SU432711A3 - - Google Patents

Description

This invention relates to a process for the preparation of new, not described in literature, 1-aminoalkylbenzocycloalkan-2-spirocycloaliphatic compounds, which have valuable pharmacological properties and can be used in medicine.

A known method for producing aliphatic diamines from the corresponding dihalide derivatives and amines in various solvents.

The proposed method, based on the known alkylamino-halogen replacement reaction, produces new compounds.

A method is proposed for the preparation of aminoalkyl spiroalkanes of the general formula

2

In lower alkylene or lower alkenylene, which 4-6 carbon atoms participates in the formation of a cycle,

alk2 is lower alkylene, Am is an amino group or

alk2 - Am together - azacycloalkyl, azacycloalkyl - lower alkyl,

R is hydrogen, hydroxy,

or derivatives thereof, in that in a compound of the general formula

R x h

P / V

alkj

arklphosphoiiiigalogenid) -alklkgruppny, (nilUUj UJv ii-ViiiliU, iiAiiiiiOj UiiaiiOj A: .. ro. iioO

cyanato lly teryfitsproyannuy li s.-izhny sfyr ivupuuKcna.ii-iiioj-alkyl-, a.Lsennl-, alkaionL-, i "iii Id J-Jli.LliaЛAK.Upyliliy, a-.iiiaO-a.iKuHl-Ijl -, ibviliJ.Oa iiidriOibi- is.iii iliViibiOiiiApUKv i-iiiikilgruiau, liiiipiLU- OR Kapua.vioii.iipyiiiiyiy. KuiiACi-iCaUiiH pcaKUriuiUiuciiCcouiiOi and up jibJoND u iSCHDN01i iJCu, t; Crijcl with a.iA ;; laKO.i ii.iil

aiviHiia.viii iitiii 1 pALIZE nUjiN iCiiiibiX is.iicLOTS IRIEVEDBY iipeHJ.iyii CCTBCiijiO 13 lip, i; yI oViOe iOcc io uCiiOBUbiX roOttiVoP. IIA

MOJiiHO, however, iso_i.z.LTo also in SKijHijalenlent11B1X O; l –1 of the facilities in 11RoadsGilp Dr) - lx cocdenciation means, for example, meorgha-shcheekyh or organic basis.

i oluchenn1e C1 unid: 1and possess tse: 1nl:, 1ts farGaalOlogicheeky-Lee eBOhCiBa-viu.

lip imper 1. iv to a solution of i-OKcu-i - (, 3-tosyloxinronyl) -1,2,3,4-terapraidyroifta1.1in2-c11irocyclohexane in OO lit aceglrila on the adduct; -r-epithel1el1nii nri -iu 3, t a) d without a single dL; eTi: a: 11l a. During this process, it is kept in an unsupplemented / ipybKe tea, it is cooled, filtered and the filtrate is evaporated with a pressure of yiiciibmeiiHOM. The residue is taken up in spruce oil and acetic acid, hydrochloric gas is obtained through a solution, and the precipitated precipitate is obtained ;; the mixture is filtered and non-recrystallized from iso-nanolanol. 1-oken-1 - (- di; 1-methyl-1-tetrangene; 1-1 rtalin-2-enyrocyclohecanan-hydrochloride, ivOiopuii is melted with nrn 2i -ziaC, decomposed 1 and Hg. In response, its European foundation is a 90-dzC.

Example 2. To a solution of 7.6 g of 1- (3-toz: 1loxyronyl) -6-methoxy-1,2,3,4 tetrahydronaphthalene-2-enyrocyclohexane in 5 ml of aUdOHirryl nribavl nrn nere1.1cshawa 1i at-3, 5 g of anhydrous di; 1Cnlaminn and doughing are heated in a non-transitional tube in a dish;} 6 hours before. The reaction mixture was cooled, filtered, and the filtrate was added at a reduced pressure. The residue is distilled, knn SchOu iri iu2-iooC 0.3 mm Hg. Art.) the fraction is captured, it is dissolved in an acetic acid mixture. Through paciiiop, a hydrochloric gas is discharged and the precipitate obtained is filtered off. 1d0 rays from 1- (3-dimethylaminsnronyl) - 6 - MeiOKeii-i, 2,3, 4-tetrahydronaphthalene - 2 - eirocyclohexanone and hydrochloride, which nlavs iri; 3 / - 141 0.

Example 3. A solution of 1 g of i- (1, C-di: methylcarbamoylethyl) - 6 - methoxy-1,2,3,4-ts: trag; Dronaphthalene-2-diminution of cyclohexane in b ml of diethyl nastoyl ester but ca. They are mixed in a mixture of C, 5 g of aluminum hydroxide and 25 ml of bc; an arsenic for ethyl naphtha; the reaction mixture is stirred overnight. Then, 1 ml of ethyl acetate, U, 5 ml of ULTRO1, 1 ml of 5% aqueous solution of sodium hydroxide and 1.5 ml of water are added.

