6.  6-methoxy 3-C1 hydrochloride PROpil-1,2,3,6-tetrahydropyridin-ylZ 1H-indole.  Step A: 6-methoxy 3 1 propyl 1,2,3,6-tetrahydropyridine -yl) 1H-, -indole.  In an inert atmosphere stirred.  10 g of 6-methoxy 3-1,2,3,6-tetrahydropyridine-yl) 1H-indole, 9.28 g of sodium carbonate and 8.93 g of propyl iodide in 200 ml of dimethylformamide, after 5 m the mixture is poured into 1 , 5 l of water, Crystallized, stirred for 1 h, the crystals are filtered under vacuum, washed with water, dried in vacuum at 50 ° C in the presence of a dehydrating agent and get g of the desired product, melting at 219-220 C.  Stage B: 6-methoxy 3 hydrochloride (1-propyl 1,2,3,6-letragidropiridi-i-yl) 1H-indole.  7.3 g of the product obtained in the previous step are suspended in 105 ml of ethanol, cooled, 7.5 ml of a saturated solution of gaseous hydrochloric acid in ethanol are added to an acidic pH, stirred for 1 hour and 30 minutes while the crystals are filtered in vacuo, washed with ethanol, dried in a vacuum when, 8.25 g of crude product is obtained, which, after recrystallization from VID, gives 6.2 g of pure target product, melting at higher.  Calculated,%: C 66, H 7.55; C1 11, N 9,12.  M. at.  thirty. 6,8АЗ.   ClNi.  Find but,%: C 66.2; H 7.7; C1 N 9.0.  The starting 6-methoxy 3 (1,2,3,6-tetragi, popyridine-yl) 1H-INDOL MO) can be obtained as follows.  30.20 g of 6-methoxy 1H-indoleL with 1.75 g of “-piperi don hydrochloride hydrate in 205 ml of 2N is heated for 8 hours with reflux condenser and in the nitrogen atom of the atmosphere. methanol solution of potassium hydroxide, and then the mixture is stirred overnight at room temperature, slowly diluted with water to 1.2 l, crystallized, stirred for 30 minutes, the crystals are filtered thoroughly, washed with water, dried to obtain 23.05 g of the desired product by melting -19 C.  PRI me R 7.  3-tl- (2-phenylLethyl) i, 2,3, b-tetrahydropyridin - α -yl 1H-indole hydrochloride.  Stage A: 3-p-C2-phenylethyl) t, 2,3,6-tetrahydropyridine- | -yl 3-indole.  6.9 g of 3- (1,2,3,6-tetrahydipopyr din-Vil) 1H-indole, dissolved in 105 ml of dimethylformamide, are mixed in during the hour, c7, | 2g of sodium carbonate and 5.95 ml of phenylethylbromide, then a mixture poured with stirring into 1 liter of ice water, crystallized, stirred for 2 hours, the crystals were filtered, dried, washed with water, dried overnight in a vacuum in the presence of a dehydrating agent, tO was obtained, 23 g of a yellow product, melting at 11.7 1210 203 ° C, which is purified by crystallization from ethanol and 7.33 g of the expected product is collected, melting at 206-207 C.  Stage B: (2-phenyl ethyl) hydrochloride, 1, 2,3,6-tetrahydropyridin-yl 2 1H-indole.  8.2 g of the product obtained in stage A are suspended in 85 cm of ice-cold ethanol. Hydrochloric acid in solution in ethanol is added with stirring until the pH of the acid is obtained, the mixture. stir for one hour, filter, wash with ethanol, recrystallize from methanol and obtain in two batches 6.99 f of the desired pure product, melting at.  Calculated,%: C 7, H 6, C1, 8.26; N 10,  GI H 2, C1N-i.  M. at.  333,888.  Found: С 7 ,; H 6.9; C1 7.9; N 10.7.  PRI me R 8.  The hydrochloride is (2-propenyl) 1,2,3,6-tetrahydropyridin-yl 1H-indole. .  Step A: 3-11-C2-propenyl) 1,2,3. 6-tetrahydropyridin-A-yl 1H-imid.  The solution of 13.86 g of 3- (1,2,3,6-tetrahydropyridin-A-yl) 1H-indole in 210 ml of dimethylformamide with 1t, 8A of sodium carbonate and 7.3 ml is stirred for 1 hour at 32 ° C. double-distilled in an inert atmosphere anr. i libromide, the mixture is poured into 2 l of water, precipitated, the crystals are filtered after another 1 h of stirring, washed, dried under vacuum in the presence of a dehydrating agent, 16.61 g of light yellow product, melting at 177-179 0, is collected, which is purified by recrystallization in ethyl acetate, and 9.72 g of the expected product are obtained in three doses, melting at 177179 Stage B: (2-nponer mil) 1,2,3,6-tetrahydropyridin-yl I 1H-indole hydrochloride.  8.79 g of the product obtained in stage A are suspended in 85 ml of ice-cold ethanol, dB of acidic pH is added. Saturated solution of hydrochloric acid in ethanol, the mixture is stirred for 1 hour at, filtered, washed with ethanol, dried in vacuo at, g of crystalline product is obtained which recrystallized from ethanol gives 7.5 g of the target, pure hydrochloride, melting at 177 1784 and at 217-218 0.  .  1193681212 is calculated D: C 69,93; H 6.96; with 10.92 g of sodium carbonate and 5 ml of N 10.19; C1 12.90. bromethane, and then slowly added C H pNjCl.  M. at.  27 +, 8, 350 ml of distilled water are dispensed; Found; C 69.7; H 7.1; N 9.9; shiy precipitate, stirred for 1 h 30 min, C1 13.0. 5 withstand the night, the crystals of the filter. p 9-5-chloro-hydrochloride in vacuo, washed three times with 6-3- (1-propyl-1,2,3,6-tetrahydropyri-doi and once with 25 ml of 50% vodnodin-yl) 1H-indole. ethanol solution, dried in the presence of Stage A: 5 chlorine-3 (1 propylene dehydrating agent, yielding-1, 2,3,6-tetrahydropyriding-yl) is 9, g of the yellow target product, 1H-INDOL. Melting at 208-21 ° C, which is stirred at room temperature in inert-recrystallization twice in ethane atmosphere and mixed with tenenol, and 7.87 g of the target product is collected and about 9.28 g dissolved in a mildect.  dimethylformamide 5-chloro 3- (1,2,3,6- is Stage B: 5-chloro 3- (1-tetrahydropyridin-yl) hydrochloride ethyl-1,2,3,6-tetrahydropyridine- - or 8.8 g of sodium carbonate and, B7 ml of 1H-indole.  propyl ibdid, the mixture is poured at 7.8 g obtained in stage A by stirring into 1.4 liters of water, crystalline duct Suspended in 40 ml of ethanol, crystals are collected, filtered, washed 20 is cooled and added to pH with water, dried in vacuum in the presence of 1 ethanol solution NSE.  Product dehydrating clean.  It is precipitated, it is stirred for 30 minutes by recrystallization from ethanol and, at this temperature, 6.95 g of the desired product is left at this temperature, the mixture is heated for 1 hour, filtered, and the ice is washed at 229-230 ° C. 25-ethanol, dried under vacuum at Stage B: 5-chloro 3- hydrochloride (1-50 ° C, 7.3 g of the desired pro-propyl-1, 2,3,6-tetrahydropyridine-duct, melted at 225 ° C, collected, which-t-yl) 1H-indole. .  It is subjected to recrystallization in 6.95 g of obtained ethanol in stage A, and 5.9 g of duct are obtained suspended in 105 ml of ethanol, j of the pure desired product, melted and cooled, added to acidic acid.  pH saturated standard solution of HC6, Calculated: С 60.61; H 6.1; stirred for 2 hours and 30 minutes at, cris-C1 23.85; N 9,2, tally filtered, washed with ethanol C E Cl Nz- M. at.  297,239 dried in a drying cabinet, assembled Found :: C 60, if; H 6.1; C1 23.6; 7.566 g of the crude product, which ne-9.3 is recrystallized from ethanol and according to Example 11.  The hydrochloride gives 5, g of a light yellow crystal-3-l- (cyclopropylmethyl) 1,2,3,6-tetlov1 target product, melting rahydropyridine-yl 1H-indole.  at. . Stage A: 5-chloro 3 11-CicloproCalculated,; C 61, H 6.47; pilmethyl) 1,2, 3,6-tetrahydropyridine01 22.78; N 8,99 -it-il 1H-indole.  CffcHjoCliN: M. at.  311,256. To a solution of 12.5 g of 5-chloro-3; Found: C 61.6; H 6.5; C1 22.7 ;-( 1, 2,3,6-tvtrahydropyridin-yl) 1NN 8.8. -indole in 120 ml of anhydrous dimethyl-; The starting 5-chloro 3- (1,2,3,6-tetra-formamide) was added 11.5 g of carbonyl hydropyridine-yl) 1H-INDOL sodium and 6.5 ml of chloromethyl cycloproduct was prepared by a known method. Pan, the mixture is stirred for 2k hours at PRI me R. ten.  Hydrochloride 5-chloro-70 C in an inert gas, cooled to 3- (1-ethyl-1,2,3,6-tetrahydro-pyridine-30 C, 300 ml of water (distilled-yl) 1H-indole are added.   .  ° poured), while stirring, cooled. Stage A: 5-chlorine 3- (1-ethyl-, and using an ice-water bath.  -1,2,3,6-tvterahydropyridin-4-yl) The precipitate formed is stirred for 5 min., 1H-INDOL. The mixture is incubated for 15 minutes, the crystals are filtered at room temperature and inert under vacuum, washed with different aether and stirred for the time with distilled water, 12 ml of 5-chloro-3- (1, 2, 3, 20 ml of 50% 6 hours and 30 minutes). 