The resulting precipitate is filtered off, washed with ethyl ether and ethyl acetate, the filtrate is dried and embedded. The remainder of the solution is submerged in the minimum amount of diethyl ether and of the ester, the solution is neutralized with hydrogen chloride in ethyl acetate, the resulting precipitate is filtered off and washed out with ether, the solvent is 1- (3-dimethylaminorononyl; - o-methoxy-1,2,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3,3. -2-downcyclohexaia is a hydrochloride with so on, or i3d-139O.

Example 4. A solution of 3 g of 1- (2-nitroethenyl) 1, 2,3,4-tetrahydronaphthalene-2-spirocyclo-ientane in i5 ml of tetrahydrofuran is added but not mixed with iri channels and, / g of lithium aluminum gndrid in 1 / ml of ether The x-reaction mixture is then boiled for about an hour under reflux, cooled, 0.7 ml of water is added, 1.4 ml

Lzio-noro aqueous solution of sodium hydroxide and 2.1 ml of water (in this sequence). Then it is filtered, the filtrate is washed with iodide, dried, taken out and the residue is taken up in ethyl acetate. The acidic solution is LOT chlorinates, hydrogen in ethyl acetate, the precipitate obtained is filtered off and non-recrystallized from acetone. Formed with 1- (2-aminoethyl) - 1,2,3,4 - tetrahydronaphthalene-2-dimeric acid and hydrochloride in the infrared spectrum at 750, 1250, ioOO and 25uu.

Example 5. To a solution of 3.2 g of 1- (bromome1ylidene) -6-methoxy - 1,2,3, i - tetrahydronaphla „1Ii-2-snnrocyclonentan in 30 ml of complex

acetic ester irnbavlat without mixing the solution of 1 g of dimethylamine in 20 ml of acetic ester and then 1 g of sodium carbamate. The mixture was stirred for 4 hours at 50 ° C, cooled and lOj ml of water was added to it. The organic layer is separated, washed with water, dried, and extracted with reduced pressure. The residue is dissolved in acetic ester, the solution is acidified with hydrogen chloride in a complex

yi-xycHOM ether and the precipitate obtained is filtered off. 1- (2-dimethylaminoethylen) -5-methoxy-1,2,3,4-tetrahydronaphthalene2-snrocyclonentane hydrochloride is obtained, which in the infrared spectrum shows strong

Nolo iri 1032, 1246, 1315, 1502 and 1602 C.M-I.

Example 6. A mixture of 8 g of 1- (2-isocyanatoethnnden) - 6 - methoxy-1,2,3,4-tetrahydronaphthann-2-sirocycloientan, 25 ml of water, 25 ml

methanol and 1.5 g of sodium hydroxide are not stirred at 60 ° C for 1 hour and left to stand for 3 hours with a thermostat. The mixture is then concentrated at reduced pressure, the concentrate is concentrated by diethyl ether, the extract

The mixture is washed with water, dried and evaporated at a pressure below. Get 1- (2-aminostilidene) - 6 - methoxy-1,2,3,4-tetrahydronaphthalene-2-sirocycloentan, which in the infrared spectrum has bands at 810, 1150,

1590 and 1620 cm-H

Example 7. A solution of 4 g of 1-hydroxy-1- (3-dimethylamino-iroyl) -1,2,3,4-tetrahydronaphthalen-2-spirocyclo-3-hexag1a in 50 l; l of chloroform and 3.35 ml of acetyl chloride are heated in reverse cooler for / min and then evaporated under reduced pressure.

The residue is dissolved in water, the solution is strongly acidified. ONC-ENT SECTIONAL SALTANIUM

acid and vyyvayut simple ether. The aqueous solution is brought to basic and n. aqueous solution of sodium hydroxide, extracted with simple ether, the extract washed out with water, dried and evaporated. The residue is dissolved in ethyl acetate, the solution is acidified with hydrogen chloride in ethyl acetate, and the resulting precipitate is filtered off and washed with ethyl acetate. 1- (3-dpmethylaminopropylidene) -1,2,3,4 - tetrahydronaphthalen-2-spirocyclo-3-hexane-hydrochloride with a m.p. IdTC (with decomposition).

Example 3. A mixture of 42 g of 1,6-dihydroxy-1 (3-dpmethylaminopropyl) -1,2,3,4-tetrahydronaphthalene-2-spirocyclohexane, 250 ml of chloroform and 38 ml of acetyl chloride are heated on a steam bath for 70 minutes and evaporated under reduced pressure. The residue is dissolved in water B, the solution is washed out with ether and the aqueous layer is brought to basic reaction with 2N. aqueous solution of sodium hydroxide. It is extracted three times; simple ether, the extract is washed with water, dried and evaporated. The residue is pacrLK) in ethyl acetate, the solution is acidified with hydrogen chloride in ethyl acetate, and the precipitate is filtered and recrystallized from pzopropanol. Formed with 1- (3-dpmethylaminopropylidene) - o-aceto1cci1, 2,3,4-tetrahydronaphthalene - 2 - spirocyclohexane hydrochloride with m.p. 188-189 ,.