6-tetra-aqueous solution of ethanol, dried in varahydropyridine-yl) 1H-indole flavor at 50 ° C in the presence of anhydrous 120 ml of anhydrous dimethylformamidative, collect 13.5 g of 13 crude product, which is re-diluted, heating with refluxing 350 ml of ethanol, filtered, concentrated to 300 ml, crystallized at room temperature, then leave for 1 h 30 min in a refrigerator, filter under vacuum, rinse with ethanol, and dry in vacuo to obtain g of the desired product, melting at.  Stage B: Hydrochloride 5-chloro- (cyclopropylmethyl) -1,2,3,6-tetrahyd ropyridine 7 -ylZ 1H-indole.  To a suspension of g of the product obtained in the previous stage in 80 ml of ethanol cooled in an ice-water bath, ethanol is added to a pH of 1, stirred for 1 hour, the resulting precipitate is settled for 15 minutes, the crystals are filtered under vacuum, washed with ethanol, dried under reduced pressure, recrystallized from ethanol and get 6.9 g of pure target hydrochloride, melting at 2Ts2-2TsS C. .  Calculated: C 63 ,. sixteen; H 6.23; C1 21.93; N 8.66.      323.268, Found: C, 63.3; H 6.2; C1 22.2 N 8.6.  P m and m 6 p 12.  6-methoxy 2-methyl-3-And-propyl 1,2,3,6-tetrahydropyridin-A-yl) 1H-indole hydrochloride.  Step A: 6-methoxy 2-methyl-3- (1-propyl 1,2,3,6-tetrahydypyruidin-yl) 1H-INDOL.  10.3 g of hydrochloride 6-methoxy 2-methyl-3- (1,2,3,6-tetrahydropyridin-t-yl) 1 H-indal with 11, g sodium carbonate, 103 ml of dimethylformamide and t, 82 ml of 1 propyl iodide, after k hours and 30 minutes, the reaction mixture is poured with stirring into water, the resulting resin is extracted with ethyl acetate, washed with water and then with salt water, dried, evaporated to dryness, 10.1 tons of the obtained resin diluted with 50 ml of ethanol, the product thus crystallized, stirred for 5 minutes at room temperature, cooled for 30 minutes with stirring And, leave alone for 30 minutes.  the crystals are filtered off with suction, washed with NOL and ether and 7.8 g of the base product are obtained, melting at 90-95 C.  12It Stage B: Zmethoxy-2-methyl-3- (1-propyl-1,2,3,6-tetrahydropyridine-α-OH 1 H-indole hydrochloride.  9J g of the base obtained in the previous step is dissolved in 70 ml of isopropanol, the solution is filtered, cooled, and saturated with dry HC is added. isopropanol, the precipitated crystals are stirred for 30 minutes, allowed to stand for 30 minutes, sucked off in vacuum at room temperature, washed with isopropanol, 8.73 g of the desired hydrochloride are collected, melting above 260 d are purified by recrystallization in methanol and get C, Zg of the target pure product melted at 275С.  Calculated: C 67.37; H 7.85; C1 11.00; N 8.73.  QgH g ClNjO.  M. at.  320.87.  Found; C, 67.2; H 8.00; C1 11.00; N 8.6.  6-methoxy-2-methyl-3 hydrochloride (1,2,3,6 tetrahydropyr-rdcyl-yl) 1H-indole can be prepared as follows.  When in an inert atmosphere, 2 g of 6-methoxy-2-methyl-1H-indole are mixed with g of 4-pyperidone hydrochloride hydrate in 40 ml of acetic acid. After 1 h of ZOmin, the mixture is cooled, poured onto 150 g of ice and 80 ml of pure ammonium hydroxide in 22 Ba, extracted with ethyl acetate, washed with water, dried over magnesium sulphate, distilled to dryness in vacuo, the resulting residue is placed in ethyl acetate, heated to boiling, cooled, I. the precipitated crystals are washed with ethyl acetate and dried under vacuum. and get 2.5 g of crude product.  Getting hydrochloride.  The resulting product is dissolved in 50 ml of hot isopropanol, cooled, a solution of ra-i zoobrazene NO in ras-i in isopropanol is added dropwise to an acidic pH, and the seed is cast to crystallize.  After one night, the crystals are washed with isopropanol, dried under vacuum, and 2.25 g of the expected product are obtained, melting at.  Calculated,%: C 6k, S2; H 6.87; 01 12.72; N 10.05.   Found: About 6.5; H 7.0; C1 13.0; N 9,  Pre-conjugated compounds: or their salts with acids possess anti-depressive and neurolitic properties as well as an antiemetic effect.  Invention 9368, a carbon atom, if X is benzyl, then / at least of the Substituents R, R or R is not hydrogen, or their salts with acids, o and l and -.  due to the fact that the compound of general formula t

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同族专利:

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公开号 | 公开日

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JPS54100380A|1979-08-08|

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EP0003199A2|1979-07-25|

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AT367418B|1982-07-12|

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HU180517B|1983-03-28|

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AU4338379A|1979-07-26|

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EP0003199B1|1981-11-11|

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EP0003199A3|1979-09-05|

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DK148477B|1985-07-15|

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IE790064L|1979-07-16|

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DK15279A|1979-07-17|

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ZA79154B|1980-01-30|

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JPS6340792B2|1988-08-12|

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AU519534B2|1981-12-10|

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ATA29079A|1981-11-15|

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ES476786A1|1979-06-01|

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PT69071A|1979-02-01|

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DE2961284D1|1982-01-14|

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FR2421899B1|1981-06-19|

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IE48366B1|1984-12-26|

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CA1115277A|1981-12-29|

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DK148477C|1986-04-01|

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FR2421899A1|1979-11-02|

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US4278677A|1981-07-14|

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GB8819024D0|1988-08-10|1988-09-14|Glaxo Group Ltd|Chemical compounds|

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HU9800417A3|1995-03-20|2001-04-28|Lilly Co Eli|5-substituted-3--indoles and 5-substituted-3--1h-indoles, their use as new 5-ht agonists, pharmaceutical compositions containing these compounds|

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AR013669A1|1997-10-07|2001-01-10|Smithkline Beecham Corp|COMPOUNDS AND METHODS|

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SE9903544D0|1999-10-01|1999-10-01|Astra Pharma Prod|Novel compounds|

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GB2359081A|2000-02-11|2001-08-15|Astrazeneca Uk Ltd|Pharmaceutically active thiazolopyrimidines|

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GB2359078A|2000-02-11|2001-08-15|Astrazeneca Uk Ltd|Pharmaceutically active pyrimidine derivatives|

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GB2359551A|2000-02-23|2001-08-29|Astrazeneca Uk Ltd|Pharmaceutically active pyrimidine derivatives|

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GB0005642D0|2000-03-10|2000-05-03|Astrazeneca Uk Ltd|Chemical compounds|

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SE0003828D0|2000-10-20|2000-10-20|Astrazeneca Ab|Novel compounds|

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SE0101322D0|2001-04-12|2001-04-12|Astrazeneca Ab|Novel compounds|

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GB0221829D0|2002-09-20|2002-10-30|Astrazeneca Ab|Novel compound|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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FR7801083A|FR2421899B1|1978-01-16|1978-01-16|

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