Example 9. Through a solution of 3.5 g of 1- (3-dimethylaminopropylidep) -6-methoxy-1,2,3,4 tetrahydronaphthalene-2-spirocyclopentane in 35 ml of ethanol at room temperature with stirring, the mixture is passed through for 20 minutes leave to stand for 2.5 days. It is evaporated under reduced pressure, the residue is extracted with ether and recrystallized from pzopronapol. Formed with 1- (3-trimethylammonium propylidene) -6-methoxy-1,2,3,4-tetrahydronaphthalene-2-spirocyclopentap bromide with m.p. 223-224 ° C.

Example 10. A mixture of 60 g of 1-hydroxy-1 (3-dpmethylaminopropyl) -6-methoxy-1,2,3,4-tetrahydronaphthalene-2-spirocyclopentane, 41 ml of acetyl chloride and 300 ml of chloroform is boiled in a reverse steam bath refrigerator for 80 minutes and evaporated under reduced pressure. The residue is dissolved in water, the mixture is brought to basic reaction with 2 n. an aqueous solution of sodium hydroxide and extracted with ether. The extract is washed with water, dried, filtered and evaporated under reduced pressure. The residue is dissolved in a minimum amount of ethyl acetate,

the solution is strongly acidified with hydrochloride .i in etplatzgate, the precipitate obtained is precipitated, washed with ethyl acetate and

recrystallized from 600 ml of acetone.

Formed with 1- (3-dimethylaminopropylidene) -methoxy-1, 2,3,4 - tetrahydronaphthalene-2-spirocyclopentane-gdrochloride with so pl. 164-166 C.

The product is identical to the product of example 5.

Example I. A mixture / g of 1-hydroxy-1- (3-dimethyl. Mypopropyl) - b - methoxy-1,2,3,4-tetrahydronaphthalen-2-spirocyclopentane (t.pl./b-UB C), 30 ml of chloroform and 5 ml of acetyl chloride are boiled for 70 minutes under reflux and evaporated in vacuo. The residue is dissolved in water, the solution is brought to the main reaction with 2 n. an aqueous solution of sodium hydroxide and extracted with D 1 ethyl ether. The extract is washed with water, dried, filtered and evaporated in vacuo. The residue is dissolved in ethyl acetate, the solution is made acidic with Xviopn with hydrogen in ethyl acetate, the resulting precipitate is filtered off and recrystallized from acetone. Formed with 1- (3-dimethyl; 1-iopropylidene) -6-methoxy-1,2,3,4-tetragpdronaphthalene-2 -proprocyclopentane-hydrochloride with m.p. 164-165 ° C.

irpemer 12. Hot solution of 2 g of 1-ox-α- (3-dimethylaminopropyl) - 6 - methoxy-1,2,3,

4-tetrahydronaphthal-2-spirocyclopentane (m.p. 76-78 ° C) in a minimum amount of ethyl acetate is slowly brought to an acidic reaction by adding dropwise hydrogen chloride in ethyl acetate. The resulting cooling precipitate is filtered and recrystallized from acetone. 1- (3-dimethylaminopropylidene) -6-methoxy-1 is formed, 2,3,4 - tetrahydronaphthalene-2-spirocyclopentane hydrochloride. Product is identical

product of example I.

Example 13. A mixture of 6.2 g of 1- (3-dimethylaminopropylidene) -6-methoxy-1,2,3,4-tetrahydronaphthal-2-spirocyclohexane, 1 g of oxide; 1 platinum and 100 ml of ethanol are hydrogenated at

550 mL of hydrogen is allowed to dissolve there The mixture is filtered, the filtrate is evaporated in vacuo, the residue is dissolved in diethyl ether, the solution is washed with water, dried, filtered and evaporated. The residue is distilled and the CAT at 162-164 ° C (0.3 mm Hg) is collected. Formed with 1- (3-dpmethylaminopropyl) -6 methoxp - 1,2,3,4 - tetrahydronaphthalp-2-spirocyclohexane.

The product is dissolved in anhydrous diethyl ether and the solution is neutralized with hydrogen chloride in ethyl acetate. The resulting precipitate is filtered and washed with di; a) simple ether. Forms a corresponding, gpdrokhlorid with t. PL. 137-141 ° C. Example 14. By the methods described in the previous examples, the following compounds were prepared:

1-OXI-1- (3-dimethylaminopropyl) - 5 - methoxy-1, 2,3,4-tetrahydronaphthalene - 2 - sppro